CANCER BIOLOGY & CHEMOTHERAPY

Prepared by

Dennis N. Muoz, P.T.R.P., R.N., R.M.

2. Please highlight the concepts tackled from modules 1-3 related to your answers.
MODULE 1: Adaptive and Regulatory Mechanism y Homeostasis & Constancy y Negative feedback Mechanism y Adaptive Mechanisms and Stress Response y Importance of Intrinsic and Extrinsic Factors in Adaptation and Disease Causation MODULE 2: Cellular Functions (Overview) y Cell Cycle Periods y How cells are Organized Module 3: Alterations in Protective Mechanism: Inflammation and Infection y Cellular and Vascular Responses to Inflammation

INTRODUCTION TO CANCER BIOLOGY Cancer is the third leading cause of morbidity and mortality in the Philippines. Leading cancer sites/types are lung, breast, cervix, liver, colon and rectum, prostate, stomach, oral cavity, ovary and leukemia. There is at present a low cancer prevention consciousness and most cancer patients seek consultation only at advanced stages. Cancer survival rates are relatively low (Ngelangel & Wang, 2001). Cancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems. Cancer is not just one disease but many diseases. There are more than 100 different types of cancer (National Cancer Institute, Retrieved 2011). The term cancer covers a number of diseases in which the growth of cells becomes uncontrolled. Cancer cells fail to respond to the usual controlling signals and their growth becomes unregulated. Indeed, the name cancer comes from a Latin word meaning a crab , and describes the manner in which the pattern of penetration into normal tissues by the abnormal growth bears a superficial resemblance to a crab s claw (Ahmed, 2007). Cancer is a genetic disease. The malignant phenotype often requires mutations in several different genes. Cancer cells generally retain the capacity to proliferate by acquiring mutations in cell cycle regulatory genes (particularly those regulating the G1 checkpoint). Often mutationsactivate cell pathways leading to proliferation and block pathways of differentiation. The normal cell has protective mechanisms that lead to the repair of cell damage; these repair pathways are often abnormal in cancer cells. When a normal cell has sustained too much damage to repair, the cell activates a suicide pathway to prevent damage to the organ. These cell death pathways are also commonly altered in cancer cells, leading to the survival of damaged cells that would normally die (Kasper , D. L. et al,2005).

The causes of cancer are complex and varied. Some arise from environmental agents called carcinogens, others are brought about by oncogenic, and that is cancer-inducing, viruses. Most cancers arise, ultimately, from mutations in DNA. These mutations may be caused by environmental agents, or may be inherited in the germ line, making individuals more susceptible to cancer Ahmed, 2007). Ahmed (2007) further stated that Germline DNA refers to the DNA which is present in the cells that give rise to the gametes, that is, the sperm and eggs. The egg and sperm fuse to form a zygote, and, as further divisions occur, that DNA is passed to all the cells in the developing embryo. Mutations which occur in germline DNA are present in the gametes and in all the cells of the individuals to which they give rise See figure1.

Figure 1. Acquired mutations develop in DNA during a person s lifetime. If the mutation arises in a body cell, copies of the mutation will exist only in the descendants of that particular cell. From the National Institutes of Health and National Cancer Institute. (1995). Understanding gene testing (NIH Pub. No. 96-3905). Washington, DC: U.S. Department of Human Services (Smeltzer & Bare, Medical Surgical Nursing, 2004, pp.129).

Treatment options offered to cancer patients should be based on realistic and achievable goals for each specific type of cancer. The range of possible treatment goals may include complete eradication of malignant disease (cure), prolonged survival and containment of cancer cell growth (control), or relief of symptoms associated with the disease (palliation) (Smeltzer and Bare, 2004).

3. Present a textual explanation or paradigm for it

The normal Cell Cycle Somatic cells proliferate by mitosis, a process that produces two identical progeny from one parental cell. Mitotic cells pass through an ordered series of states collectively termed the 'cell cycle. See Figure 2.

Figure 2. Cell cycle. The sequential phases of the cell cycle, G 1, S, G2, and M, are depicted, as well as the resting G 0 phase. Common regulatory points near the end of G1 and between G1 and G0 are shown by circles with arrows within.

This cycle has four sequential phases, labelled G 1, S, G2, and M, which are defined biochemically, morphologically, and on the basis of cellular DNA content. G1 and G2 phases were originally conceived as 'gaps' between the distinctive M and S phases of the cell cycle. G 1 is the period between M and S when cells are 2N, have finished one round of cell division, and have not yet initiated the next. G1 is the period of cell growth, and a certain increase in mass may be required before the cell can enter the next S phase. When conditions are unsuitable for cell proliferation, they arrest in G 1, and those that are already in S, G2, or M usually complete the round they have entered and arrest only when they reach G 1 again. A point in late G 1 called the 'restriction point' or 'R' has special significance and is the point past which cells become committed to enter S, even if mitogens are withdrawn. Cells may withdraw from the cell cycle and remain for prolonged periods in a metabolically active but non-proliferative state. These cells have 2N DNA content and are described as being in G 0. Terminally differentiated cells are examples of cells in G0. However, other cells reversibly enter G 0 and may be induced to return to G1 and begin cycling again under certain conditions (distinction between cells in G0 and prolonged G1, admittedly, may be difficult). EXAMPLE Hepatocytes are in G 0 unless partial hepatectomy or hepatotoxic insults induce them to proliferate to reconstitute functional liver mass. Resting, antigen-specific lymphocytes remain in G 0 until antigen and cytokine stimulation induces them to proliferate. S phase is the period of wholesale DNA synthesis during which the parental diploid cell with a '2N' complement of DNA replicates its entire genetic content and becomes a cell with 4N DNA content.

The durations of S, G2, and M tend to be relatively constant, in contrast to that of G 1 which can be highly variable depending on the cell type and is subject to regulation by environmental factors, such as the availability of mitogens and nutrients. G 2 is the period between S and M, when cells have finished replicating their DNA, have 4N DNA, and are preparing to divide. M phase or mitosis is the period of nuclear and cell division during which the duplicated DNA complement of the 4N parental cell is divided equally between the two progeny cells which are consequently 2N. M phase is morphologically obvious as the period during which chromosomes condense into their familiar, microscopically visible forms, the nuclear envelope breaks down, the chromosomes segregate into two identical sets, the nuclear envelopes reforms (which completes nuclear division or 'karyokinesis'), and the two progeny cells separate (which completes cell division or 'cytokinesis'). Adherence to the G1 S G2 M sequence during normal progression through the cell cycle means that a cell must duplicate its DNA before dividing and that it must divide before duplicating its DNA again. This insures a normal genetic complement in the progeny cells and maintains genetic constancy. The dependence of later events in the cell cycle upon normal completion of earlier events is insured by 'checkpoint' control mechanisms that prevent a cell that has not successfully completed one phase of the cycle from entering the next. Checkpoint activity is seen after cell exposure to DNA-damaging agents, such as ionizing radiation, and is manifest as delayed cell entry into S and M by inducing temporary arrest in G 1 or G2. This delay allows cells time either to repair its damaged DNA or, if the damage is irreparable, to execute a programme of self-destruction or apoptosis. According to Guyton( 2006) The major differences between the cancer cell and the normal cell are the following: (1) The cancer cell does not respect usual cellular growth limits; the reason for this is that these cells presumably do not require all the same growth factors that are necessary to cause growth of normal cells. (2) Cancer cells often are far less adhesive to one another than are normal cells. Therefore, they have a tendency to wander through the tissues, to enter the blood stream, and to be transported all through the body, where they form nidi for numerous new cancerous growths. (3) Some cancers also produce angiogenic factors that cause many new blood vessels to grow into the cancer, thus supplying the nutrients required for cancer growth. See Table 1 for further comparison between Normal and Cancer Cells. Table 1 Represents Detailed Comparison Between Cancer Cells and Normal Cells

Table 2 SUMMARY OF THE PHENOTYPIC CHANGES IN THE PROGRESSION OF NEOPLASIA. (CHANCER CHARACTERISTICS) ACCORDING TO GANONG (2007)  ,JSTRNHNSXYFGNQNY^  .RUFNWJI)3&WJUFNW  &GJWWFSYHJQQH^HQJHMJHPUTNSYHTSYWTQ  *SMFSHJIUWTQNKJWFYNTS  &ZYTSTRTZXLWT\YM  &GSTWRFQNYNJXTKHJQQH^HQJHTSYWTQ  *]FLLJWFYJIWJXUTSXJYTMTWRTSFQTWLWT\YMKFHYTWXYNRZQN  1FHPTKWJXUTSXJYTLWT\YMNSMNGNYTWXTWHJQQHTSYFHYNSMNGNYNTS  *[FXNTSTKNRRZSJX^XYJR  &SYNLJSRTIZQFYNTSFSIRFXPNSL  *QFGTWFYNTSTKNRRZSJWJXUTSXJFSYFLTSNXYNHRTQJHZQJX  .S[FXNTSTKYNXXZJFSIXYWTRF  &YYFHMRJSYYTJ]YWFHJQQZQFWRFYWN]  8JHWJYNTSTKUWTYJTQ^YNHJS_^RJX  7JHWZNYRJSYTKXYWTRFQHJQQXYTUWTIZHJUWTYJTQ^YNHJS_^RJX  1TXXTKHJQQHTMJXNTS  &GNQNY^YTLFNSFHHJXXYTFSIJLWJXXKWTRQ^RUMFYNHXFSIGQTTIXYWJFR  *SMFSHJIHJQQRTYNQNY^  7JHTLSNYNTSTKJSITYMJQNFQUWTYJNSXJVZJSHJX  (^YTXPJQJYFQRTINKNHFYNTSX  *XYFGQNXMRJSYTKRJYFXYFYNHKTHN  (JQQFIMJXNTSFSIFYYFHMRJSY  9NXXZJXUJHNKNHYWTUNXR  &GNQNY^ YT WJHWZNY [FXHZQFWN_FYNTS YT XZUUTWY LWT\YM TK UWNRFW^ TW RJYFXYFYNHYZRTW  )WZLWJXNXYFSHJ  &QYJWJIIWZLRJYFGTQNXRFSIIWZLNSFHYN[FYNTS  .SHWJFXJIX^SYMJXNXTKYFWLJYJIJS_^RJX  *SMFSHJIIWZLJKKQZ] 4. *SMFSHJI)3&IFRFLJWJUFNW

Why Do Cancer Cells Kill? Guytong (2006) stated that cancer tissue competes with normal tissues for nutrients why patients died of cancer. Because cancer cells continue to proliferate indefinitely, their number multiplying day by day, cancer cells soon demand essentially all the nutrition available to the body or to an essential part of the body. As a result, normal tissues gradually suffer nutritive death.

Cancer Development in Molecular Perspective

Normally, cells in a differentiated state are stimulated to enter the cell cycle from a quiescent state, or G0, or continue after completion of a prior cell division cycle in response to environmental cues including growth factor and hormonal signals. Cells progress through G1 and enter S-phase after passing through checkpoints, which are biochemically regulated transition points, to assure that the genome is ready for replication. The cyclin-dependent kinases (CDKs) are enzymes that critically regulate cell cycle progression from one phase to the next. One important checkpoint is mediated by the p53 tumorsuppressor gene product, acting through its upregulation of the p21WAF1 inhibitor of CDK function, acting on CDKs 4 or 6. These kinase molecules can also be inhibited by the p16INK4A and p27KIP1 CDK inhibitors, but in turn are activated by cyclins of the D family (which appear during G1) and the proper sequence of regulatory phosphorylations, See Figure 4. (Kasper , D. L. et al., 2005). Activated CDKs 4 or 6 phosphorylate, and thus inactivate, the product of the retinoblastoma susceptibility gene, pRb, which in its nonphosphorylated state complexes with transcription factors of the E2F family. Phosphorylated pRb releases E2Fs, which activate genes important in completing DNA replication during Sphase, progression through which is promoted by CDK2 acting in concert with cylins A and E. During G2, another checkpoint occurs, in which the cell assures the completion of correct DNA synthesis. Cells then progress into M-phase under the influence of CDK1 and cyclin B. Cells may then go on to a subsequent division cycle or enter into a quiescent, differentiated state (Kasper , D. L. et al. , 2005). Also shown in Fig. 3 are the sites of action of protooncogenes, regulators of cellular proliferation that, in an active state, promote cell growth, and whose deregulation produces oncogenes, originally discovered as the genes encoded by tumor-forming viruses in animals. Oncogenes can be divided into two families: (1) those that act in the cytoplasm to disrupt normal growth factor related signaling, including ras, raf, and the tyrosine kinases of the src and erbB or sis families; and (2) nuclear oncogenes, including jun, fos, myc, and myb, that act to alter transcriptional control of cassettes of genes. In contrast, tumorsuppressor genes, including p53 and pRb, act as cellular brakes (Kasper , D. L. et al. , 2005) 70 Principles of Cancer Treatment 469

Figure 3. The sites of action of protooncogenes, regulators of cellular proliferation that, in an active state, promote cell growth, and whose deregulation produces oncogenes, originally discovered as the genes encoded by tumorforming viruses in animals.

Figure 4. Proliferation of the Cancer Cell

Chemotherapy
A knowledge of cancer chemotherapy requires an appreciation of some general principles of tumour biology. Cancer results from the uninhibited growth of a single clone of cells. As cancer cells grow, they move through the cell cycle, characterized by several phases: resting (G0), pre-DNA synthesis (G1), DNA synthesis (S), post-DNA synthesis (G2), mitosis (M). Most chemotherapy drugs are active in the S phase of the cell cycle, although some directly block cells entering mitosis and most directly promote apoptosis (programmed cell death). RATINALE OF CHEMOTHERAPY IN CANCER TREATMENT 1. Foremost, chemotherapy is applied as primary therapy for the treatment of advanced-stage cancer. A few diseases, including leukaemias, lymphomas, and advanced-stage germ cell tumours are sensitive to multiple chemotherapy agents and can be cured with combination chemotherapy. More often, combinations of therapeutic agents are used to diminish tumour-related symptoms, improve the quality of life, and extend survival in patients with advanced-stage tumours. For example randomized clinical trials of chemotherapy versus best supportive care have demonstrated a survival advantage and quality of life improvement when patients with advancedstage lung cancer receive chemotherapy. 2. Second, chemotherapy can be used as neoadjuvant therapy, given prior to radiation or surgery for locally advanced disease. In this setting, the drugs are used to decrease the tumour mass, reduce the extent of the subsequent surgery or radiation, and to determine disease sensitivity to drugs. Clinical trials have identified a potential role for neoadjuvant therapy in the treatment of lung cancer, oesophageal cancer, and locally advanced breast cancer, among other diseases. In the case of osteosarcomas, neoadjuvant therapy can provide important information about tumour sensitivity, thereby permitting a more tailored approach to further management. 3. Finally, the drugs can be used as adjuvant therapy, administered after the completion of local definitive surgery and/or radiation therapy in order to decrease the risk of recurrence. For instance adjuvant chemotherapy reduces the risk of tumour recurrence and improves survival in nodepositive colon cancer and in breast cancer following surgical resection. In all of these settings, chemotherapy can be administered in conjunction with radiation therapy to optimize local effects of treatment.

Classes of chemotherapy agents Agents could be categorized (Refer to Fig. 5 and Figure 6) as: 1. cell cycle active, phasespecific (e.g., antimetabolites, purines, and pyrimidines in S-phase; vinca alkaloids in M), and 2. phase-nonspecific agents [e.g., alkylators, and antitumor antibiotics including the anthracyclines, dactinomycin (formerly actinomycin D), and mitomycin], which can injure DNA at any phase of the cell cycle but appear to then block in S-phase or G2 at a checkpoint in the cell cycle before cell division. Cells arrested at a checkpoint may repair DNA lesions. Checkpoints have been defined at the G1 to S transition, mediated by the tumor-suppressor gene p53 (giving rise to the characterization of p53 as a guardian of the genome ); at the G2 to M transition, mediated by the chk1 kinase and additional p53related pathways influencing the function of CDK1; and during M-phase, to ensure the integrity of the mitotic spindle (Kasper , D. L. et al. , 2005).

Cell Cycle

Cell Cycle Specific Agents

Antimetabolites Bleomycin Podophyllin Alkaloids Plant Alkaloids

Cell Cycle Non-Specific Agents

Alkylating Agents

Antibiotics Cisplatin Nitrosoureas

Figure 5. Cell Cycle Specific and Non-Specific Agents

Figure 6. Classification of Cytotoxic Drugs

The importance of the concept of checkpoints extends from the hypothesis that repair of chemotherapy-mediated damage can occur while cells are stopped at a checkpoint; therefore, manipulation of checkpoint function emerges as an important basis of affecting resistance to chemotherapeutic agents. See Figure 7, 8 and Cancer Resistance Figure 9.

Action sites of cytotoxic agents: Cell cycle level

Antibioti Anti etabolite

S (2-6h)

Vin a alkaloid

Mitoti inhibitor Taxoid

Alkylating agent

G1 (2-gh)
G0

Figure 7: Action Sites of Cytotoxic Agent at cell cycle level There are several distinct classes of chemotherapy agents . Because these drugs can have major sideeffects, only physicians knowledgeable in their dosing and side-effects should administer them. In order to reduce variability in exposure to drugs, doses of most chemotherapy agents are administered based on the patient's body surface area, a calculation determined by the patient's height and weight. In addition, doses of chemotherapy need to be adjusted for renal (methotrexate, bleomycin, fludarabine) and hepatic function (anthracyclines, vinca alkaloids, taxanes). Adequate intravenous access must be secured since many of the drugs are vesicants and extravasation can lead to tissue necrosis. Similarly, patients must be adequately hydrated prior to the administration of cisplatin and cyclophosphamide, to prevent renal toxicity and bladder toxicity, respectively. Careful attention must be given to fluid and electrolyte balance with the administration of many agents. Cisplatin renal toxicity can cause profound hypomagnesaemia. y Antimetabolites exert their cytotoxicity by serving as substrates in pathways vital to cellular function and replication. Many of these agents are incorporated into DNA or RNA or act on enzymes involved in the synthesis of nucleic acids. Methotrexate acts by inhibiting the enzyme dihydrofolate reductase, which maintains intracellular pools of reduced tetrahydrofolates required for the synthesis of purine nucleotides and thymidylate. 5-Fluorouricil is another commonly used antimetabolite. A metabolite of this drug, fluorodeoxyuridine monophospate inhibits thymidylate synthase, an enzyme required for the synthesis of deoxythymidine triphosphate and DNA. In addition, fluorodeoxyuridine triphosphate is incorporated into RNA, interfering with its function, and fluorodeoxyuridine triphosphate is incorporated into DNA, leading to strand breakage. A third important antimetabolite is cytarabine (ara-C) which is converted to cytarabine triphosphate (ara-CTP) in the cell. Cytarabine triphosphate is incorporated into DNA and serves as a chain terminator. A related deoxycytidine analogue, gemcitabine, has the additional actions of inhibiting the conversion of ribonucleotides to deoxyribonucleotides, which are DNA precursors. Prolonged exposure of tumour cells to some of the antimetabolites, such as 5-fluorouracil and cytosine arabinoside, through continuous intravenous infusion may be more effective than bolus injections alone.

M (0.5-2h)

G2 (2-32h)

Purine analogues also have important roles as antimetabolites; 6-mercaptopurinre (6-MP) and 6thioguanine (6-TG) are converted in the cell to monophosphates which inhibit the first step of purine synthesis. Moreover, the triphosphate nucleotides of 6-mercaptopurinre and 6-thioguanine are incorporated into DNA resulting in an increase in strand breaks. Another purine analogue is fludarabine phosphate, which serves as an adenosine analogue. Fludarabine is converted to 2-fluoro-ara-A in plasma and subsequently is phosphorylated intracellularly. The resulting triphosphate inhibits DNA polymerase and ribonucleotide reductase, interfering with DNA and RNA synthesis. Alkylating agents exert their cytotoxicity by binding to DNA and forming DNA adducts which alter DNA structure and function enough to disrupt DNA replication and transcription. They act throughout the cell cycle, but have their greatest activity on rapidly proliferating cells. These agents, including cyclophosphamide, nitrogen mustard, melphalan, busulfan, and chlorambucil were among the first chemotherapy drugs and remain important agents in cancer therapy, with particular activity in haematological malignancies and breast cancer. In a similar manner, the platinum derivatives bind to and cross-link DNA, leading to DNA breaks and apoptosis. The anthracyclines intercalate into DNA and disrupt DNA synthesis. The antitumour activity of doxorubicin and daunorubicin, the two most commonly used agents in this drug class, results in part from triggering of topoisomerase II dependent DNA breaks. Etoposide also inhibits topoisomerase II. In a similar way, other topoisomerase inhibitors interfere with topoisomerase I, which is critical in the repair of normal DNA; these agents include irinotecan and topotecan. Vinca alkaloids interfere with microtubule formation and disrupt cell division. In contrast, the taxanes stabilize microtubule assembly, also inhibiting mitosis. Along with the traditional cytotoxic agents, hormone-directed therapy can be critical in the regulation of tumours. The growth of many normal tissues and tumours is influenced by hormone exposure. Many breast cancers express receptors for oestrogen and progesterone and most prostate cancers have androgen receptors. Depriving these tumours of the hormonal stimulus can exert both cytocidal and cytostatic effects on the cell. Thus, more than 50 per cent of breast cancers expressing the oestrogen receptor will respond to treatment with tamoxifen, an antioestrogen. Similarly, the use of luteinizing hormone releasing hormone (LHRH) agonists (which reduce testosterone synthesis) or antiandrogens can have dramatic effects on prostate cancer growth.

Action sites of cytotoxic agents: Cellular level

DNA synthesis

Anti

lit s

D A

Al l ting agents

D A tr nscri ti n

D A duplic ti n
Mit sis

Intercalating agents pindle poisons

Figure 8 Cytotoxic Agent at Cellular Level

ONCOLOGY
Pri ciples
Drug resis a ce
EXTRACELLULAR INTRACELLULAR

chem herapy

PGP170

ATP

Drug

ATP

Drug
Plasma Membra e

Figure 9 This phosphoglycoprotein (P.G.P.) is responsible for multidrug resistance. It acts by rejecting the anticancer agent from the cell. Other mechanisms of resistance exist.

The Synopsis of Chemotherapeutic Drugs and the Mechanism of Action explained in Table 9-20

Detailed Action sites of cytotoxic agents during the course of cancer proliferation
PURINE SYNTHESIS
6-MERCAPTOPURINE

PYRIMIDINE SYNTHESIS

6-THIOGUANINE

RIBONUCLEOTIDES

METHOTREXATE

5-FLUOROURACIL
HYDROXYUREA

DEOXYRIBONUCLEOTIDES
LKYL TING GENTS
NTIBIOTICS

CYTARABINE

DNA

ETOPOSIDE

RNA

PROTEINS

VINC

LK LOIDS

ENZYMES

MICROTUBULES

T XOIDS

Figure 9 Detailed Mechanism of Action of the Cytotoxic Drugs.

Alternative Presentation of Specific chemotherapeutic agent during cellular proliferation and biosynthesis. (See Diagram Below Figure 9)

L- SP R GIN SE

4. SCIENTIFIC JOURNAL
1.

R
by Kathryn L. Schwertfeger, Wa Xian, Alan M. Kaplan, et al.

The tumor microenvironment, which includes inflammatory cells, vasculature, extracellular matrix, and fibroblasts, is a critical mediator of neoplastic progression and metastasis. Using an inducible transgenic mouse model of preneoplastic progression in the mammary gland, we discovered that activation of inducible fibroblast growth factor receptor-1 (iFGFR1) in the mammary epithelium rapidly increased the expression of several genes involved in the inflammatory response. Further analysis revealed that iFGFR1 activation induced recruitment of macrophages to the epithelium and continued association with the alveolar hyperplasias that developed following long-term activation. Studies using HC-11 mammary epithelial cells showed that iFGFR1-induced expression of the macrophage chemoattractant osteopontin was required for macrophage recruitment in vitro. Finally, conditional depletion of macrophages inhibited iFGFR1-mediated epithelial cell proliferation and lateral budding. These findings show that inflammatory cells, specifically macrophages, are critical for mediating early events in an inducible transgenic mouse model of preneoplastic progression. (Cancer Res 2006; 66(11): 5676-85)
Source
Cancer Res 2006;66:5676-5685. J , 2006.

http://cancerres.aacrjournals.org/content/66/11/5676.full.pdf+html, Retrieved June 6, 2011

2. Keeping Out the Bad Guys: Gateway to Cellular Target Therapy

Takanori Kitamura and Makoto M. Taketo

Abstract
Tumor-stromal interaction is implicated in many stages of tumor development, although it remains unclear how genetic lesions in tumor cells affect stromal cells. We have recently shown that inactivation of transforming growth factor-B family signaling within colon cancer epithelium increases chemokine CC chemokine ligand 9 (CCL9) and promotes recruitment of the matrixmet alloproteinase (MMP)-expressing stromal cells that carry CC chemokine receptor 1 (CCR1), the cognate receptor for CCL9. We have further shown that lack of CCR1 prevents the accumulation of MMP-expressing cells at the invasion front and suppresses tumor invasion. These results provide the possibility of a novel therapeutic strategy for advanced cancer prevention of the recruitment of MMPexpressing cells by chemokine receptor antagonist. [Cancer Res 2007;67(21):10099 102] Source
Cancer Res 2007;67:10099-10102. v 1, 2007.

http://cancerres.aacrjournals.org/content/67/21/10099.full.pdf+html Retrieved June 24, 2011

5. Please present a script or a scenario on how to explain this to the following context. a. Community or individual patient b. Students Prevention is better than as they say. But Cancer is inevitable. It has a double sword effect. You may not know you have it, since it has been imprinted in our genes, the oncogenes, the potential cancer precursor. That is why all living biological entity is a candidate of this monstrous disease and no one is 100% secure or free from getting out of it. I guess the best way to provide information to community, patients and students is through health teachings. Here are the most common health preventive measures that will somehow decrease the possibility of acquiring/developing cancer- the health promotion and prevention. Primary Prevention
The assessment or reduction of risk factors before the disease occurs:
y y y y y y y y

Make appropriate lifestyle changes. Stop smoking. Limit alcohol intake. Eat a healthy diet as outlined above. Be physically active: maintain a healthy weight and follow exercise guidelines outlined above. Avoid sun exposure, especially during the hours of 10 A.M. and 4 P.M. and cover exposed skin with sunscreen with a skin protection factor (SPF) of 15 or higher. Those at high risk for certain cancers should consider genetic counseling and testing. Chemoprevention. o Aspirin= low-dose aspirin may reduce risk of breast cancer and colon polyps. o Tamoxifen=can reduce the risk of breast cancer in women who are at high risk by nearly 50%. o Finasteride=reduces risk of prostate cancer. o COX-2 inhibitors= reduce risk of colorectal cancer in high-risk patients. o Calcium= may reduce risk of colorectal adenomas. o Beta carotene= may reduce risk of lung cancer in smokers.

Secondary Prevention

Screening and early detection to improve overall outcome and survival:

y

y y

Performing routine screening tests should be based on whether these tests are adequate to detect a potentially curable cancer in an otherwise asymptomatic person and are also cost effective. Although all major authorities recommend routine screening for certain types of cancer, each has a different opinion on when screening should begin and how often. Screening should be based on an individual's age, sex, family history of cancer, ethnic group or race, previous iatrogenic factors (prior radiation therapy or drugs such as DES), and history of exposure to environmental carcinogens. o Testicular cancer is the most common cancer between ages 20 and 34, the second most common from ages 35 to 39 and the third most common between ages 15 and 19. There is an increased risk in males with undescended testicles, gonadal dysgenesis, and Klinefelter's syndrome. There is also an increased risk in men with a family history of testicular cancer. Although not consistently found to confer a higher risk, infertility or abnormal semen parameters have been associated with a higher risk of testicular cancer in some studies. The American Urological Association (AUA) recommends annual screening beginning at age 15 with monthly testicular self examinations. o Prostate cancer occurs more commonly in men over age 60. With more widespread screening, younger men are being diagnosed in the early stages of the disease. The ACS and AUA recommend an annual prostate-specific antigen (PSA) and digital rectal examination for men over age 50. The AUA also recommends annual testing for men age 40 and over who are at high risk (black race, family history of prostate cancer). o Breast cancer is the most common type of cancer in women, and the incidence increases with age. The ACS recommends a clinical breast examination every 3 years from ages 20 to 39 and annually thereafter. Mammography should begin at age 40. o Colon cancer screening should begin for all men and women over age 50. Patients should be screened with yearly fecal occult blood test, or sigmoidoscopy every 5 years, or double contrast barium enema every 5 years, or colonoscopy every 10 years. o Lung cancer, although common in both men and women who have smoked, is not routinely screened for because there is no cost-effective method that would detect cancer early enough to make a difference in outcome.

References
1. Kasper , D. L. et al. (2005). Harrison s Principles of Internal Medicine 16th Edition. New York. McGraw Hill Companies, Inc. 2. Warrell D. A. et al. (2003). Oxford Textbook of Medicine. Volume I. 4th Edition. Oxford. Oxford Press, Inc. 3. Guyton A. C (2006), Textbook of Medical Physiology. 11th Edition. Pennsylvania. ElsevierSaunders, Inc. 4. Ahmed, N. et al. (2007). Biology of Disease. New York. Taylor and Francis Group 5. McPhee, Stephen J. & Ganong, William F. (2007). Pathophysiology of Disease: An Introduction to Clinical Medicine. 5th Edition. New York. McGraw-Hill 6. Nettina, Sandra M.; Mills, Elizabeth Jacqueline. (2006). Lippincott Manual of Nursing Practice, 8th Edition. Lippincott Williams & Wilkins

7. Ngelangel C. and Wang E. Cancer and the Philippine Cancer Control Program. Japanese Journal of Clinical Oncology Volume32, Issue suppl 1Pp. S52-S61.