T o x [ ~ ~PATHOLOOY

i c ISSfJ:O912-6233 Volume 16, Number 2, 1988

copyright o 1988 by the Society of Toxicologic Pathologists Printed in U.S.A.

Intestinal Cancer Induced by N-Nitroso Compounds*

WILLIAM
LUINSKY
NCI-Frederick Cancer Research Facility, BR I-Basic Research Program,
Frederick, Maryland 21701

ABSTRACT
Several N-nitroso compounds induce tumors of the colon, and some induce tumors in other parts of the
intestinal tract as weIl. The nitrosamines that induce colon tumors are beta oxidized n-propyl-nitrosamines.
These require metabolic activation, as do 1,2-dimethylhydrazine, azomethane, and azoxymethane, another
group of colon carcinogens. Several nitrosoalkylureas induce tumors in rat colons after oral administration,
although the monoalkylnitrosoureas are fairly unstable and might not be expected to reach the colon. However,
monoalkylnitrosoureas are equally effective with the much more stable dialkylnitrosoureas. Although nitro-
somethylurea did not induce colon tumors under these conditions, nitrosoethylurea did, together with ni-
trosodiethylurea and other nitrosoethylalkylureas. Nitroso-n-butyl-, n-amyl-, n-hexyl-urea, and nitrosohy-
droxyethylurea also induced colon tumors, but the last, like nitrosoethylurea, also induced tumors of the
duodenum and ileum. In most of these experiments male rats were more susceptible to induction of intestinal
tumors than female rats. An explanation for the differences between these compounds of similar structure
might be found in variations in their ability to alkylate DNA in intestinal cells, or in differences in stability
of the alkylated product between the compounds. The physical properties of the compounds might also
modulate the process of carcinogenesis, however.

INTRODUCTION (2-oxopropy1)amine (1 2), nitrosobis-2-hydroxypro-

Even though relatively few chemical carcinogens
induce tumors of the colon in experimental animals,
colorectal cancer is among the most common can-
cers in humans living in industrialized countries,
excepting Japan. There are two reasons for studying
the chemical induction of cancer at this site: first,
because of the need to know about human exposure
to carcinogens that might be involved in its etiology,
and second, to understand the mechanisms by which
cells in these organs are transformed into tumors.
Among the chemicals which have been found to
induce colon tumors, but usually not rectal tumors,
are several aromatic amines. These include some
that are products of pyrolysis of amino acids and
proteins (14), 1,2-dimethylhydrazine (1) and its
products of oxidation, azomethane and azoxymeth-
ane (lo), and the aglycone of cycasin, methylazoxy-
methanol acetate (2). In addition, several N-nitroso
compounds, includingnitrosomethylurea and nitro-
somethylnitroguanidine, have induced colon tu-
mors when injected directly into the colon (1 5). The
few nitrosamines that have induced tumors of the
colon (Table I) appear to be limited to nitrosobis-
Presented at the Sixth International Symposium of the So-
ciety of Toxicologic Pathologists: “Gastrointestinal Toxicologic
Pathology,” June 1-3. 1987 in Philadelphia, Pennsylvania.
I98
Downloaded from tpx.sagepub.com by guest on December 8, 2016
pylamine, and nitroso-2-hydroxypropyl-2-oxopro-
pylamine (Lijinsky et al, unpublished). Nitrosa-
mines were active when given to rats orally, which
was the route employed for the compounds related
to dimethylhydrazine. It is probable that these com-
pounds underwent extensive metabolism prior to
the induction of tumors in the colon. Some steps in
this metabolic activation were likely to have oc-
curred in the liver, since these compounds induced
tumors of the liver and other organs of the rat. On
the other hand, the directly acting N-nitroso com-
pounds, such as nitrosoalkylureas, do not require
metabolic activation and are also directly acting mu-
tagens and alkylating agents (1 3).
NITROSOALKYLUREAS INDUCING
INTESTINAL TUMORS
Some time ago, it was found that nitroso-2-hy-
droxyethylurea induced tumors of the colon (along
with tumors of many other organs) when given by
gavage to rats. The incidence of colon tumors was
not large (9), but the absence of tumors of this type
in untreated control rats suggested that the colon
tumors were due to treatment with the nitrosoal-
kylurea. A subsequent study of the relation between
the chemical structure ofnitrosoalkylureasand their
carcinogenic action revealed that many N-nitroso
Vol. 16, No. 2, 1988 INTESTINAL CANCER 199

compounds of this type-but not all-induce tu- TABLE

1.-Compounds that induce intestinal tumors in
mors of the colon, as well as tumors in the duode- rats.
num and ileum. Strangely, none of these com- Duoden- Ileum/
pounds, regardless of structure, has induced tumors Compound Colon um jejunum
of the esophagus, although the rat esophagus is ex- -
tremely sensitive to tumor induction by nitros- Azoxymcthane + -

amines. Even though more than half of all nitros-

Ethylazoxymethane + - +
amines tested have induced esophageal tumors in Nitroso-
rats (3), none of the N-nitroso compounds so far hydroxypropyloxopro-
examined has induced tumors of the esophagus in pylamine + - -
hamsters or guinea pigs, illustratingthe strong species bis-oxopropylamine + - -
bis-2-hydrox ypro-
specificity of these carcinogens.
A similar specificity of response is seen with the
pylamine + - -
ethylurca + + +
N-nitroso compounds that induce tumors in the in- hydroxyethylurea + + +-
testines of rats, since none of these compunds has methoxyethylurea + +
given rise to intestinal tumors in hamsters, even phenylethylurea - + +
though they were given to rats and hamsters by the allylurea + - +-
same route (gavage) and at similar doses. The ham- butylurea + -
ster is not refractory to the carcinogenic effect of amylurea + - +-
those N-nitroso compounds, directly acting or those hexylurea + -
requiring metabolic activation. Rather, the hamster 3-hydroxypropylurea + + +
seems to respond only in certain ways to N-nitroso diethylurca + +- '+
compounds, regardless of the structure. For exam- ethylmethylurea + +-
ple, although the N-nitrosoalkylureas that have been
ethyl-hydroxyethylurea + -
-
given to rats have induced a variety of tumors, in
hvdroxvethvl-ethvlurca + -
hamsters they have induced only tumors of the fore-
stomach and hemangiosarcomas of the spleen. No verted to carbon dioxide and excreted within 6 hours.
tumors of the colon, duodenum, or ileum were in- Nevertheless, administration of nitrosomethylurea
duced by any of these compounds in hamsters, al- to rats by gavage, to a total dose of 0.8 mmole,
though they are directly acting carcinogens and pre- induced a high incidence of nervous system and
sumably the lower gastrointestinal tract would be forcstomach tumors, but none in the intestines, in-
series of receptive organs. The difference in the re- cluding the colon. In contrast, the structurally sim-
sponses of rats and hamsters to nitrosoalkylureas ilar nitrosoethylurea, which is equally readily ab-
sheds some doubt on our concept of the mechanism sorbed and readily metabolized when given to rats
of carcinogenesis by these compounds. Perhaps they by gavage, induced few tumors in the nervous sys-
do require some type of cell activation that is pro- tem, but induced tumors in many other organs, in-
vided by the rat, but not by the hamster. cluding the duodenum, ileum, and colon. The rea-
Some well-known experiments showed the in- sons for the large difference in carcinogenic
duction of colon tumors in rats by means of a so- effectiveness in rats between nitrosomethylurea and
lution of nitrosomethylurea or nitrosomethylnitro- nitrosoethylurea are not readily apparent, since both
guanidine that was deposited in the colon through are mutagenic in many systems, are similar in sta-
the anus. This treatment was followed by various bility and in chemical properties, and are effective
diets to demonstrate the influence of fat as a tumor in inducing skin tumors by painting on mouse skin
promotor. These experiments demonstrated the (3).
susceptibility of the rat colon to the induction of An equa! dose of nitroso-2-hydroxyethylureais
tumors by nitrosomethylurea (15). It might be ex- even more effective than nitrosoethylurea in induc-
pected, therefore, that oral administration of nitro- ing tumors of the duodenum, ileum, and colon in
somethylurea might allow the colon epithelium to rats when given by gavage. Nitrosohydroxyethyl-
come in contact with some portion of the dose, thus urea gives rise to a much higher incidence of tumors
giving rise to tumors. In our experiments, the ni- in the lower gastrointestinal tract, and to a broad
trosoalkylureas were administered in solution in corn spectrum of tumors in other organs. It might be
oil, in which the compounds are stable, and pre- relevant that nitrosohydroxyethylurea is a much
sumably less readily absorbed than from aqueous more potent bacterial mutagen than is nitrosoethyl-
solution. Absorption does occur, however, probably urea (6), which is possibly related to the presence
through the lymphatic system: 60% of the dose of of the hydroxyl group. However, even though the
radiolabeled nitrosomethylurea given to rats is con- methyl ether of nitroso-2-hydroxyethylurea, nitro-

Downloaded from tpx.sagepub.com by guest on December 8, 2016

200 LIJINSKY TOXICOLOGIC
PATHOLOGY

11.-Induction of intestinal tumors in rats by nitrosoureas.

TABLE
Proportion of animals with intestinal tumors
Total dose Median week of (W
Compound (mmole) death Colon Jejunudileum Duodenum
Nitroso-
ethylurea 1.1 6 30 10 20 15
0.4 6 45 35 - -
0.4 P 40 10
allylurea 1.2 d 35 42
1.2 0 32 -
n-butylurea 1.7 6 48 25
1.7 P 41 25
n-amylurea 2.0 d 62 12
2.0 0 54 -
n-hexylurea 2.0 6 60 33
2.0 9 53 -
phenylethylurea 0.9 6 31 -
0.9 9 27 -
3-hydroxypropylurea 1.3 P 70 17
ethylurea 1.1 d 30 10
0.46 . 45 35
0.4 P 40 10
hydroxyethylurea 3.8 6 29 16
0.86 . 45 35
0.8 9 46 10
rneihoxyethylurea 0.7 6 38 50
0.7 P 33 25
diethylurea 1.2 6 33 33
0.9 P 24 -
ethyl-methylurea 1.2 6 34 25
1.2 P 30 25
ethyl-hydroxyethylurea 1.4 6 56 20
1.4 P 47 -
hydroxyethylethylurea 1.4 6 65 15
1.4 P 45 12

somethoxyethylurea, is an equally potent mutagen,
which also induces tumors of the colon and of the
duodenum when given to rats by gavage, it did not
induce tumors of the ileum or jejunum.
A series of nitrosoalkylureas has induced intes-
tinal tumors in rats when given by gavage. The re-
sults of these experiments are shown in Table 11,
and show some interesting differences, which .are
difficult to explain with present knowledge. The total
doses to which the rats were exposed are not very
different, but the time-to-death with tumors differed
somewhat. Differences in such physical properties
as lipid-water partition cannot account for the in-
duction of colon tumors, but not tumors of the duo-
denum by nitroso-n-butylurea, and tumors of the
duodenum and jejunum, but not of the colon, by
nitroso-2-phenylethylurea. Nitrosoallylurea in-
duced tumors of the colon in male rats, but not in
females. The reasons for the male-female discrep-
ancy are not known, but the discrepancy is not con-
fined to this particular nitrosoalkylurea. However,
there are nitrosoalkylureas which induce colon tu-
mors equally in male and female rats.
NITROSODIALKYLUREAS
There is a certqin similarity in the structures of
nitrosoalkylureas that induce colon tumors in rats,
including nitrosodialkylureas, which are much more
stable than nitrosomonoalkylureas, but are still di-
rectly acting alkylating agents and directly acting
mutagens (6). Nitrosodimethylurea, which is con-
siderablyweaker than nitrosomethylurea, took much
longer to induce malignant tumors in the nervous
systems of rats; like nitrosomethylurea, however, it
induced no tumors in the intestinal tract. In con-
trast, nitrosodiethylurea was as rapidly acting as ni-

Downloaded from tpx.sagepub.com by guest on December 8, 2016

Vol. 16, No. 2, 1988 INTESTINAL CANCER 20 1

trosoethylurea, and like the latter, it induced a va- to play a role, but the properties of nitrosomethyl-
riety of tumors in the colon, duodenum, and jejunum urea and nitrosoethylurea do not differ nearly so
of rats (Tables I and 11). These tumors of the in- much as nitrosodimethylurea differs from nitroso-
testines appeared only in male rats, however. The methylurea. Similarly, in reactivity and stability,
absence of such tumors in female rats cannot be nitrosomethylurea and nitrosoethylurea are much
explained by inadequate survival of the females. more similar than are nitrosomethylurea and nitro-
They died mainly from malignant mammary tu- sodimethylurea. In chemical stability,. nitroso-
mors, but not more than a few weeks earlier, on monoalkylureas resemble one another much more
average, than the males. The analogous nitroso- than they do any nitrosodialkylurea.It must be con-
ethylmethylurea produced almost exactly the same cluded, therefore, that the organ specificities dem-
pattern of tumors as nitrosodiethylurea, but the ratsonstrated by these nitrosoalkylureas is due not pri-
given nitrosodiethylurea died some weeks earlier, marily to the decomposition into alkylating agents
suggestingthat the tumors were more easily induced, (which would be alkyldiazonium ions, formed at
or progressed more rapidly, than with nitroso- different rates depending on whether the source was
ethylmethylurea. The proportion of rats with tu- a mono-, di- or trialkylnitrosourea), but to the
mors of the colon, jejunum, and ileum was very chemical structure of the nitrosourea and its affinity
similar between the two treatments. Nitrosoethyl- for some cellular receptor. Identification of these
2-hydroxyethylurea also induced tumors of the co- receptors would help in understanding the mecha-
lon in rats (1 1) in a very similar incidence to nitro-
nisms of nitrosoalkylurea carcinogenesis.
sodiethylurea. The median time-to-death of these The influence of the whole structure of the nitro-
animals, however, was much longer, by as much as sourea on organ-specific carcinogenesis is apparent,
20 weeks. but difficult to understand. For example,
Except for the higher incidence of tumors in the nitroso-2-hydroxyethylurea,its methyl ether and
nervous system induced by the hydroxyethyl com- nitroso-2-hydroxyethylethylurea,all induce tumors
pond, there was little difference in the distribution of the colon in rats, whereas nitroso-2-
of tumors induced by the three nitrosoethylalkyl- hydroxyethyl-2-chloroethylureadoes not. The latter
ureas. It can be concluded, then, that the compar- compound does, however, induce a high incidence
atively small incidence of colon tumors is not due of liver tumors and tubular cell neoplasms in the
to the early death of the rats from other types of rat kidney (8), in which the median survival is much
tumor. It seems that the affinity of the nitrosoethyl-longer than for rats treated with the other hydroxy-
urea structure for certain receptors in some types of ethylnitrosoureas. None of the nitrosoureas exam-
cells is a determinant, but the relative affinities inined in Syrian hamsters has induced tumors of the .
the various target cells remain the same. The sharp GI tract, other than in the forestomach; the only
difference between the nitrosoethylalkylureas,which other tumors that have appeared in hamsters given
induce tumors in the colon and in other parts of the nitrosoalkylureas of whatever structure, including
intestines, and the nitrosomethylalkylureas, which mono-, di- and trialkylnitrosoureas, have been he-
are potent carcinogens but do not induce tumors in mangiosarcomas of the spleen. The reason for the
the intestines, reinforces this probability. singular susceptibility of endothelial cells of the
hamster spleen to nitrosoalkylureas is an intriguing
ALKYLATION MECHANISMS IN CARCINOGENESIS but unsolved mystery.
In a homologous series of carcinogens, the methyl A comparison of the effects on the rat GI tract of
compounds are frequently anomalous in behavior. azoxymethane and nitrosoethylurea does not pro-
This is certainly true of the N-nitroso compounds, vide a simple rational explanation for their common
and especially the nitrosoalkylureas discussed here. action in inducing tumors in the colon. Azoxymeth-
The overwhelming tendency of the nitrosomethyl- ane is generally considered to be a methylating agent
alkylureas is to induce tumors in the nervous sys- (l), which methylates DNA in the colon and in the
tem, but not in the gastrointestinal tract or in the liver of rats and hamsters (4). Its higher homolog,
forestomach, which is the first organ they encounter azoxyethane, can be considered by analogy to be an
when given by gavage. Most of the higher homologs, ethylating agent. It has not, however, induced tu-
including ethyl-, butyl-, amyl- and hexyl-nitroso- mors in the lower GI tract in rats, although it is a
urea, and hydroxyethyl- and methoxyethyl-nitroso- powerful carcinogen (1 0). On the other hand, in our
urea, readily induce tumors in the gastrointestinal studies nitrosomethylurea, which is a methylating
tract, including the colon, jejunum, ileum, and duo- agent, has not induced tumors of the intestines, while
denum. However, they produce few, if any, tumors the ethylating agent nitrosoethylurea has induced
in the nervous system. Physical properties, such as tumors in those organs. As discussed above, the
liposolubility and partition coefficients, might seem nitrosomethylureas have not, in general, induced

Downloaded from tpx.sagepub.com by guest on December 8, 2016

202
tumors of the colon, while the analogous nitrosoeth-
ylureas have induced those tumors. These patterns
suggest that formation of a methylating or an ethy-
lating agent is not the source of the organ-specific
carcinogenicity of these compounds (although al-
kylation might be a step in carcinogenesis). The or-
gan-specific carcinogenicity appears to result from
some characteristics of the entire molecule.
OF N-NITROSO
ORGANSPECIFICITY COMPOUNDS
It is not known whether the cbmpounds which
induce colon tumors reach the colon by passage
through the gut, or whether they act systemically.
There is some evidence that part of the action of
carcinogens that induce tumors of the colon, and
even of the forestomach, is systemic, because tu-
mors of these organs are induced by intraperitoneal
or subcutaneous injection of the same compounds
that induce those tumors by administration in
drinking water or by gavage. Therefore, investiga-
tion of the mechanism of action of carcinogens that
induce colon tumors is less one of considering their
direct action or products of their metabolism, and
more a matter of considering why compounds with
those structures have an affinity for the colon, as
distinct from the kidney, liver, or other organs that
are not their targets.
Most of the compounds that induce intestinal tu-
mors have the colon as the main site of tumor for-
mation. Some compounds induce tumors only in
the colon, such as azoxymethane, ethylazoxymeth-
ane, nitrosobis-(2-oxopropyl)amine(BOP) and ni-
trosohydroxypropyl-oxopropylamine (HPOP), as
well as several of the nitrosoalkylureas. Only one of
the compounds, nitrosophenylethylurea, induced
tumors in the duodenum and jejunum, but not in
the colon of rats. Nitrosooxazolidone is also in this
category: it gave rise to tumors in the duodenum,
but not in the colon, of Syrian hamsters, and to no
tumors in the intestinal tract of rats. These results
can be compared to carcinogens other than nitro-
soalkylureas, which might require specificmetabolic
activation provided by the colon mucosa, but not
by other parts of the intestinal tract. There is some
evidence for this in the work of Fiala with azoxy-
methane, showing methylation ofDNA in the colon
mucosa by products of metabolism of azoxymeth-
ane (1). This does not prove that such methylation
is specifically related to the induction of tumors in
the colon, particularly since methylation of DNA in
organs that are not targets of azoxymethane carcino-
genesis was not studied. However, Fiala’s work
demonstrates that there is metabolism in the colon
which does not take place with azoxymethane in
other organs. The same is likely to be true of BOP
Downloaded from tpx.sagepub.com by guest on December 8, 2016
LIJINSKY TOXICOLOGIC
PATHOLOGY
and HPOP, that is, there could be specific metab-
olism in the colon which does not take place in other
organs. In the case of BOP, we have shown that
DNA methylation by this nitrosamine occurs both
in organs in which it induces tumors, and organs in
which it does not induce tumors (unpublished). The
mechanism by which these compounds induce tu-
mors is far from understood.
In the case of the directly-acting nitrosoalkyl-
ureas, the induction of tumors in the colon, as dis-
tinct from other parts of the GI tract, is less easily
understood. The compounds listed in Table I were
all administered orally, the nitrosoalkylureas as twice
weekly treatments of rats by gavage. Although all
of the nitrosoureas are directly-acting bacterial mu-
tagens, their potencies vary widely within a range
of at least two orders of magnitude: from the weakly
mutagenic nitrosoethylurea and nitrosodiethylurea
to the potent mutagens nitroso-2-phenylethylurea
and nitrosohydroxyethylurea (6). All of these com-
pounds presumably are mutagenic through direct
alkylation of the bacterial DNA.
The size and chemical nature of the alkyl group
seems to have only a quantitative effect. There is
little difference, for example, between nitrosohy-
droxyethylurea and its ether, nitrosomethoxyethyl-
urea, but there is alarge quantitative difference be-
tween nitroso-2-hydroxypropylurea and the much
weaker nitroso-3-hydroxypropylurea.It seems log-
ical that nitrosoalkylureas act through bathing of the
mucosa of the GI tract by the solutions placed in
the stomach (and most of them induce a high in-
cidence of tumors of the forestomach). Therefore,
it is not easy to rationalize their common induction
of colon tumors, but the failure of many of them to
induce tumors in the duodenum, ileum and jeju-
num, which the solutions enter first. Since many of
them do induce tumors in other parts ofthe GI tract,
as well as in the colon, this refractoriness to certain
nitrosoalkylureas cannot be due to constitutive re-
sistance to this type of compound.
One explanation could be that they remain in the
colon a longer time. This is borne out to some extent
by the finding that two nitrosodialkylureas, which
are much more stable than the corresponding nitro-
somonoalkylurgas (nitrosoethylhydroxyethylurea
and nitrosohydroxyethylethylurea), induced tumors
in the colon, but not in the duodenum, ileum, or
jejunum. However, this did not happen with the
equally stable compounds, nitrosodiethylurea and
nitrosoethylmethylurea. Neither did it occur with
nitroso-n-butylurea or nitroso-n-hexylurea. These
compounds also induced tumors only in the colon
of rats, although they were no more stable (6) than
the other nitrosomonoalkylureas, which induced tu-
mors in all parts of the intestinal tract in rats.
Vol. 16, No. 2, 1988 INTESTINAL CANCER
The number of animals with intestinal tumors
following treatment with any of the nitrosoalkyl-
ureas was usually relatively small. Rats frequently
died from other types of tumors, which raises the
question of competing risks. It does not seem, how-
ever, that early death from other causes precludes
development of tumors in the colon and other parts
of the intestines, since there is a large and somewhat
patternless variation in median time-to-death from
tumors (Table 11) in rats receiving nitrosoalkylureas
(5). Many of the compounds that induce colon tu-
mors in rats have failed to induce tumors in the
intestines of Syrian hamsters, when given at com-
parable doses. Except for nitrosoethylurea, which
induced a low incidence of colon tumors, the nitro-
soalkylureas restricted their action in hamsters al-
most entirely to the spleen and forestomach (7).
CONCLUSION
Examination of some consistent findings in the
studies of induction of colon tumors in rats might
suggest ways of exploring the mechanisms of colon
carcinogenesis. One result was the higher incidence
of colon tumors in male rats than in females, even
though in our experiments the males, being larger,
.received a smaller dose per unit body weight than
the females because the dose per animal was usually
the same. There was no case in which the incidence
of colon tumors was higher in females than in male
rats. Another finding was the failure of any of the
nitrosomethylureas to induce colon tumors when
given by mouth. This occurred regardless of there
being no apparent difference chemically or muta-
genically from the corresponding nitrosoethylureas
or nitrosohydroxyethylureas. It is conceivable that
a minimum molecular size for a nitrosoalkylurea is
needed in order for there to be a reaction with the
appropriate receptor in the colon cells, and that ni-
trosomethylureas are too small. However, the in-
duction of tumors in the colon by the methylating
compound azoxymethane would tend to refute this
argument. It is obvious that much remains to be
learned about the chemistry and biochemistry of the
colon carcinogens, as well as about the biology of
the colon mucosa, before the induction of colon
tumors by so special a group of compounds can be
understood.
ACKNOWLEDGMENTS
This research was sponsored by the National Can-
cer Institute, DHHS, under contract No. NOl-CO-
23909 with Bionetics Research, Inc. The contents
ofthis publication do not necessarily reflect the views
or policies of the Department of Health and Human
Services, nor does mention of trade names, com-
Downloaded from tpx.sagepub.com by guest on December 8, 2016
203
mercial products, or organizations imply endorse-
ment by the U.S. Government. Pathological diag-
noses were by Dr. R. M. Koiratch and Dr. M. D.
Reuber, whom the author thanks. By acceptance of
this article, the publisher or recipient acknowledges
the right of the U.S.Government to retain a nonex-
clusive, royalty-free license in and to any copyright
covering the article.
REFERENCES
1. Fiala ES (1977). Investigations into the metabolism
and mode of action of the colon carcinogens 1,2-
dimethylhydrazine and azoxymethane. Cancer 40:
2436-2445.
2. Laqueur GL (1965). The induction of intestinal neo-
plasms in rats with the glycosidecycasin and its agly-
cone. VirchowsArch. Pathol.Anat. Pliysiol. Klin. Med.
340: 151-1 63.
3. Lijinsky W (1984).Structure-activityrelations in car-
cinogenesis by N-nitroso compounds. In: Genofoxi-
cology ofN-nitroso coriipotrtids,TK Rao, W Lijinsky,
and JL Edler (eds). Plenum Publishing Corp., New
York, pp. 189-23 1.
4. Lijinsky W (1985). Metabolism and cellular inter-
actions of some aliphatic nitrogenous carcinogens.
Cancer Lett. 26: 33-42.
5 . Lijinsky W (1987). Structure-activityrelations in car-
cinogenesis by N-nitroso compounds. Cancer and
Metastasis Reviews (in press).
6. Lijinsky W, Elespuru RK, and Andrews AW (1987).
Relative mutagenic and prophage-inducing effects of
mono- and di-alkylnitrosoureas.Miitation Res. 178:
157-1 65.
7. Lijinsky W,Knutsen GM, and Kovatch RM (1985).
Carcinogenic effect of nitrosoalkylureas and nitro-
soalkylcarbamates in Syrian hamsters. Cancer Res.
45: 542-545.
8. Lijinsky W, Kovatch RM, and SingerSS (1986). Car-
cinogenesisin F344 rats by nitrosohydroxyalkylchlo-
roethylureas. J. Cancer Res. Clin. Oncol. 112: 221-
228.
9. Lijinsky W and Reuber MD (1983). Carcinogenicity
of hydroxylated alkylnitrosoureas and of nitrosoox-
azolidones by mouse skin painting and by gavage in
rats. Cancer Res. 43: 214-221.
10. Lijinsky W, Saavedra JE, and Reuber MD (1985).
.Organ-specificicarcinogenesisin rats by methyl- and
ethyl-azoxyalkanes. Cancer Res. 45: 76-79.
11. Lijinsky W,Singer GM, and Kovatch RM (1985).
Similar carcinogeniceffects in rats of l-ethyl-l-nitro-
so-3-hydroxyethylurea and l-hydroxyethyl-l-nitro-
so-3-ethylurea. Carcinogenesis 6: 641-643.
12. Pour P (1978). A new and advantageous model for
colorectal cancer. Cancer Lett. 4: 293-298.
13. Preussmann R and Stewart B W (1984). N-nitroso
compounds.In: ChemicalCarcinogens,CE Searle (ed).
American Chemical Society Monograph, No. 182,
pp. 643-828.
204 LUINSKY TOXICOLOGIC
PATHOLOGY

14. Sugimura T (1985). Carcinogenicity of mutagenic chevsky D (1 979). Effect ofdietaxy alfalfa, pectin, and
heterocyclic amines formed during the cooking pro- wheat bran on azoxymethane or methylnitrosourea-
cess. Mutation Res: 150: 33-4 1. induced colon carcinogenesis in F344 rats. J.
15. Watanabe K, Reddy SQ, Weisburger JH, and Krit- Natl.Cartcer Inst. 63: 141-145.

Downloaded from tpx.sagepub.com by guest on December 8, 2016