Pharmacology & Therapeutics 83 (1999) 217–244

Associate editor: S.T. Mayne

Omega-3 fatty acids as cancer chemopreventive agents
David P. Rose*, Jeanne M. Connolly
Division of Nutrition and Endocrinology, American Health Foundation, One Dana Road, Valhalla, NY 10595, USA

Abstract
There is both epidemiologic and experimental evidence that the long-chain omega-3 fatty acids (FAs), which occur at high levels in some fish oils, exert protective effects against some common cancers, notably those of breast, colon, and, perhaps, prostate. Multiple mechanisms are involved in this chemopreventive activity, including suppression of neoplastic transformation, cell growth inhibition and enhanced apoptosis, and antiangiogenicity; however, a common feature of most of these biological effects is the inhibition of eicosanoid production from omega-6 FA precursors. Several of the known risk factors for breast, and colon, cancer may be favorably modified by dietary omega-3 FA supplementation, and the implementation of clinical chemoprevention trials is now feasible. © 1999 Elsevier Science Inc. All rights reserved.
Keywords: Breast cancer; Colon cancer; Chemoprevention; Omega-3 fatty acids; Eiscosanoids

Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; DHA, docosahexaenoic acid; DMBA, dimethylbenz[a]anthracene; DPA, docosapentaenoic acid; EGF, epidermal growth factor; EPA, eicosapentaenoic acid; FA, fatty acid; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; 13-HODE, 13(S)-hydroxyoctadecadienoic acid; LA, linoleic acid; LNA, -linolenic acid; LOX, lipoxygenase; LT, leukotriene; ODC, ornithine decarboxylase; PG, prostaglandin; PGI2, prostacyclin; PKC, protein kinase C; TX, thromboxane.

Contents 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Nomenclature, chemistry, and metabolic conversion of unsaturated fatty acids . . . . . . . . . 3. Dietary sources of omega-3 fatty acids, intestinal absorption, and tissue and subcellular distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Dietary sources. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Intestinal absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Tissue and subcellular distribution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. The eicosanoids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Arachidonic acid-derived eicosanoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Eicosanoids derived from eicosapentaenoic acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Eicosanoid biosynthesis and n-3:n-6 fatty acid ratio . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. 13(S)-Hydroxyoctadecadienoic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Biomarkers of n-3 fatty acid nutritional status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Omega-3 fatty acids and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.1. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.2. Experimental studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.3. The relative potency of eicosapentaenoic acid and docosahexaenoic acid in breast cancer animal models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Colon cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.1. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.2. Experimental studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.1. Breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.2. Colon cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

218 218 220 220 221 221 222 222 223 224 225 225 226 226 226 227 228 228 228 229 230 230 231

* Corresponding author. Tel.: 914-789-7145; fax: 914-592-6317. E-mail address: david@westnet.com (D.P. Rose) 0163-7258/99/$ – see front matter © 1999 Elsevier Science Inc. All rights reserved. PII: S0163-7258(99)00 0 2 6 - 1

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D.P. Rose, J.M. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244

7.

8.

Omega-3 fatty acids and cancer chemoprevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1.1. Mammographic densities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1.2. Atypical hyperplasia and carcinoma in situ . . . . . . . . . . . . . . . . . . . . . . . . . 7.1.3. Chemoprevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1.4. Omega-3 fatty acid supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1.5. Dietary modification targeting other fatty acids: The n-3:n-6 fatty acid ratio. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1.6. Intermediate response biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Commentary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

234 234 234 234 234 235 235 236 237 237 238

1. Introduction It is becoming increasingly recognized that, at least in the long term, future advances in clinical cancer research will come from an emphasis on prevention rather than the treatment of metastatic disease. This research effort encompasses epidemiological studies, such as those responsible for the recognition that high consumption of vegetables and fruits is associated with a reduced risk of some cancers, laboratory experiments to evaluate potential natural and synthetic products as chemopreventive agents, and the execution of clinical preventive trials (Greenwald et al., 1993). As always, these different approaches are complementary: for example, work with animal models showed that nonsteroidal anti-inflammatory drugs such as aspirin possess chemopreventive activity against experimental colonic carcinogenesis, epidemiological observations supported such a potential role in human populations, and several of this class of compounds are now undergoing evaluation in clinical trials for colon cancer prevention. The progression from the initial steps in the carcinogenic process to the establishment of clinically manifest, invasive disease occurs in a series of steps, each of which merges into the next (Fig. 1). Intervention strategies follow much the same path: primary chemoprevention merges with chemosuppression, which itself is indistinguishable from the chemotherapy of early disease. However, the distinction between chemoprevention and chemosuppression is useful because it recognizes that it is not necessary to prevent the development of premalignant, or even frankly cancerous, foci in order to suppress progression to symptomatic, lifethreatening cancer. Thus, while the antiestrogen tamoxifen may have a place as a truly chemopreventive agent, its action in preventing the development of a new primary cancer in the contralateral breast of a postmenopausal woman previously treated surgically for primary breast cancer is most likely one of chemosuppression (Jordan, 1991). Experimental studies performed in our laboratory suggest that the omega-3 fatty acids (FAs), which are the subject of this review, can have a similar chemosuppressive effect on the progression of microscopic metastatic foci (Rose et al., 1996). Some drugs that were introduced originally for the treatment of metastatic cancer are now having their role extended to include chemoprevention. This changing applica-

tion carries with it the need for increased vigilance in order to avoid the introduction of undesirable side effects; for example, the long-term risk of causing a tumor at another organ site, while acceptable when treating advanced cancer, will prohibit the use of the same drug as a chemopreventive agent in healthy individuals. As cancer chemoprevention research has progressed, interest has turned to the investigation of natural products, a number of which have been found to be active in animal models when administered at levels that appear to lack systemic toxicity. Prominent among these compounds are nutrients, including vitamins and the omega-3 FA; food additives such as curcumin; and food-associated natural products, such as indole 3-carbinol and lycopene. This review deals exclusively with the omega-3 FAs. These remarkable nutrients have attracted interest because of their importance in normal brain development (Neuringer et al., 1988), as dietary supplements for the prevention and treatment of chronic cardiovascular disease (Simopoulos, 1991), and the treatment of arthritic disorders (Kremer, 1991) and diabetes mellitus (Malasanos & Stacpoole, 1991). They have been, and are currently, the subject of various clinical trials in which they have shown a lack of complications or serious side effects. Epidemiological studies, investigations utilizing a range of animal models, and mechanistic experiments in vitro all support their potential as cancer chemopreventive and chemosuppressive agents, and as auxiliary agents for cancer therapy. The tumor targets include carcinomas of the breast and colon, which are two of the most common cancers in North America and Europe. Our objective is to provide a background general discussion of the omega-3 FAs, review the current status of research into their chemopreventive activities and the biological mechanisms involved, and to consider in some depth the development of a clinical trial in women at high breast cancer risk.

2. Nomenclature, chemistry, and metabolic conversion of unsaturated fatty acids The unsaturated FAs comprise monounsaturates and polyunsaturates. The conventional chemical nomenclature is to begin the systematic numbering of carbon atoms from

did allow effective conversion of LNA to EPA. Oleic acid has its single double bond located between the 9th and 10th carbon atoms from the methyl end. (1993) showed that feeding AA to male Syrian hamsters increased the phospholipid AA levels in a variety of normal tissues. 1991). The carbon atoms number 2 and 3 from the carboxyl group are referred to as the and carbons. Nelson et al. 2). an inhibition that is achieved by EPA and DHA. However. Humans can produce EPA from LNA. 1985. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 219 Fig. and there is evidence that human 6 desaturase activity decreases with age (de Gomez Dumm & Brenner. The progression of premalignant benign breast disease to metastatic carcinoma.or n-carbon. an accepted practice in describing the chemical structure of FA molecules is to start numbering the carbons at the methyl group ( . while LA is the metabolic precursor of arachidonic acid (AA).” In Fig. J. 1997). 1997. 1991). 3. Similarly. in another human study. the last carbon is the . and so it is designated an 9 (or n-9) monounsaturated FA (Fig. amounting to 10– 15 g/day (Jonnalagadda et al. they are referred to as “essential fatty acids. involve increases in chain length and degree of unsaturation that are achieved by adding extra double bonds between the existing double bond and the carboxyl group (de Gomez Dumm & Brenner. the n-3 FAs are represented by -linolenic acid (LNA) and the n-6 FAs by linoleic acid (LA). 2.8 g EPA/day. 1998). (1993) found no changes in the neutrophil phospholipid AA levels in response to LA intakes ranging from 2. and thence to docosahexaenoic acid (DHA). In rats. In addition to any forward metabolic sequence. this contribution diminishes as dietary AA intake increases. the production of AA (de Gomez Dumm & Brenner. and the position of a double bond is indicated by the symbol .D. However. The omega-3 (n-3) and omega-6 (n-6) polyunsaturated FAs cannot be synthesized by mammals. James et al. Rose.. Hague & Christoffersen. It can be synthesized by all mammals. 1. the carboxyl terminal group.5% of energy. which are summarized in Fig. In one study (Mantzioris et al. 1975).. LNA is converted to eicosapentaenoic acid (EPA).M. and most of the AA in serum and platelets is derived from dietary LA (Grønn et al. They concluded that while dietary LA may influence eicosanoid formation by increasing the tissue AA pool. incremental elevations in LA intake did produce corresponding increases in liver AA (Lands et al.. 1975. (1997) observed a 15% decrease in the serum phospholipid DHA level in a group of adult males whose diet was supplemented with 3. Grimsgaard et al. 1984). 1990b. 1997. 9 refers to a double bond between carbon atoms 9 and 10 from the carboxyl group. but the extent of the capacity to perform this conversion has not been well defined (Hunter. whereas when dietary LA was increased by as much as 50%. respectively. 1990).. thus reducing the enzymic competition referred to above.. 1995). with the n-3 FAs having greater affinities for the enzymes.P. there was no such effect. Whelan et al. . increasing the dietary intake of n-3 FAs reduces the desaturation of LA and so. with corresponding elevations in the tissue DHA levels. Grimsgaard et al. as well as LNA (Christiansen et al. Both LNA and LA are metabolized to longer-chain FAs.. Conquer & Holub. In consequence. including humans. Competition exists between the n-3 and the n-6 FAs for the 4 and 6 desaturases. 1994). 1975).. feeding a low LA-containing diet to human volunteers.. Dietary LA generally is considered to be the major source of tissue AA. However. and because they must be obtained from the diet. retroconversion of DHA to EPA does occur in humans (Von Schacky & Weber. although lean meats and meat fat are direct sources in the human diet (Li et al. followed by a number: for example.5 to 17. These events. largely in the liver. LA is the principal polyunsaturated FA in the American diet.or n-).

.P. C20:3) and AA. but while increasing dietary LA intake results in greater hepatic conversion of LA to AA. and LNA (an n-3 polyunsaturated FA). and EPA are the substrates for the biosynthesis of 1-series PG and 2-series LT. For example. the enhanced availability of LA can result in displacement of AA.. J. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 Fig. 3.220 D. Dietary sources of omega-3 fatty acids. with the affinity being greater for n-3 FA than n-6 FA. LA (an n-6 polyunsaturated FA). In consequence. Each metabolic sequence competes for the same enzyme systems. the season of the year. the levels of AA in the platelet phospholipids. 2. were decreased (Tremoli et al. Rose. -Linolenic acid. Marangoni et al. One consequence of the AA displacement is that feeding sufficiently high levels of LA can actually result in a tissue-specific reduction in the biosynthesis of AA-derived eicosanoids (Galli et al.1. 1981. 3. and 3-series PG and 5-series LT. respectively. 1986). when LA in the human diet was increased to about 8% of total energy.. Structures of oleic acid (an n-9 monounsaturated FA). intestinal absorption. in extrahepatic tissues. The metabolism of LNA to EPA and DHA and of LA to -linolenic acid (n-6. 1986). 1984.. AA. 2 series-PG and 4-series LT. published data on the classes and levels of FAs in various species of fish vary widely. and especially the AA/LA ratio. and they still may not represent the true situation Fig. The n-numbers are counted from the methyl terminal. Tremoli et al. Dietary sources To a considerable extent. Croft et al. and the fluctuations that occur from year to year.. 1992). the FA content of fish oils is determined by the food that is available to the fish.. and tissue and subcellular distribution 3.M. and this is influenced strongly by the geographic area in which the fish live.

their consumption will have very different effects on the cell membrane FA profiles and prostanoid production (Innis et al. 1997a).1 0. 1965).8 0.2 0. 1970).7 EPA (g/100 g) 1. Pacific Halibut. albacore Herring. Reproduced from Simopoulos (1991).6 0. Tr.. Dietary deficiency of LNA in developing animals results in reduced CNS DHA levels.1. edible.4 0.05 g/100 g).1 0.2 0. soybean and canola (low erucic acid rapeseed) oils may provide a significant source of dietary n-3 FA in the form of LNA (Hunter.4 1.4 3. 1995).1 Tr (–) 0. J. 1990). chinook Bluefish Tuna.8 and 13. DHA occurs at relatively high levels in the cerebral cortex (O’Brien & Sampson. They found that the range of total lipid amounts in different fish species was greater than the variation of the percentage amount of EPA and DHA.1 0. 3. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 221 (Stansby.6 0. and in contrast to the reports by El Boustani et al. the retina (Anderson. In North American diets. In contrast. which has taken place over the past four decades and which correlates with a decrease in the dietary n-3:n-6 FA ratio (Rose.4 2. respectively.1 0. .5 0. but substantial amounts of AA. It is this imbalance of n-6 FA to n-3 FA that some investigators have associated with increased risks for both cardiovascular disease and some cancers. which led them to conclude that any beneficial dietary effects would be best achieved by the inclusion of the fattier fish.4 6. This lack of therapeutic efficacy was reflected in the lower tumor EPA concentrations and plasma EPA responses to EPA ethyl ester. Lawson & Hughes (1988) found the relative absorption capacities to be: docosapentaenoic acid (DPA. Both n-3 and n-6 FAs are important constituents of the cell membranes. the principal food sources of LNA are salad and cooking oils and salad dressing products.3. pink Trout.. 1991). 14 of these are listed in Table 1. Hudson & Tisdale (1994) compared the effect of free EPA and EPA ethyl ester on cachectic weight loss and MAC16 adenocarcinoma growth in mice. compared with those present in marine fish oils and so.1 (–) Tr Tr Tr Per 100-g raw.P. While this aspect of nutritional cancer epidemiology will be discussed in detail in Section 7. amounts of n-6 and n-3 FAs. In human subjects. but approximately equal. Tissue and subcellular distribution In humans and other mammals.3 2. rainbow Halibut. The relative amounts of EPA and DHA contained in fish oils vary considerably between species (Childs et al.0 0. (1987) and Lawson & Hughes (1988). 1986).9 4. In addition to fish and fish oils. and related this to their rates of intestinal absorption. whereas the modern Western diet contains a rela- tive excess of n-6 FA. effects that were associated with elevations in plasma and tumor EPA concentrations. The United States Department of Agriculture published fat and FA values for 30 fish of different species or location (Simopoulos. was free FA triglyceride ethyl ester.. The total amount of fat in these fish ranged from a low of 0.1 0.M.4 0. including carcinoma of the breast. Also. DHA. much of the EPA and DHA in the Western diet comprises long-chain n-3 FAs that are absorbed as 2-monoglyceride (Nelson & Ackman. trace ( 0. 1984). the n-3 FA also concentrates in the heart muscle.8 13.7 0. She pointed out that the early diet contained small. Baltimore. Puustinen et al. with permission of the author and the copyright holder. (1991) assessed the intestinal absorption of both EPA and DHA as the triglycerides or ethyl esters in healthy adults. and testis (Poulos et al.5 1.1 LNA (g/100 g) 0.8 0. In response to a DHA-supplemented diet. 1975).7 g/ 100 g in cod and haddock to highs of 13.9 13. Williams & Wilkins.0 10. which have been associated with learning disabilities and impaired visual function (Innis...1 0. 1990). 1987). the ethyl ester of EPA failed to exert a favorable effect on body weight. lack of reliable data. Pacific Swordfish Plaice.5. the major FA in chloroplast lipids.0 0. as well as the liver and lung (Innis et al.2.1 DHA (g/100 g) 0. and C22:5.1 0. the relative absorption of the different forms of EPA.9 g/100 g in Greenland halibut and Pacific herring.4 3. and the tumor volumes were not significantly different from those of control animals. one instructive example may be mentioned at this point: the increased breast cancer risk in Japanese women. The changes in the FA content of the typical human diet that have occurred over time since the Paleolithic period were discussed by Simopoulos (1991).7 0. king Salmon.0 0. 1995).3 0. Oral administration of the free EPA resulted in prevention of body weight loss and suppression of tumor growth. found them to be equally well absorbed.1 1. 3.1 (–) 0.8 1.1 0. 1988).2 0. Greenland Mackerel. Atlantic Haddock a Total lipid (g/100 g) 13.3 0. European Cod. portion. round Salmon. (1985) analyzed the total lipid content and the FA composition of 12 commonly eaten northern European fish. The per capita intake in the United States has been estimated to be 16–20 g/day for men and 12 g/day for women (Kim et al. some freshwater fish oils contain relatively low levels of EPA. (–). EPA ethyl ester was not absorbed as efficiently as the free FA (El Boustani et al.1 Tr 0. Moreover.D. C22:5) EPA and DHA.4 0..4 0.5 4. Nordøy et al. 1991). compared with that of an 18:3 n-3 control. and cell membrane FA composition of both normal and neoplastic tissues undergoes modification in animals Table 1 The total lipid and omega-3 fatty contenta of 14 edible fish that are widely available in the United States Fish species Herring. Intestinal absorption The form in which dietary n-3 FAs are ingested affects their absorption from the intestinal tract. Fish and fish oil products are mostly ingested as the triglycerides. Rose.

the cyclooxygenase (COX) activity of the enzyme converts AA to PGG2.8. Kargman et al. These eicosanoids. The n-3 FAs accumulate in phosphatidylcholine. phosphatidylethanolamine. of which COX-1 is constitutively expressed in most tissues and is considered to generate PG for normal physiological function (Herschman. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 fed different high-fat diets. 1994.11.1).99.. 1996) and breast tissue (Hwang et al. 1994). cytokines. this cleavage from phospholipids being mediated by membrane-associated phospholipase A2 activity (Verheij et al. 4). behave as “local hormones” (autacoids). The biosynthesis of the n-6 FA-derived eicosanoids is initiated by the release of AA from membrane stores. and triglycerides (de Bravo et al.. and thromboxanes (TXs). and are chemical transmitters for a variety of intercellular and intracellular signals. which produce the prostanoids—PGs. 1981).M.. 1988) (the subscripts indicate the presence of double bonds). However.222 D. prostacyclin (PGI2).11. 1991). reflecting the FA content of the consumed lipid. EPA was also effective in channeling LA from phospholipid to the neutral lipid pool (Hatala et al. Arachidonic acid-derived eicosanoids AA (5. the prostaglandin (PG) synthases (EC 1. The eicosanoids 4.13. The metabolism of AA to the prostanoid subfamily of eicosanoids (2-series PG and TXA2). it is expressed Fig. LA was found to be preferentially esterified to phosphatidylcholine.12). 4. The phospholipid pool is the major site of FA incorporation in both cultured normal and transformed cells. J...P. including mitogens.14. it has become commonplace for the complete entity to be referred to as COX. 4. It is the substrate for two classes of enzymes. and the lipoxygenases (LOXs) (EC 1. and hormones (Herschman. whereas EPA was incorporated largely into phosphatidylethanolamine. in spite of these two distinct reactions. In a human breast cancer cell line. Rose. 1998). which catalyze the biosynthesis of the hydroxyeicosatetraenoic acids (HETEs) and leukotrienes (LTs). 1994). 1995a). .1. so called because of their common origin from a 20-carbon (eicosa-) polyunsaturated FA. There are two forms of COX. COX-2 undergoes rapid induction in response to a variety of stimuli. The PGH2 formed from AA is then converted to the various prostanoids (Fig.14-eicosatetraenoic acid) is an omega-6 polyunsaturated FA metabolically derived from LA. PG synthase catalyzes two sequential reactions: first... and then the peroxidase activity reduces PGG2 to PGH2 (Oates et al. While COX-2 is undetectable in normal intestine (Kargman et al.

The incorporation of 1 mol of oxygen forms the corresponding 5-. The metabolism of LA to 13-HODE and of AA to 5-. feeding an EPA-supplemented diet caused an in- . and LTs are believed to have a role in the pathogenesis of asthma. and 15-HPETE. and there is considerable interest in the potential for pharmacological inhibitors of their biosynthesis as a new approach to cancer chemoprevention and therapy (Rose & Hatala. 1979). The HETEs are involved in the regulation of a wide range of biological activities. 1987. 1994. PGI2 is synthesized primarily by vascular endothelial cells and inhibits platelet activation and aggregation. 1987). In humans. 1984. 1983. and the immune response. but include ion transport. 5-HETE. 1998). Strasser et al. TXA2 exerts an enhancing effect (Honn. which is further metabolized to PGE3. 5. 1998).. The n-3 FA is converted by COX to the 3-series endoperoxide PGH3. and 15-HETE). 1992). and 12-HETE concentrations were all reduced in the lungs of rats fed a range of n-3 FA levels with a constant amount of n-6 FA (Hwang et al. and ischemic injury. which are only now being understood. Hwang et al... is the principal COX product in platelets. with 5 double bonds (Prescott. They have been associated with rheumatic and collagen diseases. Fischer & Weber. atherosclerosis... Spector et al. and LTs of the 5-series.P. and thence to the inactive metabolites 17-6-keto-PGF1 and TXB3 (Fig. Not shown are the intermediate compounds 5-. Rioux & Castonguay. These pathways correspond to those by which AA is converted to the 2-series prostanoids. 12-. specific cell types are usually highly selective in their formation of bioactive prostanoids. but whereas PGI2 inhibits metastasis. The PGs possess a broad spectrum of biological activities. and 15-HETE production occur in alveolar macrophages (Peters-Golden & Thebert. 1975).. The 5-.. For example. 12-.. Both LTs and HETEs influence various aspects of tumor cell biology. in the majority of colonic carcinomas (Kargman et al. Rose. 12-. 4. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 223 Fig.. 1996). 1984). and TXA3. by way of PGG3. 1979. There may be a place for n-3 FAs in the management of these respiratory diseases: in one study. and pulmonary hypertension. hormone secretion. which is reduced to the hydroxy analogue (5-. 1995b) and in some primary breast cancers (Parrett et al. J.D.. LOX activity and 5-. a product of TX synthase-mediated metabolism of PGH2 (Hamberg et al. while TXA2. Eicosanoids derived from eicosapentaenoic acid EPA is a precursor of the prostanoids of the 3-series. 1988) (Fig. or 15-hydroperoxyeicosatetraenoic acid (HPETE).2. 12-. 5). but in addition. but once PGH2 has been produced.M. 12-. has opposing actions to PGI2. and promotes platelet aggregation.. 6). and 15-LOXs insert molecular oxygen into polyunsaturated FA (Fig. with 3 double bonds (Needleman et al. Within the lung. and AA. 1985). Both PGI2 and TXA2 have important roles in cancer biology because they are involved in tumor cell-vascular endothelial cell and tumor cell-platelet interactions. 5-HPETE is converted to the bioactive LT (Malle et al. cystic fibrosis.. Lee et al. 1988). 1984. Chen et al. PGI3. the levels of 12-HETE in lung homogenates were reduced by approximately 60% in mice fed fish oil compared with those in mice fed LA-rich safflower oil (Zhang & German. and EPA competes effectively with the n-6 FA for available COX activity (Needleman et al. 7). and 15-HETE. 12-. which are converted to the corresponding HETE by peroxidase activity. 1997.

crease in PGI3 production. the EPA content in serum.. This competition between the two classes of polyunsaturated FAs was also demonstrated in human volunteers by feeding them a fixed level of dietary n-3 FA. but also on the amount of n-6 FA in the diet. rather than the absolute levels of the two classes of unsaturated FAs. In one.3. it was found that there was no dose-dependent change in tissue AA or in the levels of TXB2. 8). When DHA is incorporated into platelet and other cell membranes. Rose.. The metabolism of AA to the 4-series LTs. 1991. and neutrophil phospholipids was significantly higher in those fed the low LA diet (Grønn et al. it can competitively inhibit eicosanoid biosynthesis from AA. but in combination with high or low intakes of n-6 FA. 1991). The importance of the dietary n-3:n-6 FA ratio has been re-emphasized by two cancer-related studies. it is not metabolized to a TX (Aveldaño & Spre- cher.. 4.3. Eicosanoid biosynthesis and n-3:n-6 fatty acid ratio A number of investigators have stressed the importance of the dietary n-3:n-6 FA ratio. 1981. 1984. 1983) or to LT (Corey et al. which possesses only 5–10% of the activity of LTB4 as a chemotactic and aggregating factor for polymorphonuclear leukocytes (Lee et al.. Kramer et al. 1996). Murphy et al.. platelets. Although the earlier studies largely attributed the inhibitory effects of dietary fish oil on eicosanoid biosynthesis to EPA.M. concerned with dietary n-3 FAs as potential modifiers of colon cancer risk.3-dinor-6-keto-PGF1 (Fischer & Weber. being dependent not only on the amount of n-3 FA. J. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 Fig. 1981).P.224 D. 1988). Even so. Strasser et al. 1984). However. 1981). 1980. Cleland et al. 1992). whereas EPA-derived TXA3 has only weak aggregatory activity. EPA can also be metabolized by way of the 5-LOX pathway. LTC4. LTA5.. and these biosynthetic pathways are subject to dietary manipulation (Murphy et al. This arises because the competitive inhibition that exists between n-3 and n-6 FAs for the desaturases and elongases results in the capacity of dietary n-3 FA to suppress the conversion of LA to AA. 1983) and of LTB4. we are not aware of any studies that have related these LTs to the cancer chemopreventive properties of EPA. in modulating eicosanoid biosynthesis from AA.. and 12-HETE when groups of rats were fed 10% total fatcontaining diets providing different amounts of fish oil. via 5-HPETE.. 6. and 12-HETE. DHA was found to be a potent inhibitor of PG production in vitro (Corey et al.. the net result is that the COX products of EPA metabolism are associated with diminished platelet aggregation (Fischer & Weber. with 4 double bonds. In one study (Boudreau et al. 6-keto-PGF1 . products of LOX-catalyzed AA metabolism (Lokesh et al. The immediate product of this 5-LOX activity. The synthesis of LTB5 and LTC5 by mastocytomas in fish oil-fed mice was accompanied by pronounced reductions in LTB4 and LTC4 (Murphy et al.. 1985). Some tumor cell types have been shown to produce LTs of the 5-series from EPA (Jakschik et al.. Here. as reflected in the urinary excretion of 17-2. but with equivalent increases in safflower oil so as to maintain a constant n-3:n-6 FA ratio of 0.. is metabolized to LTB5. which parallels the metabolism of AA to the 4-series LT (Fig. The LTA synthase is a dehydrase. a relatively high n-3:n-6 FA ratio was required . 1984). Because the PGI3 derived from EPA is as antiaggregatory as PGI2 derived from AA.. 1983).

1993. In the other. 1992). Rose. 1998). there were no results upon which to judge the relative merits of the two n-3 FAs as markers of n-3 FA intake. 4. 5. 17. given the wide variations in n-3 content. and the percentage of n-3 FAs in the diet. and subcutaneous adipose tissue FA analyses in American postmenopausal women and men. The only structural difference between PGH3 and PGH2 is that PGH3 has an additional. dietary intakes were also assessed by 7-day diet records. 1996. 1991. Brown et al. in contrast to these stimulatory effects. and 13-HODE modulates the EGF mitogenic signal (Glasgow et al. 15-LOX metabolism of LA is stimulated by epidermal growth factor (EGF). 7. 1995).M. Biomarkers of n-3 fatty acid nutritional status The FA composition of the plasma lipids and the membranes of platelets and erythrocytes provides an assessment of the dietary intake of the long-chain n-3 FAs over the preceding 2 days to 18 weeks (Bjerve et al. which. However. J.. was inversely associated with breast cancer risk (Simonsen et al. The metabolism of EPA to 3-series prostanoids. 1995a). However..4. Hunter et al. One point worth making is that the instruments of n-3 FA intake used in this and other epidemiological studies do not distinguish between the types of fish consumed. 1991). to obtain suppression of PGE2 production in human rectal mucosa (Bartram et al. the DHA content of adipose tissue provided a better marker of fish and marine n-3 FA intake than did EPA. Although the analysis of adipose tissues is necessary to evaluate dietary FA intake over extended periods of time and is unaffected by temporary variations in diet. Marckmann et al. and the LA-stimulated growth of these cells in vitro requires the . In this study. suggesting that the less complex method provides an equally reliable assessment. their acquisition is not amenable to the large-scale sampling required for many epidemiological studies. this method of evaluation gave a similar level of correlation to that obtained with the semi-quantitative food-frequency questionnaire. 13HODE opposes the 15-HETE and 12-HETE stimulation of tumor cell adhesion. as determined by a foodfrequency questionnaire. 1990.. Welsch (1995) has described the stimulation of mouse mammary epithelial cell proliferation by 13-HODE.. (1993).P.. The apparent discrepancy may have resulted from the elongation of EPA to the less metabolically active DPA. diet records.. 1987). a result that was also obtained by Tjønneland et al. This metabolite is attracting the attention of tumor biologists because it may be involved in both carcinogenesis and cancer progression. 1991). a multinational epidemiological study. it is necessary to obtain an index of consumption over a relatively long period of time. which are generally regarded as more accurate. On the other hand. In the study of American males. For this purpose. Both showed significant correlations between the percentage of n-3 FAs in adipose tissue.D. and the presence Fig. both under the catalytic influence of 15-LOX (Fig. but not the absolute levels of the two classes of FAs per se. although the food record estimates of dietary EPA and DHA intakes were both considerably higher than that of DPA. 1992). 1988. Two other studies provided a comparison of data from food-frequency questionnaires. These two studies are discussed in more detail in Section 6. In some cell types.. most investigators have utilized adipose tissue obtained by percutaneous biopsy.. 1984). (1995) found adipose tissue DHA and DPA levels to be much higher than that of EPA. may reduce their sensitivity. the ratio of n-3 FAs to n-6 FAs in adipose tissue biopsies. 1991. Grønn et al. Andersen et al. unsaturation. which is an integral part of the metastatic process (Bastida et al. In neither study were separate data collected for EPA and DHA and so. 13(S)-Hydroxyoctadecadienoic acid LA can form an oxidation product. for epidemiological studies aimed at determining the association of dietary FAs with disease risk or outcome... respectively (London et al. 5) and by nonenzyme autoxidation (Welsch.. Innis et al. for which the turnover time for FAs has been estimated to be 1–3 years (Field & Clandinin. Liu et al. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 225 presence of EGF (Bandyopadhyay et al... 13(S)-hydroxyoctadecadienoic acid (13-HODE).

1. a correlation was found between dietary total fat intake and breast cancer mortality rates for different districts. Support for this interpretation came when Kaizer et al. respectively. Two studies that have addressed this issue concluded that the DHA and EPA contents of adipose tissue were even stable at room temperature ( 20 ) over a 7-month period (Deslypere et al. (1996) found that the EPA and DHA contents of adipose tissue aspirates and erythrocyte membranes had similar correlations with fish consumption.1.M. The authors suggested that the remarkable stability of DHA and EPA in adipose tissue may be due to the presence of high levels of vitamin E. it is encouraging that a carefully executed comparative study by Godley et al. for which the reverse is true. to countries such as the United States. in which breast cancer risk and dietary fat intake are relatively low. Even within Japan. The influence of dietary fat intake on breast cancer risk continues to be a topic of considerable interest.. the n-3 FA in erythrocytes exhibited little loss over 12 months (Stanford et al. 1997). 1978). While this important issue is unlikely to be resolved in the immediate future. The metabolism of EPA and AA to their LT products of the 5. It was esti- mated that 178. and controversy (Hunter et al. with both being higher in urban locations (Hirayama. Epidemiology Breast cancer is the most common cancer among woman in the United States. and that. J. and that 43. 1997b).. appropriate storage is a prime concern when accruing samples for later analysis.. With this in mind.500 American women would die of the disease (American Cancer Society.1. Moreover. and is second to lung cancer as the most frequent cause of cancer-related deaths. (1989) pointed out the inverse association between breast cancer incidence and mortality rates and dietary fish intake for the same 32 countries that previously had been shown to exhibit a direct relationship for total fat consumption (Arm- . Breast cancer 6. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 Fig. at least when stored at 70 . 1998). ecologic studies do show a wide spread in breast cancer incidence and mortality rates between countries and correspondingly large variations in dietary practices. as estimated by a food-frequency questionnaire. 1993). 1996. 1993).. their breast cancer incidence rates increase within one generation (Ziegler et al. Omega-3 fatty acids and cancer 6. via 5-hydroperoxyeicosapentaenoic (5-HPEPE) and 5-HPETE. Wynder et al.P.226 D. of large amounts of nonessential FAs can obscure the relatively low levels of n-3 FAs. Because the n-3 FAs are very susceptible to peroxidation.700 new cases would be diagnosed in 1998. 6. 8.. which prevents deterioration due to lipid peroxidation because of its antioxidant properties.and 4-series. 1991). migration studies consistently have shown that when women move from countries such as Japan. One possible explanation for the conflicting evidence concerning dietary fat and breast cancer risk is that the emphasis has been largely on the total amounts consumed rather than the nature of FA contained in those fats (Rose. Rose.

by multiple regression analyses using dietary animal fat minus fish fat intake. and for cancers of the prostate and colon in men (Lanier et al. whereas the n-3 FAs decreased this indicator of ras proto-oncogene expression. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 227 strong & Doll. which are reflected in the plasma and erythrocyte membrane EPA and DHA levels. a country with an exceptionally high fish consumption and low breast cancer mortality rate.M. there has been an increase in the use of LA-rich vegetable oils. 1976) and fish (Nobmann et al.. it has to be recognized that all epidemiological evidence for an association between dietary n-3 FA intake and cancer risk is inferential and correlative. whereas those of n-3 FAs are low.2. Although Japanese women continue to have a relatively low breast cancer risk. and liable to confounding by other factors. A survey conducted for the years 1969–1973 showed that although the total cancer incidence rates among Alaska Eskimos and Aleuts did not differ significantly from that of the United States white population.1 and 4.. this analysis was heavily dependent on the inclusion of data from Japan. A recent study of Canadian Eskimos found that plasma DHA and. there were significantly lower rates for cancers of the breast. endometrium. and an increasing breast cancer mortality rate since 1960 has been accompanied by dietary changes. In their experiment. while remarking on a low breast cancer risk among Inuit populations in the circumpolar region. rightly point out that other known protective factors. 1990). the n-6 FAs increased the levels of ras p21 protein. It is well established that chemically induced rat mammary carcinogenesis is promoted by dietary n-6 FA. are also prevalent among the Inuit. 1975). rather than the absolute levels of their intake. 1994). and hence..3. EPA levels were positively correlated with age. An analogous study was performed by Telang et al. whereas EPA exerted inhibitory activity.. a further survey of cancer incidence for the years 1989–1993 found that there were significant increases in the incidence rates for cancers of the breast and endometrium in women... 1998). Rose. Their diet is high in fat.. Although these epidemiological studies of special populations support a protective role for dietary n-3 FA. Interestingly. Indeed. This distinction is likely to be particularly important in Western countries. This interpretation is supported by the results of a multi-national case-control study of adipose tissue FA profiles that was performed in 5 European countries with an approximately 2-fold range in breast cancer incidence (Simonsen et al. 1976). (1988) using explant cultures of mammary glands from mice harboring the murine mammary tumor virus. 1992). (1992) used ionizing radiation of mouse embryo fibroblasts. a decrease in fish consumption. Experimental studies Although the emphasis of research has been on the effects of n-3 FA on the later stages of carcinogenesis in vivo. This age-related difference in plasma FA and the n-3:n-6 ratio was due to a high consumption of marine mammals and fish by the older Eskimos and replacement of this fat source by vegetable oils in the younger members of the community. However. there is some direct evidence that they also affect cell transformation.. but this comes largely from marine mammals (Bang et al.P. However. and the n-3:n-6 ratios (Innis et al. there was a highly significant positive relationship with breast cancer mortality rates for women over 50 years of age. and prostate (Lanier et al. the relationship between breast cancer and the ratio of LNA to n-6 FA was inconsistent across centers. early age at first pregnancy and prolonged lactation. A contributing factor to these changes may be urbanization of the Alaska native population. 1996). Takahashi et al.. In association with these opposing effects. Although the level of n-3 or n-6 FA showed no consistent association. and. whereas age was negatively correlated with plasma n-6 FA (Rode et al. 1991). in addition to an increase in the consumption of red meat.. they have exceptionally high intakes of n-3 FA. this has risen over the past 40 years. 1990a). and they associated this with the inhibition of eicosanoid production from AA. as models to demonstrate suppression of transformation by EPA and DHA. While ecologic studies have generally associated high breast cancer risk with high dietary fat intakes. where the levels of dietary n-6 FAs are generally high. 6. 1995). When this was done. These also may be changing over time in response to Western influences. the native Eskimos of Greenland and Alaska provide an instructive exception. and altered dietary practices. a separate analysis for fish intake showed the expected negative correlation. 1988.1. to a lesser extent. prominent among which is an increase in the average fat consumption from 9% of total energy in 1955 to 25% in 1987 (Wynder et al. 1987) and in Norway (Vatten et al. Parkinson et al. which is critical in influencing cancer promotion and progression. Nielsen & Hansen (1980) had drawn a similar conclusion from an analysis of breast cancer incidence among indigenous Greenlandic women for the years 1950–1979. 1997). a reduction in the dietary n-3:n-6 ratio (Lands et al. A similar absence of benefit was found in prospective studies performed in the United States (Stampfer et al. Miller & Gaudette (1996). (1993) analyzed the data from 30 countries. including Japan. most case-control studies have not supported a protective effect of fish consumption (reviewed by Willett. Despite these widely quoted results from ecologic studies. the ratio of longchain n-3 FA to total n-6 FA was inversely correlated with breast cancer in four of the five centers. it was shown that both LA and AA enhanced the formation of preneoplastic hyperplastic alveolar lesions in vitro. However.. Sasaki et al. In consequence.D. the transfection of these and NIH 3T3 cells with the H-ras oncogene. it may be the ratio of n-3 FA to n-6 FA in the diet. in separate experiments. J. but is inhibited by feeding n-3 FA-rich menhaden oil (Jurkowski & .. as noted in Sections 3. Although these observations were consistent with earlier reports. a country with a relatively high consumption of n-3 FA-rich-cold water fish.

diet. the nude mouse model is of limited clinical relevance because the tumor growing at the injection site is left in situ throughout the experiment.. Human breast cancer cells growing as xenografts in athymic nude mice have proved invaluable for assessing the influence of dietary FAs on metastasis. with no significant differences between the two n-3 FAs. Some partial suppression was observed. As generally used.. A more realistic approach was introduced when the ethyl es- ters of EPA or DHA were used as nutritional adjuvant therapy after the surgical removal of the primary breast cancer (Rose et al. the focus was on the chemosuppression of residual disease and of microscopic metastases. but statistically insignificant. 1995). (1989) obtained inhibition of mammary tumorigenesis and of PGE2 and LTB4 production by tumor cells when they fed a diet containing FAs with an n-3:n-6 FA ratio of 1.600 American women and 23.. 0.P. When we compared the two n-3 FAs in experiments using nude mice bearing human breast cancer xenografts. however. in animals fed a 20% menhaden oil diet. 1988. Noguchi et al. There was. suppression of growth once the tumors had developed. 1998a) The control of primary tumor growth and metastasis appeared to be superior to that obtained with EPA in our earlier experiment. 6-keto-PGF1 . Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 Cave. 1995) and metastasis (Rose & Connolly.. FAs affect both the growth of transplanted tumors and the expression of the metastatic phenotype.2. Karmali et al. Cohen et al. Epidemiology Colon cancer is the fourth most common cancer in the United States and ranks second among cancer-related causes of death. It was estimated that 24. It is also now possible to compare the efficacy of the two long-chain n-3 FAs. More recently.. we found no difference between EPA and DHA ethyl esters in achieving partial suppression of tumor growth. The extent of lung metastasis was reduced to a greater degree by feeding 2% or 4% DHA. and LTB4 were associated with enhanced mammary carcinoma development in dimethylbenz[a]anthracene (DMBA) exposed rats fed a 20% corn oil. 1996). when pure EPA and DHA ethyl esters became available.. 1997). (1997) used the DMBA-induced mammary tumor model to examine the effects of low doses of EPA and DHA ethyl esters on tumor incidence and growth in rats fed a high-fat. A second study in which the n-3 FAs were employed in an experimental protocol designed to mimic postsurgery. 1989. (1994) to compare the effects of EPA and DHA. (1985) showed an enhancing effect of dietary LA on the growth of transplanted mammary carcinomas in BALB/c mice. on primary tumor growth and metastasis to the lungs.. 1993.. The DHA-treated rats showed a 69% reduction and the EPA-treated rats a 47% reduction in tumor incidence compared with the incidence in the high-fat-fed controls. J. Earlier. but it is questionable whether such an extreme situation has any implications for the design of human dietary intervention trials. 1993). 1989. Braden & Carroll. we have had the opportunity to evaluate DHA triglyceride prepared from microalgae in the MDAMB-435 breast cancer cell/nude mouse model (Connolly & Rose.5 mL of the 98% pure n-3 FA was given by gastric gavage twice a week to provide a calculated dietary n-3:n-6 FA ratio of 1:1. Rose & Connolly. A number of studies have shown that diets rich in the long-chain n-3 FA inhibit the growth (Borgeson et al. 6. These relative degrees of efficacy of the two n-3 FAs were paralleled by a partial. compared with the same levels of EPA (Rose et al. Rose et al. Gonzalez et al.1.228 D.100 American men would die of the disease . despite the limitation that estrogen-dependent cell lines do not metastasize. 1995). (1988) showed that high tumor production rates of PGE2.. or more specifically. Gabor et al. and subsequently reported that feeding a diet containing 10% menhaden oil suppressed growth. 1985. these were shown to be effective in suppressing tumor progression when fed at levels of 8% and 4% (wt/wt) in a diet containing a total of 20% fat (Rose et al. enhanced tumor cell loss (Gabor & Abraham. adjuvant chemotherapy produced opposite results.M. 1993). so that the model cannot be used to study estrogen-FA interactions on the metastatic process (Rose & Connolly.. The optimal level of menhaden oil to be fed in order to suppress experimental mammary tumor development remains uncertain. or do so rarely.8. Rose. In their second study. some indication that EPA was more effective in inhibiting metastasis (Rose et al.1. While fish oil was used in the earlier studies. (1984) had also reported inhibition of R3230AC mammary tumor growth in rats fed MaxEPA. but so also does the relevance of these feeding studies to the chemoprevention of human breast cancer by n-3 FA. Abou-El-Ela et al. it may actually enhance mammary tumor development (Cohen et al. 20% corn oil. 6.2. 1993. LA-rich diet. Colon cancer 6. where there is no possibility of attempting such high intakes. In this experiment. 1995) of human breast cancer cell lines growing as solid tumors in nude mice.2 (15% menhaden oil and 5% corn oil) compared with a 20% corn oil diet. Abou-El-Ela et al.. Abou-El-Ela et al. In this way. a fish oil concentrate that contains approximately 18% EPA and 12% DHA. 1986). There is evidence that when menhaden oil is fed as 18% of the diet. whereas the levels of these eicosanoids were reduced and tumorigenesis was partially suppressed. The relative potency of eicosapentaenoic acid and docosahexaenoic acid in breast cancer animal models The recent availability of EPA and DHA in bulk quantities and of unique DHA-rich oils derived from microalgae has offered a new approach to n-3 FA chemoprevention and the suppression of cancer progression. In addition to their effects on mammary carcinogenesis in animal models. again given at low dose by intragastric intubation. 1996). A transplantable mouse mammary carcinoma was used by Kinoshita et al. Rose et al. 1991. 1986.3.

2%. These appear in young adulthood.. such as that provided by a diet containing 20. (1990). 1996. 1988.2-dimethylhydrazine-induced aberrant crypt foci. on colon carcinogenesis. 1998). This could be interpreted as a direct adverse effect of diets containing supplemental n-3 FA.2.4% corn oil (50–55% LA) or 16% corn oil with the lowest (4. and so it is of particular interest that when those data were reanalyzed for breast and colorectal cancer. Rose.. and this increase was partially suppressed by feeding the highest level of MaxEPA (16% wt/wt) with an n-3:n-6 FA ratio of approximately 1.2. 6. Diets containing 4.4% corn oil. an excess risk of colon cancer was observed in women who had a previous history of breast cancer (Teppo et al.5. S-phase. Epithelial cell proliferation in the colonic crypts showed the expected elevation as a result of exposure to azoxymethane. there was evidence of a protective effect of a high fish intake relative to that of dietary sources of n-6 FAs for both tumor types (Caygill et al. the experimental design was somewhat unusual in that DHA ethyl ester (0. and when these colonic preneoplastic lesions did occur. 1998). The effects of different fish oil-containing diets.. but not 4. formulated to provide several n-3:n-6 FA ratios. MaxEPA. In the experiment performed by Minoura et al. was elevated in treated breast cancer patients. but recent epidemiological studies indicate that we cannot ignore shared endocrine mechanisms (Fernandez et al..2% or 16% MaxEPA. at relatively low levels. However. 1993). 1995). The effect of n-3 FA on the early stages of colon carcinogenesis was also examined by Takahashi et al. it is tempting to focus on dietary FA. and while the present focus is on selective COX-2 inhibitors. Reddy et al. One additional point that came out in analyzing the results of this experiment is that both tumor incidence and number of tumors per animal were actually higher in rats fed the 16% corn oil:4. the occurrence of early dysplastic foci was reduced significantly in carcinogen-exposed animals fed either 16% or 10. the place for dietary n-3 FA supplementation merits careful evaluation. (1990) examined the effect of the same levels of MaxEPA on the full development of azoxymethane-induced colonic carcinomas. 1986.. 1986). the EPA was exerting its protective effect in the presence of an already favorable low-fat. Some of the international comparisons of breast cancer mortality rates apply also to colon cancer (Rose et al. 1991) or supplemented with n-3 FAs (Minoura et al. the fish oil concentrate MaxEPA was the source of n-3 FA. Similarly. (1990) reported that rectal mucosal cell proliferation.. and other studies have shown an increased incidence of precancerous colonic polyps in breast cancer patients (Bremond et al. 1996). or 10. Therefore. Among these. 1988. 1984. 1975). with differing n-3:n-6 FA ratios.. .4% corn oil.3. cells in the middle and upper thirds of the crypts. at least for Western countries. all produced similar reductions in colonic tumor incidence.3% LA to prevent essential FA deficiency inhibited azoxymethane-induced colon carcinogenesis in rats compared with tumorigenesis in rats fed a 5% LA control diet.. a presumptive marker of colon cancer risk. A similar trend for females did not achieve statistical significance. and virtually all of these individuals develop colon adenocarcinoma by age 40 years (DeCosse et al. lowLA diet. Familial adenomatous polyposis is an example of a genetically determined precancerous condition in which numerous polyps develop in the colon and rectum.4% corn oil without any n-3 FA addition. This regimen reduced the formation of 1. but its effect was incomplete (Giardiello et al. 1977). We have described the study by Deschner et al. in some detail because it is one of the few in which different levels of n-3 FAs. there was retardation of their subsequent growth. an inverse correlation was found in males between colorectal cancer mortality and current fish intake. and there was no association for breast cancer (Caygill & Hill. Jouin et al... a diet containing 5% total fat and supplemented with 4. Deschner et al. The 16% MaxEPA-containing diet also inhibited the increase in DNA-synthesizing.. it could also be a reflection of the dietary LA level and the reduced production of AA-derived eicosanoids that can occur with very high LA intakes (Section 2).7% EPA (91% pure.4% fat. They used an azoxymethane-induced rat model fed diets that all contained a total of 20. Deschner et al.7 mL) was given by intragastric intubation in single doses 5 times a week.. J. 1990. (1988). 1988). the importance of the dietary n-3:n-6 FA ratio was stressed in Section 4.4%) level of MaxEPA. In an analysis involving 24 European countries. and a positive correlation was found between the geographic distribution of the breast and colorectal cancer mortality rates within the United States (Jansson et al. However. These relationships suggest the presence of either a common risk factor(s) or the same relative lack of factor(s) that are protective against the two tumor types. Rozen et al. on the early pathological stages of experimental colon carcinogenesis were studied by Deschner et al. (1993). It should be noted that the LA content of the control diet generally would be considered as providing a “low” intake of the n-6 FA. However. Nelson et al. In a second part of this study.M.. which is a feature of a carcinogenic response. 1989). Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 229 in 1998 (American Cancer Society.P. In Finland. as suggested by the authors. The standard therapy is total colectomy. HébertCroteau. Experimental studies A number of studies have shown that experimental rat colon carcinogenesis is inhibited by feeding a diet containing a high level of fish oil (Reddy & Maruyama.4% MaxEPA diet than in those fed 20. This precancerous condition is an obvious target for chemopreventive intervention. in human terms. Reddy & Sugie.4%. the nonsteroidal antiinflammatory drug and unselective COX inhibitor sulindac reduced the number and size of polyps. without DHA) together with 0. have been compared for their chemopreventive efficacy. 1985). The highest tumor incidence occurred in rats fed 20. In a controlled clinical trial.D.

.3.3% other n-3 FAs. 1994). 1994). inhibitors induced apoptosis that was partially reversed by exogenous 12- . Similarly. 1988. 1995) and 12-LOX (Tang et al.M.1. at high levels. In the males. Suzuki et al. Both tumor numbers and size were reduced in male and female mice fed the n-3 FA-rich diet. but not COX. or a combination of these two cellular events (McDonnell. but it induced apoptosis (Calviello et al. (1989) concluded that a reduction in tumor LTB4 production due to 5-LOX inhibition was causally associated with n-3 FA inhibition of DMBAinduced rat mammary tumorigenesis. In experiments performed by Rose & Connolly (1990). a result that is not consistent with the overall experience concerning the relative effects of n-3 FAs and n-6 FAs on breast cancer cell growth (Rose & Connolly. which is a critical part of the invasive phenotype (Liu & Rose. 1994).. Oshima et al. 1997). DHA was considerably more effective than EPA in suppressing the growth of estrogen-independent MDA-MB231 breast cancer cells. In both cases. 1986. Suzuki et al. this inhibition was not due to cytotoxicity. and overexpression of 12LOX in MCF-7 breast cancer cells resulted in increased growth in nude mice and suppressed apoptosis (Connolly & Rose.7) activity.. In contrast. which can occur due to the formation of peroxidation products from polyunsaturated FAs (Welsch.2.P. these inhibitory effects on tumor progression were associated with a reduction in matrix metalloproteinase (EC 3. The two long-chain n-3 FAs. DHA produced the least thiobarbituric acid-reactive substances. Mechanisms 6. reduced programmed cell death (apoptosis). to female and male Apc 716 heterozygotes. and provide a model for human familial adenomatous polyposis (Moser et al. Kerr et al. Rose. 1990. The mechanism for this sex difference is obscure and was not reproduced in a similar study performed by Paulsen et al. DHA had no effect on mitosis. 1994). 1997). The inhibitory effects of DHA and an EPA/DHA-enriched fish oil concentrate on the development and progression of intestinal polyps have been demonstrated in two of these models. 1988).. As discussed in Section 6. Although there is direct evidence that the long-chain n-3 FAs can induce apoptosis. 1998b). but this may be inferred from a publication by Gabor & Abraham (1986). the determination of which provides a crude index of lipid peroxidation. and brings into question the physiological and clinical relevance of these cell culture experiments performed in vitro with very high FA concentrations. Mitogenesis and apoptosis Both EPA and DHA inhibit the growth of human breast cancer cell lines in vitro. 1996). We are not aware of any published studies that have investigated the effects of n-3 FAs on breast cancer cell apoptosis. Thus. the administration of pure EPA or DHA has also been shown to inhibit colon cancer cell metastasis to the lungs in experimental animal models (Iigo et al.4% EPA.. The relative importance of these eicosanoid families in mammary tumorigenesis and breast cancer progression is uncertain. and 8. Abou-El-Ela et al. Buckman et al. How- ever. J.. The females showed a 69% reduction in polyp formation and a significant suppression of polyp growth. 1997. this appears to be cell-type specific. apoptosis is a physiological process important to tissue development and organ modeling. 1998). 30. 1987). 1991) and DMBA-induced tumor growth in vivo (Kitagawa & Noguchi. (1995) fed a 3% DHA ethyl ester-containing diet.3. 1993. As in the case of breast cancer.230 D. This cytotoxic activity was shown to correlate with the levels of intracellular thiobarbituric acid-reactive substances.1. 1996) expression have been shown to downregulate the apoptotic pathway. (1997).4.. 6. and is carefully regulated by the expression of specific genes.1. suggesting that the cell loss was due to inhibition of mitosis rather than cytotoxic cell death. While there was a 50% reduction in cell number when 2 g/mL of DHA was added to the culture medium.. of unspecified total and n-6 FA content. In contrast to cytotoxin-induced necrosis.3. the inhibition of DMBAinduced rat mammary carcinogenesis by feeding n-3 FArich menhaden oil is associated with a reduction in tumor PG and in LOX-mediated AA product levels. They reported that the inhibition of growth of a transplantable mouse mammary adenocarcinoma by dietary n-3 FA was a result of cell loss and suggested the involvement of PG in this process. and to a lesser degree LNA. 1995). 1995. this n-3 FA produced an inhibition of Morris hepatocarcinoma 3924A growth in vivo that was primarily due to reduced proliferation. Again. Although nonspecific cytotoxicity does not appear to be responsible for the growth inhibition induced by n-3 FA at low concentration.. a monocytoid cell line that arose spontaneously in the mammary gland of a pregnant rat.. These investigators used the Min (“multiple intestinal neoplasia”) mouse. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 Various germ line mutations of the murine Apc gene result in multiple intestinal polyposis. Both COX-2 (Tsujii & DuBois.. Buckman et al. which predated the current intense interest in apoptosis and cancer. Treatment of W256 cells..24. Begin & Ells. The acquisition of solid tumor mass and increasing cell number is the consequence of active mitogenesis. and the highest levels were generated by -linolenic acid and AA (Begin et al. and fed a 12% total fat diet and a fish oil concentrate containing 54. Breast cancer 6. while culture with EPA resulted in apoptosis in a human pancreatic cancer cell line (Lai et al. although LOX rather than COX inhibitors were effective in inhibiting human breast cancer cell growth in vitro (Rose & Connolly. which is heterozygous for a nonsense mutation of the Apc gene at codon 850...3% DHA. with LOX. 1990. Fodde et al. 1990. there was no effect on polyp number and a lesser effect on polyp size. 1991). trypan blue exclusion indicated that the cells present were viable.1. also inhibited the growth of the estrogen-dependent MCF-7 breast cancer cell line (Grammatikos et al. both n-3 FA and n-6 FA caused lysis of human breast cancer cells in vitro (Begin et al.

1. 1996). 1997).3. R. and did so without increasing the tumor levels of secondary lipid peroxidation products to those that were necessary to inhibit growth in experiments reported by Gonzalez et al. Rose. 6. J. at least in part. the inhibitory effects of the fish oil was reversed when antioxidants were added to the diet in sufficient amounts to reduce lipid peroxidation. Gonzalez et al. we have already noted that the lytic effects of polyunsaturated FAs on cultured tumor cells correlated with the degree of lipid peroxidation product formation... We found that feeding DHA as the triglyceride at a level of 2% of diet retarded the growth of MDA-MB435 human breast cancer cell solid tumors in nude mice.. With this background. Cyclooxygenase-2 inhibition Sakaguchi et al. Colon cancer 6.4.3.1. 1997). unpublished data). which were known to reduce hepatic 3-hydroxy3-methylglutaryl co-enzyme A reductase activity. 1983.5.. Yoshimi et al. Mevalonate synthesis 3-Hydroxy-3-methylglutaryl co-enzyme A reductase (EC 1.3. causes rapid growth with not only reduced apoptosis.. (1991) found that when diets containing 19% menhaden oil were fed to mice. which inhibit 12-HETE. Angiogenesis Neovascularization. Fox et al. is essential for solid tumor growth (Folkman. M. or angiogenesis.1. Angiogenic activity in primary breast cancers has been associated with metastasis and a poor prognosis (Heimann et al. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 231 HETE or 15-HETE (Tang et al.34) is the rate-limiting enzyme in the cholesterol biosynthetic pathway and catalyzes the synthesis of mevalonate. Mongru.1.. there was both an inhibition of growth of human breast cancer cell xenografts and an accumulation of secondary products of lipid peroxidation in these tumors. which include both PGs (Form & Auerbach. 1998b). In Section 6. In a preliminary study.1. breast atypical hyperplasia. Thus. 1990). & D. Estrogen metabolism The natural estrogen 17 estradiol.2. 6. 1996. dietary n-3 FAs may prove to be antiangiogenic because of their suppressive effects on eicosanoid biosynthesis (Connolly et al. 1992) and 12-HETE (Tang et al.3. 1997) in benign breast lesions with a propensity for progression to malignant disease (Guinebretière et al. 1995). Moreover.D. thus establishing the potential for metastatic disease progression. Connolly. Mevalonate exerts a number of effects that signal increased cell proliferation.. in combination with other steroid and polypeptide hormones and growth factors. The process of neovascularization is promoted by a variety of angiogenic factors. are inhibitors of tumor cell growth (Elson. it seems reasonable to postulate that dietary n-3 FAs.. and that the tumors contained elevated levels of AA. and in this section..3. partial suppression of rat colon carcinogenesis by EPA was associated with a reduction in the PGE2 content of the tumors that did appear compared with that present in normal mucosa..2) reduced the extent of 16 -hydroxylation. 6.2..2. or carcinoma in situ (Section 7. El-Sohemy & Archer (1997) extended these observations to n-3 FAs. 6. and selective COX-2 inhibitors are effective in experimental colon cancer chemoprevention (Reddy et al. Again. 1994.. Kargman et al. 1995). (1984) showed that a high-fat. A series of studies has shown that a shift in estradiol metabolism in favor of 16 -hydroxylation and away from the formation of catechol derivatives produces aberrant hyperproliferation in mammary explant experiments. 1996a. The colonic mucosal levels of PGE2 and 6keto-PGF1 are elevated during the initiation and postinitiation stages of carcinogenesis in this model (Kulkarni et al. (1988) found that feeding an n-3 FA-rich fish oil supplement to women with either a family history of breast cancer. 1997b).1.P. and compounds such as dietary isoprenoids. 1994. but also neoplastic transformation. and PGE2 production by human breast cancer cells growing as solid tumors in nude mice. the PGE2 concentrations are increased compared with the corresponding normal colonic mucosa (Rigas et al. 1995b). 15-HETE.M.2. Fregene et al. 1993).2. The mechanism(s) by which these degradative products of n-3 FAs inhibit breast cancer cell growth is uncertain. and found that both immunoreactive enzyme expression and mevalonate production were suppressed in the mammary glands of menhaden oil-fed female rats. but also high angiogenic activity (Connolly & Rose. the down-regulation of mevalonate synthesis in preneoplastic mammary epithelial cells provides another plausible mechanism that may contribute to the chemopreventive activity of n-3 FAs. which inhibit mevalonate synthesis. (1988).. 1997). 1996). may exert their suppressive effect on tumor mass acquisition. Lipid peroxidation The role of lipid peroxidation in the suppressive effects of n-3 FA on mammary tumorigenesis was reviewed by Welsch (1995).1.3. Spisni et al. P.. by activation of the apoptotic pathway (Rose & Connolly. and in human surgically excised colon cancers. 1994) and in breast ductal carcinoma in situ with later invasiveness (Heffelfinger et al. we referred to a study by Minoura et al. stimulates not only normal mammary development. This potentially important observation should be pursued in any future trials of n-3 FAs as breast cancer chemopreventive agents. and also provides the tumor cells with access to the vascular circulatory system. . Rose. (1993) (J.. and clinical studies suggest that an elevated C16 -hydroxylation of estradiol may provide a biomarker for breast cancer risk (Telang et al. 6.1. LA-rich diet enhanced colon carcinogenesis in rats treated with the chemical colonic carcinogen azoxymethane. as is the relevance of this effect of very high fish oil intakes to the clinical application of n-3 FA for breast cancer chemoprevention. Increased production of PG in colon cancers is associated with the up-regulation of COX-2 (Eberhart et al. Osborne et al. Singh et al. 1992). and here.3. We have shown that transfection of the MCF-7 human breast cancer cell line so that it stably overexpresses 12-LOX and secretes high levels of 12-HETE..

Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 (1997) showed that there was a time-related increase in COX-2 expression in rat colonic mucosa after azoxymethane administration. Hussey & Tisdale (1994) showed that the growth in two murine colon adenocarcinoma cell lines was stimulated by both LA and AA in vitro.10) Under physiological circumstances.3. 1997).. 1998). 1991). while the expression of COX-1 was unchanged. Given the relationships between both COX and LOX and angiogenesis referred to in Section 6. Sautebin et al.. Total PKC was found to be reduced in human colon adenocarcinomas compared with the uninvolved mucosa (Guillem et al. the extent of this translocation increased and there was a concomitant reduction in total PKC activity. 6.3. the reported down-regulation of total PKC activity in human and rat colon tumors contrasts with the elevated total activity and changes in PKC isoform expression seen in breast cancer (MorseGaudio et al.3. with concomitant PKC translocation from the soluble to the particulate fraction of colonic cells. Both LA and AA. the proportion of the total PKC activity associated with the particulate. Moreover..M.. but was suppressed by a high-fat. but not with reduced cell proliferation. Certainly.. 6. as well as the monounsaturated oleic acid. n-6 FA-rich diet. it should be noted that a selective inhibitor of COX-2 suppressed intestinal polyposis in the Apc 716 knockout mouse model for familial adenomatous polyposis (Oshima et al.. membrane. these investigators obtained similar results in vivo and demonstrated the particular importance of 12-LOX inhibition in achieving growth suppression (Hussey & Tisdale.232 D.2. Protein kinase C (EC 2. while the current emphasis is on COX-2 inhibitors as potential colon cancer chemopreventive agents. 1998). Rose.2. the hallmark of PKC activation. 1996). Reddy et al. Apoptosis Chang et al. While the role for nitric oxide in tumor angiogenesis is currently under investigation (García- Cardeña & Folkman. AA was the most effective of the three FAs (Craven & DeRubertis. it seems very likely that the inhibition of PG and HETE production in colon cancer cells by n-3 FAs provides an antiangiogenic mechanism for their chemopreventive activity. 1991). Baum et al. n-3 FA-rich diet. 1995). total PKC activity was higher in the colon tumors that developed compared with the corresponding mucosa. The apoptotic pathway in colon cancer cells is regulated by COX-2 expression. fraction was greater in mucosa from the colon cancer patients (Sakanoue et al. (1993). (1997) assessed both cell proliferation and apoptosis in the colonic crypts of rats exposed to azoxymethane and fed either a high-corn oil or a high-fish oil diet. including the reduced formation and progression of aberrant crypts described by Takahashi et al. 20% menhaden oil diet. this same group of investigators showed that these changes in PKC were also present in the tumors that subsequently developed when they were accompanied by increases in 1.3.. The activation of PKC has been implicated in the stimulation of colonic epithelial cell growth by unsaturated FAs.. J. and that this effect could be blocked by a selective LOX inhibitor. n-6 FArich diet. In this context.2-dimethylhydrazine and examined prior to the appearance of microscopic neoplastic change. are intimately related to the down-regulation of COX-2. it is noteworthy in the present context that nitric oxide is known to activate COX-2 and regulate PG biosynthesis (Salvemini et al. it appears that the suppressive effects of n-3 FAs on colon carcinogenesis.2. but . and both the inducible and endothelial constitutive nitric oxide synthases were elevated in rat colon tumors induced by azoxymethane (Takahashi et al.2. and particularly high levels were present in the tumors that subsequently developed. 1987) and in the histologically normal mucosa from colon cancer patients compared with colonic mucosa from patients without cancer (Sakanoue et al.P. This effect was enhanced by feeding a highfat.. 6.. In later experiments.. In contrast to the experience of others. 1996). 1998). 1991). 1993.4. Chapkin et al.3. However. stimulated [3H]thymidine incorporation. This enzyme induction was enhanced further by feeding a high-fat. deserves attention. In a second study. a high degree of angiogenic activity in colonic carcinomas has been associated with a poor prognosis (Takebayashi et al. Consistent with this relationship is the finding that microvessel density is higher in aggressively invasive colon cancers (Saeki et al... (1993) also examined the effect of dietary fish oil on PKC activity and intracellular distribution. the synthesis of which is also blocked by n-3 FA.1. The calcium-independent and -inducible nitric oxide synthase-2 was found to be expressed at high level in approximately 60% of human colon adenomas and 20–25% of colon carcinomas (Ambs et al. 1998). When these FAs were instilled into the colon in vivo. 1988). but not by a high-fat.. treatment of a human colon cancer cell line that possessed a high constitutive level of COX-2 expression and PGE2 production with a selective COX-2 inhibitor increased apoptotic activity. and found that the tumor-inhibitory effect of dietary n-3 FA was associated with increased apoptotic activity. Over time. 1996). Thus. In one study. (1990) found that colonic mucosal PKC activity exhibited translocation to the membranes in fractions prepared from the colons of rats treated with the procarcinogen 1. These elevations in COX-2 expression correlated with the incidence and multiplicity of colon tumors.7. protein kinase C (PKC) is activated by the combined effects of phospholipids and diacylglycerol (Hannun et al. 1986). in both cases. Angiogenesis As in the case of breast cancer and some other solid tumors. which was reversed by exogenous PGE2 (Sheng et al. the involvement of LOX products.2-diacylglycerol (Wali et al.2. 1997). The reason for this contradictory result is unclear. (1996b) found that the exposure of rats to the direct-acting chemical colonic carcinogen azoxymethane increased diacylglycerol kinase activity in the colonic mucosa.

5% menhaden oil compared with the activity ratio in animals fed a 15% corn oil. There is clearly a need for further research on PKC activity. there was an increase in ODC activity when colonic epithelial cells were exposed to n-6 FA. After 4 weeks. The excretion of the secondary bile acid lithocholic acid was lower after n-3 FA administration compared with that after dietary supplementation with the n-6 FA-rich corn oil.. the fecal secondary bile acid concentrations. and altered PKC isoform signaling appears to be involved in colon cancer development. Aside from the total PKC activity. and that EPA and DHA (Connolly & Rose.5. corn oil-containing diet than that in animals fed a 20.6. Bartram et al. n-3 FA-rich diet compared with those in rats fed a high-fat. Fitzer et al. and the biological and molecular significance of the changes resulting from dietary FA modification. 1994. and this potentially tumor-promoting effect is preceded by both the translocation of PKC from the cytosolic to the membrane fraction and increased ODC activity (Craven et al. 1973. In the present context.5% menhaden oil and 3. inhibition occurs because the bile acids interact with the Ca2 and the phosphatidylserine. Various studies have related these effects of bile acids and the associated fecal neutral sterols to colonic cell PKC and ODC activities. (1996b) determined fecal bile acid excretion in their studies of dietary fats and azoxymethane-induced rat colon carcinogenesis. Reddy et al. The first and generally the rate-limiting step in polyamine biosynthesis is catalyzed by ornithine decarboxylase (ODC). including adenomatous polyps. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 233 they found that the ratio of membrane to cytosolic PKC activity in normal colonic mucosa increased in rats fed a diet containing 11. The investigators postulated that the tumorpromoting activity of bile acids in colon carcinogenesis may be modified by the relative absorption of Ca2 and bile acids by the colonic mucosa. In a second study. which is involved in the transformation of primary to secondary bile acids. Moreover. it is noteworthy that tumor cell 12-HETE production is inhibited by dietary n-3 FA (Rose et al. 1994). 1998). 1987). n-3 FA appeared to have the potential for reversing the PKC changes associated with colon carcinogenesis. 1991). Reddy et al. 1994) inhibited the invasive capacity of a human breast cancer cell line in an in vitro assay. cytoskeletal rearrangement (Timar et al.. (1987) showed that the unconjugated bile acids chenodeoxycholate and deoxycholate stimulate conventional (calcium and phospholipid-dependent) PKC activity in vitro when assayed in the presence of a high calcium concentration.. Ornithine decarboxylase (EC 4. The expression of several biological characteristics of tumor cells has been shown to involve the regulation of PKC activity by the LOX-mediated product of AA metabolism 12-HETE. n-6 FA-rich diet. and in colorectal carcinoma tissues..D.0 % corn oil diet. the total membrane PKC activity. 1995). (1997) is of particular interest. 1994). were reduced in rats fed a high-fat.1... 1989. and the intracellular content of these compounds is highly regulated. Thus..P. Davidson et al. 1993). 23. 1993). Hixson et al. there was a positive correlation between the activity ratio. such as that which occurs in the colon.. These investigators found that dietary fish oil blocked the decrease in the steady-state levels of the atypical PKC isoforms.5%. Without this ionic excess. in spite of the report by Craven & DeRubertis (1988) that LA and AA increased the membrane PKC activity in colon cells in vivo and in vitro. Also.17) The polyamines that are produced from the metabolism of ornithine have a role in cell proliferation. compared with the corresponding uninvolved colonic mucosa (Narisawa et al. J. the report by Jiang et al. they are supported by animal experimentation.. an inducible enzyme that is elevated during the promotion phase of multistage carcinogenesis.4 g n-3 FA) or 11 g of corn oil. These include tumor cell adhesion to endothelial cells (Liu et al. There was.1. and invasive capacity (Liu et al. Increased ODC activity is present in premalignant adenomas. 6. Fecal bile acid and neutral sterol excretion Both epidemiologic and animal studies have provided evidence that colon cancer risk and the adverse influence of dietary fat on risk are associated with increased levels of secondary bile acids within the colonic lumen (Reddy & Wynder. In the present context. and colon cell proliferation.. Rao & Reddy (1993) demonstrated a stimulatory effect of an n-6 FA-rich diet on ODC activity and a relative suppression of the enzyme by dietary n-3 FA in colonic mucosa exposed to azoxymethane for 2 weeks. including lithocholic acid. although the difference was not statistically significant. and to LOX products of AA metabolism. with calcium exerting a chemopreventive function and bile acids a promoting one. While these preliminary data need to be confirmed. (1995b) performed a short-term experi- ment to examine the effects of dietary fish oil on fecal bile acid excretion in which the daily diet of healthy volunteers was supplemented with either 11 g of fish oil (4. Rose. n-6 FA-rich diet.. 6.3. was higher in the rats fed a high. there was no change in the total bile acid excretion. Craven & DeRubertis (1988) found that in addition to PKC activation.2. expression of the various isoforms in colon cancer.2. They found that although the total bile acid excretion was unaffected by the type of FA in the diet.. which is otherwise induced in the rat colonic mucosa by azoxymethane.3. 1977). . however.M. the activity of cecal bacterial 7 -dehydroxylase. the colonic mucosa exhibits a distinct pattern of isoform expression (Doi et al. Bile salts stimulate colonic epithelial cell growth. a significant reduction in the excretion of the putative colon carcinogen 4-cholesten-3-one (Bartram et al. Reddy & Sugie (1988) assayed ODC activity in their study of the influence of dietary FA on azoxymethane-induced rat colon carcinogenesis and observed an inverse relationship between the enzyme and the level of menhaden oil in the diet. 1993) and a pharmacological inhibitor of PKC activity (Connolly et al.

there was an accumulation of 12-HETE.. is a distinct entity. Rose. 1996). which is most likely attributable to the beneficial effect of mammographic screening on the clinical stage at diagnosis. 1989. 1985. treatment with indomethacin. 1996. 7. Epidemiological studies have shown a positive correlation between dietary fat. Ductal carcinoma in situ is the common form of noninvasive breast cancer. with a latency of 10–20 years (Page et al. 1994). 12-HETE. but high in n-3 FAs.1. which. the proportion of the breast volume occupied by radiological densities is determined by digital planimetry (Lee-Han et al. together with the success of adjuvant chemohormonal therapy in the management of the postsurgically resected breast cancer patient (Chu et al. is the report by Lee et al.. socalled “mammographic dysplasia. Of particular interest in the context of a chemoprevention trial.M. sister.” Later. Chemoprevention The risk of invasive breast cancer in patients with carcinoma in situ is sufficiently high to merit the application of some form of chemoprevention. more often have favorable mammographic patterns relative to breast cancer risk than do British women whose diet is high in fat.. given that only a maximum of about one-third of carcinomas in situ will progress to invasive disease and that invasive breast cancer is now generally treated by local resection.2. increased 12-HETE production. 1993). Some of these are direct radiological abnormalities.. with a traditional diet low in total fat and n-6 FAs. Atypical hyperplasia and carcinoma in situ Benign breast disease with hyperproliferation of the ductal epithelium. Boyd et al.1. presumably by shifting AA metabolism into the LOX-mediated pathway. J. (1994) that cytological abnormalities present in exfoliated breast epithelial cells collected by nipple aspiration correlate with the presence of mammographic densities. and highest in the DY category. Omega-3 fatty acids and cancer chemoprevention 7. This has created a new clinical problem because whereas the standard treatment for this condition was radical mastectomy.. bile salts. Interestingly. which is characterized by extensive nodular densities. Its presence provided one criterion for entry into the National Surgical Adjuvant Breast and Bowel Project’s Breast Cancer Prevention Trial. Their elimination would provide an appropriate intermediate response end-point as part of a clinical trial of n-3 FA for women with mammographic densities. the parenchyma being composed largely of fat. 1995). In the study by Dupont & Page (1985). 1995. but without invasion through the basement membrane into the surrounding stroma.234 D. 7.3. potentially life-threatening breast cancer. Japanese women. ODC activity. this atypical hyperplasia merges into ductal carcinoma in situ. Here. Several studies assessed the risk of developing invasive breast cancer from a pre-existing in situ lesion and estimated that this occurs in 10–30% of cases. which in the past was a relatively uncommon diagnosis. and the distinction between the two conditions may be difficult on histological examination. 1995). a COX inhibitor. Page et al. There is a significant interaction between the presence of atypical hyperplasia and a family history of breast cancer involving first degree relatives (mother. two histopathological abnormalities that are the themselves risk factors for invasive breast cancer (see below). which was followed by an elevation in colonic mucosal ODC activity and increased [3H]thymidine incorporation into DNA. (1984). 1989).. the risk of developing breast cancer in patients with atypical hyperplasia was 5. this risk increased to approximately 11-fold. Breast cancer A reduction in the breast cancer mortality rate is now evident in the United States. (1992) reported a study of women aged 40– 49 years that showed that extensive mammographic densities predict a more than 9-fold increase in the likelihood of developing carcinoma in situ or atypical hyperplasia. is being recognized with increasing frequency. itself performed in response to a mammographic abnormality. One consequence of routine breast cancer screening by mammography is that abnormalities that are known to constitute risk factors for invasive carcinoma of the breast are being recognized with increasing frequency. Nordevang et al. Hetelekidis et al. while others constitute histopathological features that are observed in breast tissue obtained by biopsy. One consequence of mammographic screening is that ductal breast carcinoma in situ.. Mammographic densities Wolfe (1976) originally defined four categories of mammographic parenchymal patterns and breast cancer risk. Fregene et al. is associated with increased risk of invasive breast cancer (Dupont & Page.1. .. When a first degree breast cancer family history was also present. There is no reliable means of predicting which cases of breast carcinoma in situ will progress to invasive. It is characterized by the proliferation of cancerous epithelial cells. while approximating to the Wolfe classification in significance.1.P. 1988). Risk is lowest in the N1 category.. In its severest form. particularly if the epithelial cells exhibit morphological abnormalities. 1991). this is now difficult to justify.. 7. They showed that when deoxycholate stimulated the release of AA from rat colon in vivo. intake and mammographic dysplasia (Brisson et al. daughters). and by implication LA. and this resulted in a further increase in ODC activity and thymidine incorporation. but low in n-3 FAs (Gravelle et al. attention focused on mammographic density per se. 7. and colonic epithelial cell proliferation was brought together by DeRubertis et al..1.3fold that of women with nonproliferative benign breast disease. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 This association of dietary FA. the presence of angiogenesis may be such a predictive marker in both carcinoma in situ and atypical hyperplasia (Heffelfinger et al. However. or benign breast disease with atypia (Lubin et al.

and l. has been evaluated. 1998). 7. as discussed in Section 1. and showed that estrogen independence was particularly likely in the case of the comedo histological subtype. this was not a problem in patients undergoing cardiac surgical procedures. for invasive cancers that are not responsive to antiestrogen therapy. 1993). (1991) showed that while a high intake of n-6 FA reduces the incorporation of dietary n-3 FA into the serum FA. antiestrogen administration. because of the presence of microcalcifications. Omega-3 fatty acid supplementation There are no published studies in which n-3FA has been fed to women with the intention of achieving a reduction in breast cancer risk. perhaps. The n-3 FA supplement provided 6 g per day from 10 capsules of Eicomarine 60 (Nycomed. this effect is usually of modest degree. even with n-3 FA doses as high as 8 g/ day (Knapp. Alternative approaches to chemoprevention are likely to be needed for women who are not considered suitable for. later. The possibility that an n-3 FAinduced bleeding tendency might become clinically significant during a surgical procedure has been considered. The fish oil preparation MaxEPA was administered to provide a daily supplement of 3. it is possible that the suppression of estrogen-dependent cell growth by tamoxifen would select for estrogen-independent cells. Also.6 g of EPA for the first year and 1. and in all of these diverse situations. and 60 mg of DPA. He points out. In the serum. it did show a disturbing increase in the occurrence of endometrial cancer. 1. or pure n-3 FA ethyl esters.P. However. Dietary modification targeting other fatty acids: The n-3:n-6 fatty acid ratio Most of the cardiovascular disease n-3 FA supplementation trials did not attempt to modify the consumption of other fat components. which.23. However. There are. the amounts of saturated and monounsaturated FAs consumed have no significant effect on n-3 FA incorporation. At present. The n-3:n-6 FA ratios with n-3 FA supplementation were 0. Rose. A suppressive effect of dietary n-3 FA supplementation on wound healing needs consideration in the context of breast cancer chemoprevention because the possible need for surgical intervention is always present. (1994) reported that this did not appear to be a problem in the trial of fish oil. however. the n-3 FAs have attracted attention as potential interventions for a number of non-neoplastic diseases. Experiments with a standardized animal model did indicate that dietary n-3 FA administration may result in some impairment in wound healing (Albina et al. It was a 7-year dietary n-3 FA intervention in which the changes in blood lipids and fibrinogen were assessed in 304 male and 61 female patients at risk of fatal myocardial infarction. however. to prevent restenosis after angioplasty. The comparison here was between diets containing 36 g of n-6 FA per day and diets with only 6 or 4 g of n-6 FA per day. He did. the accumulation of n-3 FA was at the expense of LA. Leaf (1992) concluded that the potential benefits of n-3 FA in the prevention of cardiovascular disease were evident.M. An important point that emerged from this study relates to the effects on LA and AA. Norway). are identified by mammography. Omega-3 FA supplementation for breast cancer chemoprevention is strongly supported by the epidemiologic and experimental studies described in this review. J.D. cells in which there is active and physiologically . Knapp (1997) agreed that although hematological testing may show the bleeding time to be increased. pulmonary embolism. and deep vein thrombosis (Bruzzi. However. but the clinical relevance of this observation is uncertain. A study performed by Grønn et al.1. (1997) pointed out that more than 50% of ductal carcinomas in situ may be estrogen receptor negative. confirm much of the data acquired using cruder preparations. 260 mg of DHA. 8 g/day n-3 FA. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 235 which demonstrated a 49% reduction in breast cancer incidence among women designated as being at high breast cancer risk and randomized to receive tamoxifen compared with those in the placebo-assigned group (Fisher et al.. and.1. albeit largely in male subjects. usually as a fish oil preparation. but not AA. Holland et al. that the few studies that have been performed using oils of defined composition.5. although here the presurgical n-3 FA supplementation lasted only 12–14 days. however. unresponsive to antiestrogen therapy. 7. Moreover. many reports of cardiovascular disease clinical trials in which n-3 FA supplementation. younger women with atypical hyperplasia or carcinoma in situ fall into this category. Another concern which needs emphasis is that ductal breast carcinomas in situ may be estrogen-independent and so. 1997).82. Knapp (1997) has discussed the variation in FA composition and other components of fish oils and how this complicates the interpretation of clinical trial outcomes. we believe that women with mammographic densities predictive of enhanced breast cancer risk and. Leaf et al. there is convincing support for such a combined approach. in platelets. while this trial was discontinued on ethical grounds without assessing the long-term effects on breast cancer mortality.4. and that there was no cause for concern about postulated adverse side effects such as bleeding due to the suppression of TXA2 production and of platelet aggregation.8 g/day for the duration of the trial.. In an earlier commentary. and he noted that in no case has serious bleeding occurred.25. note that the co-administration of vitamin E should be considered in order to prevent the formation of lipid peroxidation products. a notable feature was a lack of serious side effects. and specifically did not seek to reduce the intake of n-6 FA. A trial reported by Saynor & Gillott (1992) merits special attention because of its size and duration. However. or who reject. and the platelet phospholipids (Section 2). The desired reductions in blood lipid profiles and fibrinogen concentrations were obtained without any detectable adverse effects. 1998). each of which contained 280 mg of EPA.

King et al.4. FA concentrations are high in nipple aspirates and are influenced by the dietary lipid composition (Petrakis et al. 1992). all of the patients had elevated mucosal cell proliferative activity before the dietary intervention. 1995a) performed two human studies in which fish oil supplementation was given in order to suppress rectal epithelial cell proliferation and PGE2 biosynthesis. Mammographic densities Ursin et al. Rose. R.. and this was reduced by the n-3 FA administration. Sauter et al.6%) n-3 FA.. Intermediate response biomarkers 7. with the difference being substituted by olive oil derived n-9 FA. the n-3 FA-supplemented groups showed dose-related increases in their rectal mucosa EPA and DHA levels and corresponding decreases in AA. 1988. which 3-day food intake records showed provided a daily intake of 70 g of fat (29% of the total calories) with 47 g (67%) n-9 FA. After 30 days. Also. and 0. (1993.9 g (7%) LA. This was achieved when the dietary n-3:n-6 ratio was 0.25. Mongru. While this preliminary study needs to be confirmed. they showed that regression of the putative risk marker could be detected in the tamoxifen-treated group. Comparison was with a placebo-administered group consuming an estimated 0. (1994) studied patients with sporadic adenomatous colorectal polyps in order to establish an optimal dose of fish oil for achieving a chemopreventive effect. Rose. P. 1988) and polypeptide growth factors (Connolly & Rose. 5..3. Rose et al. including the detection of atypical hyperplasia and neoplasia (King et al. 1977.. and a subsequent prospective study by the same group of investigators provided support for the hypothesis that as evidenced in these aspirated cells. 1997). 1975. M.1. Breast fluid obtained by nipple aspiration also contains steroid and protein hormones (Petrakis. the patients were maintained on their typical Italian diet. The levels of daily n-3 FA supplementation were 2.1.have been reported in fluids from patients with proliferative benign breast disease (Rose. There were no significant changes in LA content. 1995. estrone. both LA and AA levels were reduced in the membrane phospholipids. tamoxifen. 0.6. These changes in rectal mucosal n-3 FA were accompanied by decreased cell proliferation. it was also suggested that cytological atypia in specimens of breast fluid correlates with the presence of mammographic densities (Lee et al. In Section 6. 1994). assays of the principal serum estrogens. hyperplasia and atypia is associated with an increased breast cancer risk (Wrensch et al. and 7. Bagga et al. an endocrine-based intermediate response biomarker is particularly attractive.7 g per day.1.. 1986. 17. 1992.3.P. (1994). While there do not appear to be any published data on the effect of dietary n-3 FA on tumor phospholipid FA in breast cancer patients. 4. 1992). In a second experiment.1.1. or of the biologically active unbound estradiol fraction. From this background.4 g of which was LNA.. and the LA component reduced from the typical Western level of 15–20 g/day to 5 g/day. lack the precision and specificity and are too variable to provide a marker of risk in the individual woman.236 D. In a single report. and away from the production of the catechol derivative .5 g (25%) saturated FA. 1994). Unfortunately. (1996) discussed the application of mammographic density as a potentially reversible intermediate marker of breast cancer risk in cancer prevention trials. Anti et al. 1986. n-3 FA supplementation with a placebo over a 6-month period.1. 1992). 7..6. the longitudinal evaluation of nipple aspirates appears to offer a promising intermediate response biomarker during dietary n-3 FA supplementation in women at increased breast cancer risk. may be significant because there is evidence that the incorporation of n-3 FA into cell membranes is enhanced by feeding an olive oil-rich diet (Cleland et al. and estrone sulfate. As in the first study. we have demonstrated a reduction in human breast cancer cell phospholipid AA.2. derived from olive oil. (1994) compared the low dose. but not LA.3.. estradiol. This recommendation is supported by the results of both epidemiologic and experimental studies that suggest that a high olive oil consumption is associated with reduced breast cancer risk (reviewed by Rose. 7. and treated postsurgically with radiation.1. which are considered to reflect the hormonal microenvironment of the ductal epithelium and may prove to be significant biological response markers. 2.55 g of n-3 FA per day.M. Connolly. (1983) reported an encouraging agreement between the cytological findings in nipple aspirates and the histopathological features observed in biopsy material. This high level of n-9 FA.6.. High levels of transforming growth factor. we suggest that in North American and Northern European patients. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 important synthesis of eicosanoids from AA.5 g/day. Gann et al.55 g (0. 1983.. From an examination of mammograms of the contralateral breast of premenopausal women diagnosed with unilateral breast cancer. n-3 FA supplementation to favorably impact on potentially precancerous breast lesions be combined with a dietary modification in which the total fat intake is reduced to 25–30% of energy intake. essentially all oleic acid (C18:1). in the nude mouse model. Rose. 1997b). It is of interest that in the studies reported by Anti et al. Rose. with concomitant reductions in both AAderived COX and LOX products (Rose et al. but this did not differ significantly between the three dose levels. 7. & D. unpublished data. Cytology and biochemistry of nipple aspirates The cytological examination of exfoliated breast epithelial cells in fluid collected by nipple aspiration provides a noninvasive procedure for acquiring material for pathological evaluation. Urinary estrogen metabolites Given the important role of endogenously produced estrogens in breast cancer etiology.5. 1997). or chemotherapy. Anti et al. we referred to the hypothesis that increased metabolism of estrogen to 16 -hydroxyestrone.) Bartram et al.6. but not with the same absolute level of fish oil intake and an n-3:n-6 FA ratio of 0. J. J.

the mechanisms involve the biosynthesis of eicosanoids by prostate cancer cells (Rose & Connolly. stability. 1997). Acknowledgments We thank Ms. 1994). 1997).3... the membrane fluidity of skin fibroblasts was increased when the cellular phospholipids were enriched with DHA. and the validity of using single (“spot”) urine samples has been established (Bradlow et al. Once again. Our own work has been supported by NIH grant CA-53124.. as exists in the commercially available fish oil concentrates? The two n-3 FAs do have different effects on the plasma lipids (Subbaiah et al. Because the basic mechanisms for therapeutic efficacy do not involve the reproductive endocrine system. Ewings & Bowie. We are now at a stage in our knowledge of n-3 FAs and cancer when we can consider the translation of our efforts from the laboratory to the clinic. tumor-associated angiogenesis. 1998). Some epidemiological studies have suggested that n-3 FAs exert a protective effort (Mishina et al. 1993) and lipoproteins (Childs et al. constitutes a breast cancer risk factor. but they have been resolved now that pure n-3 FA preparations and unique sources of high potency are available. and it has been proposed that the antimetastatic prop- erties of DHA are ascribable. J. there is currently a high level of interest in selective COX-2 inhibitors as chemopreventive agents. a constituent of cruciferous vegetables (Telang et al. Ghosh & Myers. 1988. it has been shown that this effect may be achieved by inducing cytochrome P450 1A1dependent C2-hydroxylation of estradiol with indole-3-carbinol. indirectly reduce eicosanoid synthesis by both decreasing 6 and 5 desaturation (Section 2) and displacing the AA. which demonstrated a strong positive association between the urinary 16 -hydroxyestrone excretion and breast cancer and an inverse one for the ratio of 2-hydroxyestrone to 16 hydroxyestrone (Kabat et al. (1988) provide the only indication that a similar potentially chemopreventive effect can be obtained by dietary n-3 FA supplementation. Hebert et al.. Enzyme immunoassays have been developed for the two key estrogen metabolites 16 -hydroxyestrone and 2-hydroxyestrone. 1989). 1997c). 1990). 1984. and there is an urgent need to resolve this issue. there is sufficient support for their entry into clinical chemopreventive trials. 1983. the limited amount of experimental data that are available does not suggest that DHA and EPA differ significantly in their ability to suppress mammary carcinogenesis and tumor progression. However. patients with advanced disease. but not with EPA (Brown & Subbaiah. Moreover. 1998). Commentary In this review. The problems of variation in n-3 FA composition. 1985).. but this observation certainly merits further examination. and they may have critical effects on hormone and growth factor function (Cave & Jurkowski. in part. However. Connolly / Pharmacology & Therapeutics 83 (1999) 217–244 237 2-hydroxyestrone. whereas EPA only displaces the n-6 FA substrate (Grimsgaard et al.. those who have received surgical treatment for their breast cancer (“secondary prevention”). however. Rose. 1988.1.. Kabat et al. we chose to focus our attention on the potential that long-chain n-3 FAs exhibit as breast and colon cancer chemopreventive agents. and in a combination of clinical and experimental studies. as discussed in Section 6. In colon cancer.. The long-chain n-3 FA can cause increased cell permeability (Jenski et al. the likely involvement of products of LOX-mediated AA metabolism in colon carcinogenesis. An immediate decision to be made when designing a dietary n-3 FA cancer chemoprevention clinical trial is the source of the supplement and the specific n-3 FA to be used in order to achieve maximal biological activity. This does... 8. This seemed appropriate because in our view. Roz Alexander for her assistance in preparing the manuscript. 1997). 1987.. the experimental evidence that n-3 FA may enhance the antitumor activity of cytotoxic drugs (Burns et al.. to its effect on the tumor cell plasma membrane (Zerouga et al. Reichel et al. and in one study.D. 1985) by altering the composition of lipid bilayers in cellular membranes. 1997. Tsai et al.. and cancer progression suggests that again there is a place for combined treatment with n-3 FA.. is the recognition that dietary fat and FAs also influence the biological behavior of prostate cancer cells (Rose & Connolly. However. 1991)... 1985. and feeding diets containing high levels of n-3 FA suppressed human prostate cancer cell growth in nude mice (Karmali et al.M. the relationships were only evident in postmenopausal women. and suitable intermediate response markers exist. A shift in estrogen metabolism to obtain an increase in 2-hydroxyestrone would be expected to have a favorable influence on breast cancer risk. grants CN-100 and RPG-93-003-04- . quality control. Cell membrane fluidity is also associated with the metastatic capacity of tumor cells (Taraboletti et al. 1997). or the two in combination. 1997) suggests that they merit a place in future trials of combination therapy. 1992.P. These methods were used for a case-control study. The very preliminary data published by Osborne et al. Nevertheless. There is also evidence that DHA may depress phospholipid AA levels and so. raise an additional question: Should the n-3 FA dietary supplement consist solely of DHA or EPA. Connolly et al. Rose & Cohen. 1997). and. relevant high-risk groups have been identified. Clinical trials should focus on women at increased breast cancer risk. 1991. an n-3 FA intervention would complement rather than compete with antiestrogen-based chemoprevention and adjuvant therapy. Jurkowski & Cave. Less well developed. 1997a). One aspect of cell biology that we have scarcely touched upon is the role of the cell membrane. perhaps.. even here there is evidence for the involvement of the eicosanoids (Dave & Witorsch. but in the forefront of current interest. 1996. Rose. and patient acceptance of fish oil preparations were recurring issues.

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