Pharmacy Practice An Update on Ch e m o p reve n ti o n By Tammy Chernin, RPh

I N T R O D U C T I O N CHEMOPREVENTIVE AGENTS Cancer chemoprevention is an innovative area of p h a rmaceutical cancer re s e a rch that focuses on the pre v e n- Selective -Receptor Modulators tion of cancer through pharmacological, nutritional, or The SERMs are a relatively new promising class of endocrinologic intervention. The challenge rests in identi- agents. In November, 1998, following the impressive re s u l t s fying agents that are efficacious, but of low or no toxicity. of the first fully completed prospective, randomized Bre a s t M o re than 50 promising agents and agent combinations Cancer Prevention Trial (BCPT), tamoxifen re c e i v e d a re currently being clinically evaluated for chemopre v e n- a p p roval for the reduction of breast cancer incidence in tive activity against major cancer targ e t s . 1 Four classes of women at high risk.7 Tamoxifen citrate, which inhibits the p reventive agents have shown particular promise in clinical action of estrogen on breast tissue, improves disease-fre e trials and are considered priority substances for study by s u rvival among women who have estro g e n - receptor positive the National Cancer Institutes’ Prevention and Contro l b reast cancer and reduces the risk of contralateral bre a s t P rograms. These include selective estrogen receptor modu- c a n c e r.8 The BCPT re p o rted that tamoxifen reduced bre a s t lators (SERMS) and other hormonal agents, nonstero i d a l cancer risk by about 50% among women who had a high a n t i - i n f l a m m a t o ry drugs (NSAIDS), calcium compounds, risk of cancer because of age (older than 60 years) or a and retinoids (chemical cousins of vitamin A).2 combination of other risk factors. However, most breast occur in women who are not identified to be at CHEMOPREVENTION STRATEGIES i n c reased risk (see Table 3). In addition to increased rates Over the past decade, advances in understanding of endometrial cancers in the tamoxifen group, rates of c a rcinogenesis have made possible the identification of s t roke, pulmonary embolism, and deep-vein thro m b o s i s candidate chemoprevention agents that are being devel- w e re also elevated, which may limit its use for primary oped to hit key molecular targ e t s . 3 - 5 D rug development p revention of breast cancer.9 strategies involve modulation of the activities occurring at To have a substantial impact on breast cancer re d u c t i o n the cellular and tissue level of carcinogenesis that are in the whole population, a preventive agent needs to be safe characterized by mutagenesis and proliferation. The initia- and effective for long periods and to be acceptable for use tion and pro g ression of precancers to invasive disease has in women who have an average or low risk of breast cancer. been linked with many enzymes, genetic lesions, and other Raloxifene hydrochloride is a SERM, chemically distinct cellular constituents. Table 1 summarizes many of the f rom tamoxifen and , that binds to estrogen cellular chemopreventive mechanisms, molecular targ e t s receptors to competitively block estrogen-induced DNA for inhibiting these mechanisms, and corre s p o n d i n g transcription in the breast and endometrium. Raloxifene agents/agent classes currently being explored for chemo- was evaluated in the multicenter, randomized, double-blind p reventive eff i c a c y. Multiple Outcomes of Raloxifene Evaluation Trial (the An essential issue in the development of chemopre v e n- MORE trial) for prevention of fracture. Participants were tion agents is the role of markers, also called surrogate end- also monitored for the occurrence of breast cancer, a point biomarkers (SEBMs), intermediate markers, and s e c o n d a ry endpoint of the trial. Raloxifene reduced the risk sometimes even tumor markers.6 I n t e rmediate biomarkers of newly diagnosed invasive cancer by 76% during a of cancer are the phenotypic, genotypic, and molecular median of 40 months of treating postmenopausal women for changes that occur during carcinogenesis. Many are poten- o s t e o p o rosis. Women with osteoporosis have a lower risk of tially SEBMs for cancer incidence and understanding their b reast cancer, presumably because of lower endogenous i n t e rrelationship is very important to chemoprevention. e s t rogen levels, so the women who entered the MORE trial Agents judged to have potential as human chemopre- w e re not comparable to those entering BCPT. Raloxifene ventives are subjected to preclinical toxicity and did not increase the risk of endometrial cancer during the p h a rmacokinetic studies, and then phase I clinical safety first 3 years of the MORE trial treatment, but the total and pharmacokinetic trials. The most successful agents number of cases was small. Raloxifene, tamoxifen and then pro g ress to clinical chemoprevention trials (Table 2). e s t rogen increase the risk of venous thromboembolic disease to a similar degree. Reprinted with permission from O N E; 2 0 0 0 : 1 ( 4 ) 5 8 - 6 2 . Ms. Chernin is a consultant pharmacist for long-term care facilities affiliated with Clinical Research Services in Berkeley Heights, NJ, and for Abbott Consulting Services, in Suff e rn, NY. Volume 2 – Number 4 • April 2001 276 O N C O L O G Y S P E C T R U M S Pharmacy Practice

TABLE 1. MECHANISMS FOR CHEMOPREVENTION: POSSIBLE MOLECULAR TARGETS AND PROMISING AGENTS

M e c h a n i s m Possible molecular targ e t s R e p resentative agents

Antimutagenesis Inhibit carcinogen uptake Bile acids (bind) Calcium Inhibit formation/activation of carcinogen Cytochromes P450 (inhibit) PEITC, tea, indole-3-carbinol, soy isoflavones PG synthase hydroperoxidase NSAIDs, COX-2 inhibitors, lipoxygenase 5-lipooxygenase (inhibit) inhibitors, iNOS inhibitors, glucocorticoids Bile acids (inhibit) Ursodiol Deactivate/detoxify carcinogen GSH/GST (enhance) Oltipraz, NAC, sulforaphane Prevent carcinogen-DNA binding Cytochromes P450 (inhibit) Tea Increase level or fidelity of DNA repair Poly (ADP-ribosyl) transferase NAC, protease inhibitors (Bowman-Birk) (enhance)

Antiproliferation/antiprogression Modulate hormone/growth factor activity Estrogen receptor (antagonize) SERMs, soy isoflavones receptor ( antagonize) Bicalutamide, flutamide Steroid aromatase (inhibit) Exemestane, vorozole, arimidex Steroid 5a-reductase (inhibit) Finaseride, epristeride IGF-I (inhibit) SERMs, retinoids AP-1 (inhibit) Retinoids Peroxisome proliferator Retinoids, NSAIDs Activated receptor (activate) Inhibit oncogene activity Farnesyl protein transferase (inhibit) Perillyl alcohol, limonene, DHEA, FTI-276 Inhibit polyamine ODC activity (inhibit) DFMO ODC induction (inhibit) Retinoids, NSAIDs Induce terminal differentiation TGFβ (induce) Retinoids, vitamin D, SERMs Restore immune response COX (inhibit) NSAIDs, COX-2 inhibitors, tea, curcumin T, NK lymphocytes (enhance) Selenium, tea, NSAIDs, COX-2 inhibitors Langerhans cells (enhance) Vitamin E, NSAIDs, COX-2 inhibitors Increase intercellular communication Connexin 43 (enhance) Cartenoids (lycophene), retinoids Restore tumor suppressor function p53 (inhibit HPV E6 protein) — Induce apoptosis TGFβ (induce) Retinoids, SERMs, vitamin D RAS farnesylation (inhibit) Perillyl alcohol, limonene, DHEA, FTI-276 Arachidonic acid (enhance) Retinoic acid, NSAIDs, COX-2 inhibitors, lipoxygenase inhibitors Caspase (activate) Retinoids Guanosine monophosphate NSAIDs, sulindac, sulphone diesterase (inhibit) Inhibit angiogenesis FGF receptor (inhibit tyrosine kinase) Soy isoflavones, COX-2 inhibitors Thrombomodulin (inhibit) Retinoids Correct DNA methylation imbalances CpG island methylation (enhance) Folic acid Inhibit basement membrane degradation Type IV collagenase (inhibit) Protease inhibitors (Bowman-Birk) Inhibit DNA synthesis Glucose 6-phosphate dehydrogenase DHEA, fluasterone (inhibit)

Reprinted with permission from Kelloff, et al. Eur J Cancer. 1999.1 PEITC=phenethylisothiocyanate; PG=Prostaglandins; NSAIDs=nonsteroidal anti-inflammatory drugs; COX=cycloxygenase; iNOS=inducible nitric acid synthase; GSH=glutathione; GST=glutathione-s-transferase; NAC=N-acetyl-l-cysteine; SERMs=selective estrogen receptor modulators; IGF-I=insulin-like growth factor-1; AP- 1=(transcription) activator- p rotein-1; DHEA=dehydro e p i a n d rostenedione; ODC=ornithine decarboxylase; DFMO=2-difluro m e t h y l o rnithine; TGFβ=tumor growth fac- tor beta; NK=natural killer cells; HPV=human papilloma virus; FGF=fibroblast growth factor; CpG=cytosine-guanosine.

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Since metastatic breast cancers can develop re s i s t a n c e Hormonal Therapy to tamoxifen after long-term exposure it is important to A multicenter study of women at high risk of developing d e t e rmine the long-term effects of raloxifene and other b reast cancer is underway testing the effects of a combina- SERMs. The effectiveness of tamoxifen for prevention of tion of hormones administered as a nasal spray.1 0 The spray, p r i m a ry breast cancer beyond 5 years of treatment which contains deslorelin (a compound that inhibits is uncert a i n . p roduction of estrogen by the ovaries), estradiol (a type of The Study of Tamoxifen and Raloxifene (the STAR trial) e s t rogen), and testosterone, stops the ovaries from re l e a s i n g will randomize 22,000 postmenopausal women to tamoxifen eggs, as well as hormones. The spray induces horm o n a l vs raloxifene, without a placebo group, to compare the two changes similar to menopause, and may provide an altern a- agents in reducing the incidence of breast cancer in women tive to prophylactic mastectomy. “The goals of this study are who are at increased risk at developing the disease. to reduce breast density, reduce the risks of breast and Tamoxifen and raloxifene may be useful preventive thera- ovarian cancers, pre s e rve the re p roductive organs, and pies for women who have an increased risk of estro g e n i m p rove the quality of life for women who are at high risk re c e p t o r-positive breast cancer and vertebral fractures. The for developing breast cancer,” according to Jeff rey N. MORE trial is continuing to assess the effectiveness and Weitzel, MD, director of the Department of Clinical Cancer safety of long-term use of raloxifene. Genetics and the Cancer Screening and Pre v e n t i o n P rogram for the City of Hope Comprehensive Cancer Center TABLE 2. S U M M A RY OF PHASE II AND III in Duarte, California, one of the re s e a rchers working on the TRIALS DIRECTED AT 12 MAJOR s t u d y. “There is clear need for the development of safe and CANCER TA R G E T S e ffective chemoprevention options,” Dr. Weitzel added. “ C h e m o p revention studies are and will most likely Ta rg e t Agent continue to be an important part of breast cancer re s e a rc h Breast Fenretinide, DFMO in the future,” said Debbie Saslow, PhD, director of bre a s t Fenretinide with tamoxifen and exemestane and cervical cancer for the American Cancer Society. Prostate Antiandrogens Antiestrogens NSAIDs and Cox-2 Inhibitors Soy proteins In the United States the lifetime incidence of colore c t a l Fenretinide cancer is about 6%, and it is the second most common 1 1 Colon Ursodiol cause of cancer death. About 75% of patients diagnosed Calcium alone and with Vitamin D with colorectal cancer have no special risk factors for the DFMO alone and with sulindac disease with 15% to 20% having a family history. The Sulindac remainder suffer from here d i t a ry nonpolyposis colore c t a l Piroxicam Celecoxib cancer (3–8%), familial adenomatous polyposis (FA P ) ( 1 % ) , or ulcerative colitis (1%). Most colorectal cancers develop Head and neck 13-cis-retinoic acid with interferon f rom adenomatous polyps or adenomas. Over 5 to 10 years, and vitamin E 1 2 Fenretinide about 5% of adenomatous polyps become malignant. DFMO S u rg e ry and chemotherapy are not very effective for Curcumin advanced forms of colorectal cancer making the quest for Esophagus DFMO early detection and preventive measures very import a n t . Selective COX-2 inhibitor A c c o rding to a re p o rt in the August 1999 issue of Lung Fenretinide G a s t ro e n t e ro l g y, results of previous studies have suggested Oltipraz that NSAIDs reduce the risk of colorectal cancer and Anethole trithione indicated that this antineoplastic effect may be mediated Aerosolized budesonide (pilot study) t h rough cyclooxygenase inhibition.1 3 But the potential Bladder Fenretinide benefit of conventional NSAIDs in the prevention of col- DFMO o rectal cancer is offset by the risk of toxicity, part i c u l a r l y Selective COX-2 inhibitor NSAID-induced gastritis. Cervix DFMO Evidence suggests that NSAIDs reduce the risk of col- Retinoids o rectal cancer through the inhibition of cycloxygenase Skin DFMO (COX), the enzyme that catalyzes the rate-limiting step in Fenretinide the conversion of arachidonic acid to pro s t a g l a n d i n s . Selective COX-2 inhibitor Cyclooxygenase exists in two forms, COX-1 and COX-2. Topical tea polyphenols COX-1 is produced constitutively in tissues throughout the Oltipraz body including platelets, the gastric mucosa, and the kid- Multiple myeloma DHEA and Biaxin neys. The production of COX-2 is primarily induced at sites of inflammation.1 4 COX-2 has also been found in tissues 2 7 Adapted from National Cancer Institute. 1998 Annual Report . f rom colon, breast (H E R - 2 / n e u-positive), and head and Volume 2 – Number 4 • April 2001 278 O N C O L O G Y S P E C T R U M S Pharmacy Practice neck cancers. High levels have also been found in the blood with FAP will develop colon cancer by the age of 40 years vessels that supply tumors (see Table 4). unless some intervention is pro v i d e d . 1 9 In animals models of FA P, COX-2 inhibitors appeare d Patients with FAP need to continue to be monitore d m o re effective than traditional NSAIDs at preventing polyp a c c o rding to the usual guidelines, and surg e ry be per- f o rm a t i o n . 1 5 The results of a 6-month clinical trial evaluat- f o rmed when indicated. The approved dose of 400 mg bid is ing celecoxib, a selective COX-2 inhibitor, re p o rted an higher than for the other indications with celecoxib and 11.9% decrease in the rate of pre c a n c e rous polyps with should be taken with food to help increase absorption. 100 mg daily and a 28% decrease with 400 mg daily.1 6 Research programs for chemoprevention of colorectal Whether NSAIDs decrease the risk of colorectal cancer cancer are also in progress for rofecoxib, aspirin, and by inhibiting cyclooxygenase and inhibiting PG synthesis sulindac. A derivative of sulindac called exisulind is not entirely clear. Recent re s e a rch suggests that the appears to inhibit polyp formation without inhibiting induction of apoptosis (“programmed cell death”) is an COX-2 and has received a priority review by the FDA i m p o rtant component underlying the action of a number of for the treatment of colorectal adenomatous polyps in diverse chemopreventive agents including sulindac and patients with FAP. other NSAIDs. The efficacy and potential application of these agents in In August, 1999, the Food and Drug Administration the inhibition of colon carcinogenesis continues to be (FDA) granted GD Searle a 6-month priority review of studied and, most likely, more potent inhibitors will be celecoxib for the treatment of colorectal adenomatous designed based on the molecular stru c t u re of COX-2. And polyps in patients with FA P, and in December, 1999, accel- if COX-2 inhibition is shown to be related to the chemopre- erated approval was granted.1 7 , 1 8 Nearly 100% of patients ventive effects of NSAIDs it may suggest that inhibition of

TABLE 3. PERSONAL FACTORS INFLUENCING INCIDENCE OR RELATIVE RISK OF BREAST CANCER

F a c t o r C o n d i t i o n I n c i d e n c e Relative risk

Age-annual incidence by 5-year group 35–39 years 0.06% (female only) 40–44 years 0.12% 45–49 years 0.20% 50–54 years 0.25% 60–64 years 0.35% 65–69 years 0.41% 70–74 years 0.46% 75–79 years 0.48% 80–84 years 0.47% 85+ years 0.42% lifetime 12.0% Genetics (lifetime risk) BRCA1 or BRCA2 (+)(found in 1/800 women) 56-80% Number of primary relatives with 0 12% breast cancer (lifetime risk) 1 (dx>50 years) 12% 1 (dx<50 years) 13-21% 2 (dx>50 years) 11-24% 2 (dx <50 years) 25-48% Radiation to breast (lifetime risk) age <16 (for Hodgkin’s disease) 35% by age 40 Chest x-ray 12% Age of menarche <12 years 1.3 Age of menopause >55 years 1.5–2.0 <45 years 0.77 Age of first live birth 25–29 years 1.5 After 30 years 1.9 After 35 years 2.0–3.0 Nulliparous 1.4 –3.0 Breast Disease Nonproliferative cysts, fibrosis, fibroadenoma, etc. 1.0 Proliferative hyperplasia, papilloma 1.5–2.0 Atypia atypical Hyperplasia 4.0–5.0 Carcinoma in situ 6.9–12.0 Alcohol intake 3–9 drinks per week 1.3

Reprinted with permission from Adams. D r ug Store News.2 8

Volume 2 – Number 4 • April 2001 279 O N C O L O G Y S P E C T R U M S Pharmacy Practice this isoenzyme may be broadly effective in the chemo- as a biomarker for successful therapy with retinoic acid as p revention of colorectal cancer. a chemopre v e n t a t i v e . In Dr. Hong’s original study, “high-dose” 13 cis-re t i n o i c Retinoids acid was used but considerable toxicity was noted. In a Scientists are studying both natural and synthetic subsequent study, a lower dose was used and appro x i m a t e- retinoids alone and in combination with other compounds in ly 60% of patients with lesions of leukoplakia showed com- the prevention of cervical cancer, lung cancer, cancers of plete reversal of these lesions. Forty percent, however, are the head and neck, and skin cancer. de novo resistant to the retinoic acid derivative, and of the Waun Ki Hong, professor of medicine and chair of 60% who originally responded, approximately 50% go on the department of head and neck and thoracic medical to become resistant and redevelop leukoplakia. To oncology at the University of Texas M.D. Anderson Cancer o v e rcome primary resistance, Dr. Hong’s group developed Center in Houston, is a world-renowned expert in the use of a combination approach using retinoic acid, interf e ron, and retinoids as chemoprevention for development of malignan- vitamin E as a combined chemopreventative re g i m e n . cies in the aerodigestive tract. The main hypothesis Vitamin E is used for its ability to decrease the re t i n o i c underlying all of Dr. Hong’s work in this area has been that acid side effects and is believed to be chemopre v e n t a t i v e by understanding the early molecular events, which lead to in and of itself. Interf e ron was synergistic in reversing the induction of tumors in the aerodigestive tract, strategies p remalignant lesions when used with retinoic acid. In the can be designed to prevent malignant transform a t i o n . 31 patients evaluable on this trial, there was a disparity in Retinoic acid is known to be important in the control of response based on the site of leukoplakia. 50% of patients cellular proliferation in the epithelium.2 0 Six retinoic acid whose larynx tissue was primarily affected showed good receptor subtypes have been identified of which the beta- resolution of the premalignant lesions but only 1% with retinoic acid (RAR-beta) appears to be the key marker. In oral lesions showed any reversal. Dr. Hong’s group contin- n o rmal tissues, all six receptor subtypes are expre s s e d . ue to make strides in the prevention of second primary H o w e v e r, in patients with leukoplakia, a pre c a n c e ro u s , head and neck cancers and is currently conducting a very slowly developing change in the normal tissue of a mucus l a rge trial in which he is looking at 13-cis-retinoic acid as membrane, the beta-subtype is essentially not expressed in a chemopreventative in well over 1,000 patients treated for those lesions. Patients with oral leukoplakia have a high p r i m a ry head and neck cancers. The hope is that a better chance of developing malignancies in the area of the understanding of the salient molecular events will lead to leukoplakia. After 3 months of retinoic acid therapy, better chemopreventative strategies. D r. Hong’s clinical study re p o rted an upregulation of RAR-beta in these patients, which corresponded to re g re s- Calcium sion of the lesion. This suggests that RAR-beta can be used Calcium compound studies focus on colon cancer p revention mainly in individuals previously diagnosed with TABLE 4. S U M M A RY OF PHASE II AND III colon polyps or cancer. During a 4-year study period, 31% TRIALS DIRECTED AT 12 MAJOR of the individuals taking two 600 mg tablets of calcium each CANCER TA R G E T S day developed at least one polyp, compared with 38% of those taking the placebo.2 1 The calcium group also had L o c a t i o n C O X - 1 C O X - 2 fewer polyps per person than the placebo group. “If you can p revent polyps from forming, you can prevent the cancer, ” Chondrocyte X X said Gabriel Feldman, MD, director of colon and pro s t a t e X cancer for the American Cancer Society. The study authors, Platelets X led by J.A. Baron, MD, of Dartmouth-Hitchcock Medical Endothelial cells X Center in Lebanon, New Hampshire, recommend more re s e a rch be conducted to clarify risks and benefits of Renal medulla X calcium in various groups. Older men should be especially Renal cortex X cautious about taking calcium supplements to reduce their Brain X risk of colon cancer because of recent re s e a rch suggesting Synovial tissue X a diet high in calcium may increase the risk of prostate c a n c e r. More studies are underway involving a variety of Colorectal tumors X calcium compounds. Breast cancer X Lung X FUTURE RESEARCH Liver X Newer and future re s e a rch on chemopreventative agents will include pharmacodynamic modeling, which is the top- Spleen X ical application of a chemopreventive agent to target tissue Adapted from Hawkey CJ. Cox-2 inhibitors. L a n c e t 2 9; Cada DJ. Celecoxib. to avoid systemic metabolism and toxicity. The appro a c h 3 0 3 1 Hosp Pharm ; GD Searle and Co. Celecoxib package insert . has particular promise for the lung, but is applicable to Volume 2 – Number 4 • April 2001 280 O N C O L O G Y S P E C T R U M S Pharmacy Practice several target organs. Retinoids formulated and delivere d qualified for use in lower-risk populations. As we develop by this means could well improve efficacy without toxicity. m o re sophisticated evaluations to calculate those at risk a A recent example of pharmacodynamic modeling con- c l e a rer picture will develop defining subsets of the popula- f i rmed the chemopreventive potential of aero s o l i z e d tion most likely to benefit from drug interv e n t i o n . s t e ro i d s . 2 2 A pilot study, currently in pro g ress, is looking at the potential for locally-administered budesonide in CONCLUSION patients with pre c a n c e rous lesions in the bronchus. The past 2 decades have seen a tremendous increase in One strategy to improve efficacy and reduce toxicity is media coverage, publications (both trade and publication), agent combinations. In some combinations of two agents and educational programs on disease prevention, which are with diff e rent presumed mechanisms of activity, synerg i s t i c d i rected at the general population. A future challenge is or additive activity may be seen. For example, synerg i s t i c educating the population on the potential additional bene- activity has been observed in rat colon studies with combi- fits of active intervention, whether it is by prescribed dru g nations of alpha-difluoro m e t h y l o rnithine (DFMO; a specific or specific dietary substances. inhibitor of polyamine biosynthesis) and the NSAID The focus of chemoprevention re s e a rch in the next p i ro x i c a m 2 3 and in rat mammary and prostate cancers with millennium will include defining the functional and combinations of retinoids and antiestro g e n s . 2 4 - 2 6 Thus, the histological changes during carcinogenesis, the cancer risk identification and evaluations of potentially effective c o n f e rred by these changes, their modulation in pre c l i n i c a l agent combinations will be an ongoing re s e a rch eff o rt experimentation and randomized clinical trials by for chemopre v e n t i o n . c h e m o p reventive drugs, dietary agents and regimens and The Prostate Cancer Prevention Trial is designed to see t reatments resulting from early detection. The large number whether taking the drug finasteride (used to treat patients of chemoprevention re s e a r ch programs now ongoing with benign prostatic hyperplasia) can prevent prostate e n s u res that the promise of chemoprevention will continue cancer in men ages 55 and older. The drug reduces levels to be realized in the future. of dihydro t e s t o s t e rone (DHT), a male hormone that plays a key role in benign prostate enlargement and is also believed to be involved in the development of prostate cancer. The R E F E R E N C E S trial has completed re c ruitment of 18,500 men, and re s u l t s 1. K e l l o ff GJ, Sigman CC, Greenwald P. Cancer chemopre v e n t i o n : a re expected in 2001. p ro g ress and promise. Eur J Cancer. 1 9 9 9 ; 3 5 ( 1 3 ) : 1 7 5 5 - 1 7 6 2 . In addition, certain other chemopreventive compounds 2. National Cancer Institute. Highlights of NCI’s Prevention and Contro l a re under investigation. These include oltipraz (which can p rograms. Available at www. g r a y l a b . a c . u k : 8 0 / c a n c e rn e t / 6 0 0 0 4 5 . h t m l . change the way in which people respond to a cancer- Accessed Febru a ry 20, 2000. causing agent produced by a fungus that contaminated 3. K e l l o ff GJ, Hawk ET, Crowell JA, et al. Strategies for identification and clinical evalulation of promising chemopreventive agents. c e rtain foods), selenium, vitamin E, and N-acetylcysteine. Oncology (Huntington). 1 9 9 6 ; 1 0 : 1 4 7 1 - 1 4 8 4 . 4. K e l l o ff GJ, Hawk ET, Karp JE, et al. Pro g ress in clinical chemopre- PUBLIC HEALTH IMPACT vention. Semin Oncol. 1 9 9 7 ; 2 4 : 2 4 1 - 2 5 2 . P roof of chemopreventive drug efficacy based on cancer 5. Hong WK, Sporn MB. Recent advances in chemoprevention of can- incidence reduction can re q u i re up to 45,000 subjects over c e r. Science. 1997;278:1073-1077. a period of more than 10 years depending on the risk of the 6. Meyskens FL. Principles of human chemoprevention. Hematol Oncol population under study. The impracticality of conducting Clin North Am. 1 9 9 8 ; 1 2 ( 5 ) : 9 3 5 - 9 4 1 . such large human intervention trials, due partly to high dol- 7. Fisher B, Costantino JP, Wi c k e rham DL, et al. Tamoxifen for lar cost and the scarcity of eligible and willing patients, p revention of breast cancer: re p o rt of the National Surg i c a l emphasizes the importance of more accurately pre d i c t i n g Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. an individual’s risk and identifying surrogate endpoint bio- 1 9 9 8 ; 9 0 ( 1 8 ) : 1 3 7 1 - 1 3 8 8 . 8. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene markers. A challenge for the future is to define this pro c e s s on risk of breast cancer in postmenopausal women: results from the which will potentially reduce the size and duration of some MORE randomized trial. JAMA. 1 9 9 9 ; 2 8 1 ( 2 3 ) : 2 1 8 9 - 2 1 9 7 . cancer incidence trials to as few as 500 to 1,000 patients 9. Cobleigh M. Breast cancer prevention: raloxifene’s role still being over a period of 3 years. Besides reducing the cancer studied. American Society of Clinical Oncology 35th Annual Meeting b u rden, it is hypothesized that chemoprevention dru g s May 18,1999. Available at www. m e d s c a p e . c o m / m e d s c a p e / c n o / 1 9 9 9 / could improve the quality of life for some high-risk patients A S C O / S t o ry. c f m ? / s t o ry_id=663. Accessed Febru a ry 21, 2000 who may otherwise undergo invasive screening pro c e d u re s 10. American Cancer Society. Hormonal chemoprevention for or surgical treatments. women at high risk. 1999. Available at http://www2.cancer. o rg / Safety evaluation in humans is perf o rmed incre m e n t a l l y e z i n e C F M L / d s p _ s t o r y I n d e x . c f m ? f n = / 0 0 2 _ 0 5 2 7 1 9 9 9 _ 0 . h t m l . and often begins in individuals at high risk, and thus at Accessed Febru a ry 21, 2000. g reater potential for benefit. As these drugs are found to be 11. PDQ Screening and Prevention—Health Professionals. Prevention of colorectal cancer. Available at http://cancern e t . n c i . n i h . g o v / e fficacious for these high-risk patients, the public health c l i n p d q / S c re e n i n g _ f o r _ c o l o rectal_cancer_Physician.html. Accessed impact of chemopreventive drug intervention will also F e b ru a ry 22, 2000. develop incrementally since they will be justifiably Volume 2 – Number 4 • April 2001 281 O N C O L O G Y S P E C T R U M S Pharmacy Practice

12. Midgley R, Kerr D. Colorectal cancer. L a n c e t . 1 9 9 9 ; 3 5 3 : 3 9 1 - 3 9 9 . 23. Reddy BS, Nayini J, Tokumo K, et al. Chemoprevention of colon 13. S i n i c rope FA, Lemoine M, Xi L, et al. Reduced expression of cycloxy- c a rcinogenesis by concurrent administration of piroxicam, a nons- genase 2 proteins in here d i t a ry nonpolyposis colorectal cancers re l a- t e roi dal anti-inflammatory drug with D,L-a-difluoro m e t h y l o rn i t h i n e , tive to sporadic cancers. G a s t ro e n t e ro l o g y. 1 9 9 9 ; 1 1 7 ( 2 ) : 3 5 0 - 3 5 8 . an ornithine decarboxylase inhibitor, in diet. Cancer Res. 14. F rolich JC. A classification of NSAIDs according to the relative 1 9 9 0 ; 5 0 : 2 5 6 2 - 2 5 6 8 . inhibition of cyclooxygenase isoenzymes. Trends Pharmacol Sci. 24. Anzano MA, Byers SW, Smith JM, et al. Prevention of breast cancer 1 9 9 7 ; 1 8 : 3 0 - 3 4 . in the rat with 9-cis-retinoic acid as a single agent and in combination 15. Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part II). with tamoxifen. Cancer Res. 1 9 9 4 ; 5 4 : 4 6 1 4 - 4 6 1 7 . J Natl Cancer Inst. 1 9 9 8 ; 9 0 : 1 6 0 9 - 1 6 2 0 . 25. Anzano MA, Peer CW, Smith JM, et al. Chemoprevention of mammary 16. Burton TM. Monsanto’s Celebrex may treat cancer. Wall Street c a rcinogenesis in the rat: combined use of raloxifene and 9-cis-re t i n o i c Journal. September 24, 1999:B3. acid. J Natl Cancer Inst. 1 9 9 0 ; 8 8 : 1 2 3 - 1 2 5 . 17. GD Searle. Celebrex to get priority review for colorectal polyps. 26. Lucia MS, Anzano MA, Slayter MV, et al. Chemopreventive activity P ress release. August 31, 1999. of tamoxifen, N-(4-hydro x y p h e n y l ) retinamide, and the vitamin D 18. Anon. Celebrex data requested by FDA may clarify cancer risk re d u c- analogue Ro24-5531 for andro g e n - p romoted carcinomas of the rat tion potential. F-D-C Reports- “The Pink Sheet” January 3, 2000. seminal vesicle and prostate. Cancer Res. 1 9 9 5 ; 5 5 : 5 6 2 1 - 5 6 2 7 . 19. King J, Dozois R, Lindor N, et al. Care of patients and their families 27. National Cancer Institute. 1998 Annual Report: Cancer Pre v e n t i o n with familial adenomatous polyposis. Mayo Clin Pro c . 2 0 0 0 ; 7 5 : 5 7 - 6 7 . R e s e a rch Program. Available at http://dcp.nci.nih/gov/CB/AR98.htm. 20. H e rman TS. Understanding molecular events and better chemopre- Accessed Febru a ry 21, 2000. ventative strategies for the next millennium. American Society for 28. Adams V. Breast cancer prevention with tamoxifen. Drug Store News. Therapeutic Radiology and Oncology’s 41st Annual Meeting. Available at http://secure . 1 f . c o m / d rug/ce/99_5_lesson.htm. Accessed November 2, 1999. Accessed at http://oncology. m e d s c a p e . c o m / F e b ru a ry 29, 2000. M e d s c a p e / C N O / 1 9 9 9 / A S T R O / S t o r y. c f m ? s t o r y_id=864. Accessed 29. Hawkey CJ. Cox-2 inhibitors. L a n c e t . 1 9 9 9 ; 3 5 3 : 3 0 7 - 3 1 4 . F e b ru a ry 18, 2000. 30. Cada DJ. Celecoxib. Hosp Pharm . 1 9 9 9 ; 3 4 : 5 6 0 - 5 7 6 . 21. American Cancer Society. Protective Powers of Calcium Supplements. 31. GD Searle and Co. Celecoxib package insert. Chicago, IL, May 1999. Available at http://www2.cancer. o rg / e z i n e C F M L / d s p _ s t o ry I n d e x . cfm?fn=002_03011999_0.html. Accessed Febru a ry 24,2000. 22. Wa t t e n b e rg LW, Wiedmann TS, Estensen RD, et al. Chemopre v e n t i o n of pulmonary carcinogenesis by aerosolized budesonide in female A/J mice. Cancer Res. 1 9 9 7 ; 5 7 : 5 4 8 9 - 5 4 9 2 .

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