Chemopreventive Drug Development: Perspectives and Progress

Vol. 3, 85-98, January/February 1994 Cancer Epidemiology, Biomarkers & Prevention 85

Review

Gary J. Kelloff,1 Charles W. Boone, James A. Crowell, many cancers. While prevention ofexposune and changes in Vernon E. Steele, Ronald Lubet, and Caroline C. Sigman diet may someday alter incidence, chemical intervention Chemoprevention Investigational Studies Branch, Division of Cancer offers an attractive approach with potential for more imme- Prevention and Control, National Cancer Institute, Bethesda, Maryland diate results. The NCI’s2 chernoprevention drug develop- [G.J.K., C.W.B., ).A.C., yES., R.L.[; and CCS Associates, ment program, which has been described previously (1-3), Palo Alto, California EC.C.S.[ has as a goal the identification of safe and effective chemical agents for the prevention of human cancers. This program is an applied drug development science effort with clinical Abstract trials as the endpoint. It begins with the identification of Chemoprevention drug development has the goal of candidate agents for development and the characterization identifying safe and effedive chemopreventive agents for of these candidates for efficacy using in vitro and animal clinical use. Several distinctive strategies are pursued in screens. Promising agents are then further tested in animal developing chemopreventive agents: (a) identifying models to evaluate the design of regimens for clinical testing and validating predysplastic and early dysplastic lesions and use. Agents judged to have potential as human cherno- that can be used instead of cancers as endpoints for preventives are subjected, as appropriate, to preclinical tox- measuring chemopreventive adivity; (b) identifying and icity and phanmacokinetic studies. The most successful testing candidate agents based on considerations of agents then progress to clinical trials. The purpose of this mechanisms of adion; (c) evaluating combinations of article is to discuss the strategies, perspectives, and progress agents with potential for maximizing efficacy and of chemoprevention drug development, often using ex- minimizing toxicity; and (d) applying a systematic amples from the NCI program. As evidence of progress, the methodology for identifying and ranking candidate status and rationale for development of agents that currently agents at each stage of development to ensure discovery appear to be most promising (Table 1 ) are reviewed. of the best agents and most effedive use of available resources. This article discusses 22 drugs and three drug Strategies for Chemopreventive Drug Development combinations which have reached an advanced stage of Epithelial Lesions that Are Targets for Chemopreventive development as chemopreventive agents. The first Agents. The rational design and development of chernopre- generation of drugs are the most advanced, now being ventive agents requires a clear understanding of the epithe- in Phase II and Phase Ill clinical trials. These drugs hal lesions that are targets for the action ofthese agents. Fig. include several retinoids [vitamin A, 1 3-cis-retinoic acid, i diagrams the early development of epithelial neoplasia. A all-trans-N-(4-hydroxyphenyl)retinamidel, calcium, major target epithelial lesion is that of histologically visible j3-carotene, tamoxifen, and finasteride. The second neoplasia very early in its development, long before it in- generation drugs are those in Phase I clinical trials. From vades across the basement membrane. This “intraepithelial most to least advanced, these drugs are neoplasia,” as it is called at this stage, begins as a mono- 2-difluoromethylornithine, sulindac, piroxicam, oltipraz, clonal focus near the basement membrane and expands up- N-acetyl-I-cysteine, aspirin, ibuprofen, carbenoxolone, wand and laterally. When it finally becomes invasive across 1 83-glycyrrhetinic acid, and the combination of the basement membrane, it is at this point termed “cancer.” 2-difluoromethylornithine with piroxicam. The third Prior to invasion, the morphological changes of intnaepi- generation includes agents with significant evidence of thelial neoplasia are collectively termed “dysplasia.” It is the chemopreventive activity in animal models. These agents consensus of pathologists that carcinoma in situ and severe are now in preclinical toxicity testing. They are dysplasia form an indistinguishable continuum (4). The S-allyl-I-cysteine, phenhexyl isothiocyanate, curcumin, other major target lesion for chernopreventive agents may be ellagic acid, fumaric acid, fluasterone, and the termed “predysplasia,” which is the stage of neoplastic de- combinations of all-trans-N-(4-hydroxyphenyl)retinamide velopment after initiating DNA mutational changes have oc- with oltipraz and all-trans-N-(4-hydroxyphenyl) cunned but before the onset ofdysplasia, when the tissues still retinamide with tamoxifen.

Introduction As the understanding ofthe process ofcancer increases, pre- 2 The abbreviations used are: NCI, National Cancer Institute; AFB,, aflatoxin ventive intervention is becoming scientifically practical for B,; B(a)P, benzo(a)-pyrene; DFMO, 2-difluoromethylomnithine; 1)HEA, dehydroepiandrosterone; DMBA, 7, 1 2-dimethylhenz)a)anthracene; DMH, 1 ,2-dimethylhydrazine; G6PDH, glucose-6-phosphate dehydmogenase; GSH, glutathione; 4-HPR, all-trans-N-)4-hydroxyphenyl)retinamkle; MN U, N-methyl-N’-nitrosourea; MTD, maximum tolerated dose; NNK, 4-)methyl- Received 4/5/93; revised 7/6/93; accepted 7/i 6/93. nitrosamino)-i -)3-pyridyl)-1 -butanone; NOEL, no observed eftect level; I To whom requests for reprints should be addressed, at Chemoprevention NSAID, nonsteroidal anti inflammatory drug; ODC, omnithine dcc amboxylasc’; Investigational Drug Unit, National Cancer Institute, Executive Plaza North, PAH, polycyclic aromatic hydrocarbon; TPA, 1 2-O-tetradecanoylphorbol- Suite 201, 9000 Rockville Pike, Bethesda, Maryland 20892. 1 3-acetate.

Table 1 Cancer chemopr eventive age nts unde r development have (e.g., the netinoids) confounds the discovery ofthe most important mechanisms. Nevertheless, the known phanma- Preclinical Clinical trials cological properties of the agents being evaluated and the toxicology Phase I Phase II Phase III experimental testing data on various classes of agents pro- vide very useful insights into mechanism that may lead to the First generation Retinoids development of more effective chemopreventive drugs. In

Vitamin A” b (3)c + (2) some cases, the pharmacological activity of a compound 13-cis-metinoic acid” + + (2) + (2) suggests very specifically the target tissues and cancers 4-HPR” + + + + against which a chemopreventive drug may be active. For + + (3) + (2) Calcium example, an antiestrogen such as tamoxifen would be de- n-Carotene + + (6) + veloped for use against estrogen-sensitive cancers such as Tamoxifen” + + + Finastenide” + + those of the breast. In other cases, the testing of classes of compounds known to have a very general chemopreventive Second generation” activity may lead to the discovery oftissue specificities, such DFMO + + +(2) as those of antiinflammatonies in colon and bladder. Sulindac” + + (2) Table 2 presents a working classification of the che- Pinoxicam + + mopreventive agents listed in Table 1 arranged according to Oltipnaz + + structure or pharmacological effects associated with che- N-acetyl-l-cysteine + + Aspirin + + mopreventive activity. Note that many ofthe agents fall into Ibuprofen + + monethan oneclass. Moreover, the Iistofclasses is undoubt- Carbenoxolone + + edly incomplete. 18f3-Glycymrhetinic Acid + + In Table 2, the specific chemopreventive activities and DFMO + Pinoxicam + + structures are grouped into three general classes. The firstis inhibitors of cellular proliferation (antiprolifematives), mani- Third generation” S-Allyl-l-cysteine + + fested in such specific mechanisms as ODC inhibition, pro- Phenhexyl Isothiocyanate + tein kinase C inhibition, and antiestrogenic activity. Anti- Curcumin + proliferatives i nclude netinoids, polyphenols, anti hormones, Ellagic acid + calcium, DFMO, and the DHEA analogue, fluastenone. A Fumanic acid + second general class is carcinogen blocking agents. Block- Fluasterone + ing is often produced by enhancing the carcinogen- 4-HPR + Oltipraz + detoxifying enzymes, especially the Phase II metabolic en- 4-HPR + Tamoxifen + zymes, including GSH S-tnansferases, which perform a Previous development by the pharmaceutical industry. conjugation and other reactions. Wattenbeng and Talalay b Testing is completed or in progress. (6-8) have emphasized the desirability of selecting chemo- ‘ For Phase II and III studies, numbers in parentheses, number of trials. (I Second- and third-generation agents are listed in order from most to least preventive agents which induce mostly Phase II metabolic advanced in development. enzymes as opposed to compounds which induce both Phase I mixed function oxidases and Phase II enzymes. In- duction of mixed function oxidases carries the potential of activating procancinogens. appear rnorphologically normal. The natural history of in- A third general class of inhibitors is antioxidants, tnaepithelial neoplasia in the major human epithelia, with such as S-allyl-/-cysteine, curcumin, N-acetyl-i-cysteine, implications for chernopreventive strategy, has been me- NSAIDs, and polyphenols. These agents trap electrophilic cently reviewed (5). The field of chemoprevention rests on sites on activated carcinogens, scavenge oxygen-free radi- the fundamental concept that the progression of neoplasia cals and organic free radicals, and terminate lipid penoxi- will be much easier to slow on eliminate with chemopre- dation. These activities may be either a direct on indirect ventive agents at the predysplastic and dysplastic stages of effect of the antioxidant agent. Examples of agents with in- neoplastic development than with chemothenapeutic agents direct antioxidant effects are those that enhance the Phase at the postinvasive, cancer stage of neoplastic development. II metabolizing enzymes, thereby elevating electrophile The scientific basis for this concept is the progression of cells trapping potential via increased GSH production and induc- from a normal homogeneous state to more and more het- tion ofthe enzyme GSH peroxidase. The antioxidant mecha- emogeneity as cancinogenesis evolves. Therefore, more cells nism is reputed to be both antimutagenic (9) and antipro- can be affected by treatment in early stages of cancinogenesis lifenative (10). when they are more homogeneous than in later hetenog- Combinations of Agents. At least two factors limit the po- eneous stages. An important element of chemopreventive tential usefulness of chemopreventives in the clinic. One is drug development is the identification and validation of that cancers are not reduced to zero by administration of markers for predysplasia and dysplasia that can serve as end- these agents. The second is toxicity. Several very promising points for chemopreventive activity. agents are toxic at efficacious doses. The simultaneous or General Mechanisms of Chemopreventive Adivity. An- sequential administration of multiple inhibitors can increase other important aspect in the development of chemopre- the efficacy of chemopreventive agents and reduce toxicity. ventive agents is the mechanism(s) by which they inhibit Such an approach uses differences in the mechanisms of cancers. As is evident in the discussions of individual agents cancer inhibition among the agents to increase the inhibitory below, the knowledge of mechanisms of chemopreven- activity. Further, the increased efficacy achieves desirable tion is fan from complete, and the multiple possible levels ofcancen inhibition at lower and presumably less toxic chemoprevention-assoc iated activities that any agent may doses of the individual agents.

NEOPLASIA lntraepithelial Neoplasia Invasive = Pneinvasive neoplasia Neoplasia = Precancer = Cancer = Pnemalignant Normal = Malignant

Yc:7z9

Normal I Mild Moderate Severe DYSPLASIA

Fig. 1. Development of Epithelial Neoplasia. In estimating the severity of intraepithelial neoplasia (dysplasia), the extent of the lesion as well as the deviation from normal cellular morphology is used. Adapted from Boone ef al. (5), with permission.

Positiveeffects have been demonstrated in animal mod- fying those agents for preclinical toxicity and Phase I clinical els using combinations oftwo chernopreventive agents. 5ev- trials. At each stage, criteria are applied to set priorities for eral of the combinations have shown synergism; i.e., the the agents. In most cases, these priorities are based on four inhibitory potency ofthe combinations of agents was greater factors: efficacy; toxicity; commercial availability; and pos- than the sum ofthe potencies ofthe single agents. Synergistic sible mechanisms of action. chemopreventive activity has been reported for DFMO and Efficacy is judged by previous animal studies, in vitro piroxicam in rat colon (1 1 , i 2) and for 4-HPR and tamoxifen results (e.g., inhibition of cell transformation and antirnuta- in rat mammary (1 3, 1 4). In other studies (data not shown), genesis), epidemiology studies, and anecdotal reports in hu- synergistic activity has been observed in hamster lung for mans. Toxicity is determined by formal toxicology studies in j3-canotene with 4-HPR and with vitamin A and for 4-HPR animals, case reports in humans, and, when available, pre- with oltipnaz. Likewise, combinations of DFMO with 4-H PR vious clinical experience. The commercial availability of and with oltipnaz and 4-HPR with oltipraz have synergistic large amounts of agents at reasonable cost is an important activity in the bladder. Three ofthese cornbinations-DFMO factor. Cost is generally related to ease of synthesis on iso- and piroxicarn, 4-HPR and oltipraz, and 4-HPR and lation, the amount of agent manufactured for other corn- tamoxifen-are currently undergoing toxicology testing in rnercial uses, and the interest of the manufacturer in pro- the NCI chernopreventive drug development program. moting the development of the agent as a cancer These three combinations are proceeding because of the chernopreventive. Possible mechanisms of action may be promise they and their single agent components have against used to lower the ranking of a candidate when other agents cancers in colon and bladder, lung and bladder, and breast, with the same mechanism of action and range of chemo- respectively. The other combinations, which include either preventive activity are already under development, or to f3-canotene on vitamin A, are scheduled for further testing by promote a candidate agent that is desirable because it has the NCI in the coming year. multiple mechanisms by which it may produce its chemo- Prioritization of Newer Chemopreventive Agents. Because preventive effect. of the many compounds under consideration for develop- Other factors that may be considered, particularly for ment, a systematic methodology for identifying and ranking agents ready for toxicology and Phase I clinical trials, are candidate chemopneventive agents is essential to find the pharmacokinetics, the availability ofappropniate dosage for- best agents and to make the best use of available resources. mulations, and regulatory status for clinical use (e.g., a can- In the NCI program, this activity ranges from selecting can- didateagentthatalneadywas approved bythe U.S. Food and didates for initial testing in efficacy screens, as well as those Drug Administration for human use would likely be ranked most appropriate for further efficacy evaluation, to identi- higher than one without such approval).

noids, which demonstrate chemopreventive activity in Table 2 Working pharmacological and chemical structural classification of promising chemopreventive agents mammary glands, bladder, and skin (reviewed in Refs. iS

Antiprol iferatives and 1 6). Several epidemiology studies have examined the Retinoids/carotenoids relationship between blood levels of vitamin A and cancer fl-carotene, 4-HPR, 1 3-cis-retinoic acid, vitamin A risk (e.g., Refs. 1 7-22). Retinoids are active in the prolifena- tion and progression stages of cancinogenesis (23). Retinoids Antihormones inhibit several activities involved in tumor promotion, in- Finastenide, tamoxifen cluding induction of ODC; they probably participate in sig-

Anti inflammatonies nal transduction via cellular receptors. They induce terminal Aspirin, carbenoxolone, curcumin, 1 8f3-glycyrrhetinic acid, differentiation in selected cells, and this activity may be me- ihuprofen, piroxicam, sulindac diated by binding to receptors. They stimulate intercellular communication and are immunostirnulants. Unfortunately, G6PDH inhibitors there is also significant potential toxicity associated with reti- Fluasterone noids. For example, vitamin A and many of its analogues

ODC inhibitors accumulate in liven and cause hepatic damage; they also can Aspirin, carbenoxolone, curcumin, DFMO, 1 8f3-glycynrhetinic cause eye damage, and they are teratogens (24). Although acid, 4-HPR, ibuprofen, N-acetyl-l-cysteine, piroxicam, the toxicity of certain of the efficacious synthetic netinoids 1 3-cis-retinoic acid, sulindac, vitamin A such as 4-HPR appears to be less severe than that of vitamin A, there is still concern. Because of this potential toxicity, Protein kinase C inhibitors clinical trials of the synthetic netinoids have been limited Carbenoxolone, 1 8)3-glycyrrhetinic acid, 4-HPR, tamoxifen to patients with previous cancers and those at high risk for Other cancer. Calcium The rationale for the development of -canotene as a chernopneventive agent is based on case-control epiderni- Blocking agents ology data from lung cancer patients (2i , 25-33), a chemical Phase II metabolic enzyme inducers structure indicating ability to scavengefree radicals, and bio- S-allyl-l-cysteine, N-acetyl-l-cysteine, oltipraz, phenhexyl isothiocyanate conversion to vitamin A. Unlike the retinoids, there is little concern about toxicity; however, there are only scattered Polyphenols animal efficacy results. Several clinical trials of n-carotene Ellagic acid are ongoing which include well subjects at increased risk for cancer (e.g., chronic smokers) as well as patients with pre- Other cancerous lesions (e.g., colon polyps). Curcumin, fluasterone These clinical trials are not yet completed, except that Antioxidants/electrophile scavengers there has been one negative result from a randomized trial Anti inflammatories of -canotene in skin cancer (34). Although this outcome See under “Antiproliferatives”) appears to be conclusive, the dosage used may have been Antioxidants too low to be effective in skin. Encouraging results have been n-carotene, curcumin, ellagic acid, fumaric acid, N-acetyl- obtained from a preliminary trial of 3-carotene in patients l-cysteine Phase II metabolic enzyme inducers with oral leukoplakia, which is associated with increased See under “Blocking agents”) risk of oral cancer and, particularly in the presence of dys- Thiols plasia, is considered a premalignant lesion (35, 36). Of 24 S-allyl-l-cysteine, N-acetyl-l-cysteine, oltipraz patients treated with 30 rng f3-canotene/day, 1 7 showed signs of lesion regression within 3 months (35). Meanwhile, the activity of -canotene in animal efficacy experiments is pro- viding insight for interpreting the clinical data. One difficulty Status of Chemopreventive Agents Currently Under with obtaining reliable results in animal efficacy studies has Development been poor absorption of dietary -canotene in rodents (see, Table 1 presents the 22 drugs and three drug combinations for example, Ref. 37). Recently, chernopreventive efficacy that currently have reached an advanced level of develop- has been observed in studies with injectable forms of ment as chemopreventives. Based on the status of their de- -canotene where adequate blood levels of the agent have velopment, the chemopreventive drugs in Table 1 are been obtained. For example, injectable 3-canotene inhibited grouped into three generations. Chemopreventive agents in the induction of mammary carcinoma induced in rats by the first generation are well documented clinically or epi- MNU (data not shown). Also, this form of the agent proved demiologically and are now in Phase II on Phase Ill clinical to be efficacious against carcinogen-induced lung tumors trials. Second-generation drugs are those which have dem- when administered in combination with vitamin A, oltipraz, onstrated chemopreventive efficacy in animal studies, have on DFMO; under the conditions of these experiments, none been through toxicological testing in rats and dogs, and are of the agents was effective when administered alone (38). now in Phase I clinical trials. Third-generation agents are Prominent among ongoing clinical trials of first gen- those which have demonstrated chernopreventive efficacy eration drugs is the six-center CARET study, which is testing in animal studies and are now undergoing toxicology the chemopreventive effect of a combination of 25,000 in- testing. tennational units vitamin A and 30 rng f3-carotene/day in First-Generation Agents. Several fi nst-genenation agents al- preventing lung cancer in heavy smokers and workers ex- ready have progressed significantly as chemopreventive posed to asbestos (39). Trials of 1 3-cis-netinoic acid in pne- agents; these are the retinoids, f3-canotene, and calcium. ventingonal leukoplakia (36, 40, 4i), second primaries of the Many animal efficacy studies have been completed on reti- upper aerodigestive tract (42), and bronchial dysplasia in

Table 3 NCI chemopr evention dn ug development pr ogram: chemoprev entive e fficacy in animal models (sec ond- and third-generati on agents)”

Hamster Colon Rat mammary Agent ----- Mouse bladder Mouse skin Lung Trachea Mouse Rat DMBA MNU

DFMO ,b - + + + -c Piroxicam + + + + Oltipraz + + + + + + + + N-acetyl-/-cysteine + + + +

Aspirin + - Ibuprofen + +

Carbenoxolone + - +

-Glycyrnhetinic acid - + - + + Curcumin + +

Ellagic acid - + - - + Fumanic acid + + Fluasterone + + a Agents listed in order from most to least advanced in development. b . Chemopreventive activity observed; significant at P < 0.05; -, no significant chemopreventive activity observed.

chronic smokers (43) are underway. Positive results have mouse (68) urinary bladder, and rat mammary gland (68- been obtained in studies of oral leukoplakia (36, 40) and in 72). Previous clinical trials of DFMO involving cancer pa- prevention of second primary head and neck tumors (42). tients established a p.o. MTD for DFMO of 9-1 2 g/rn2/day 4-HPR is now being tested for chemopreventive effect on (approximately 230-300 mg/kg body weight/day) (73, 74). cancer in the opposite breast of patients who have under- The dose-limiting side effects observed included diarrhea, gone mastectomy for breast cancer (24). anemia, leukopenia, thnombocytopenia, and loss of hearing Phase II clinical trials of calcium in preventing adeno- acuity. Chronic (1 -year) p.o. toxicity studies in rats and dogs matous polyps of the colon are in progress. The chemopre- found NOELs at 400 mg/kg body weight/day and <50 mg/kg ventive potential of calcium was first shown by its protective bw/day (the lowest dosage tested), respectively. A recently effectagainstpmoliferation in thecolon ofpatients at high risk completed Phase I cancer prevention clinical trials showed for cancer (44-46). Calcium has shown chemopreventive drug effect with no toxicity, particularly otoxicity, in patients activity at the cellular level (44, 45, 47, 48), in animals (49- treated with a low dose level of 500 mgjm2/day (i 3 mg/kg Si), and clinically (48). A total dose of 2000 mg elemental body weight/day) for 1 0-1 2 months (75), suggesting that this calcium/day has been proposed to be the likely efficacious dose level is appropriate as a starting pointfonfurthen clinical and highest nontoxic dose that can be recommended cur- studies. Additional animal studies are characterizing the nently (48). otoxicity. Tamoxifen is a well known antiestrogen used in the Four of the second generation chemopreventive agents adjuvant therapy of breast cancer (52). This clinical use mi- are NSAIDs, sulindac, pinoxicarn, aspirin, and ibuprofen. A tially was based on its efficacy in causing the regression of prominent biological activity of the NSAIDs is inhibition of carcinogen-induced mammary tumors in rats, as well as its the synthesis of prostaglandmns and other eicosanoids, par- ability to prevent new tumors in the same animals (53, 54). ticulanly inhibition of fatty acid cyclooxygenase (e.g., Refs. Recently a Phase III trial of tamoxifen for the prevention of 76-78). Epiderniological and experimental data strongly breast cancer began (55). Finastemide is an inhibitor of tes- suggest that carcinogenesis in epithelial tissues may be tostenone 5a-reductase. Interest in it as a potential cherno- modulated by inhibiting some aspects of the prostaglandmn preventive agent arose because of its efficacy in treatment of prolifenativedisease in prostate, benign prostatic hypenplasia biosynthetic cascade (e.g., Refs. 76, 77, 79, 80). The mechanism(s) may involve reductions not only in growth- (56). A Phase III trial offinastemideforthe prevention of prostate cancer has recently begun. promoting tissue prostaglandmn levels but also in suppressed immune surveillance (8i , 82) and in oxidation (activation) Second- and Third-Generation Agents. For second- and of proximate carcinogens (80, 83, 84). third-generation agents, much evidence establishing their In animal studies, NSAIDs have chernopreventive ac- efficacy as chemopreventive agents has come from preclinical efficacy studies. Table 3 shows the efficacy of some of tivity in numerous tissues. They reduce formation of both these agents in the animal models of carcinogenesis that are colon polyps and carcinomas in laboratory animals given part of the NCI chemopreventive drug development screen- carcinogens (1 1 , 66, 85-95). They also inhibit the induction ing process. The models have been described in detail pre- of tumors in rat urinary bladder (96, 97), hamster buccal viously (i , 3, 57). The chemopreventive activities and ma- pouch (98, 99), rat mammary gland (100-i03), mouse skin tionale for developing these agents is summarized below. (104-108) and duodenum (88), and hamster esophagus DFMO alkylates and irreversibly blocks ODC, prevent- (1 09), pancreas (1 1 0), and uterine cervix (i i 1). ing conversion ofomnithine to putnescine. This is the first and In animal efficacy screens carried out under the NCI nate-limiting step in polyamine synthesis, which is closely chemopreventive drug development program (Table 3), the linked to cell proliferation (58-60). ODC is believed to be NSAIDs were active in the rat colon (aspirin, ibuprofen, important in tumor promotion (61 , 62), and its inhibition piroxicarn), mat mammary (pinoxicam), mouse bladder (ibu- thus may be a mechanism for inhibiting carcinogenesis. profen, piroxicarn), and mouse skin (piroxicam). Sulindac DFMO has chemopmeventive activity in mouse skin (61 , 63, has not been tested in the NCI screens but has demonstrated 64), mouse colon (65), rat colon (1 1 , 1 2, 66), rat (67) and efficacy against DMH-induced colon tumors in mice (95). In

preliminary clinical studies, sulindac has also shown dna- administration (124). In chronic (i-year) toxicity studies in matic effects in causing the total on almost total regression rats and dogs carried out under the NCI drug development of colonectal adenornatous polyps in patients with familial program, NOELs were established at 1 0 and 1 5 mg/kg body adenomatous polyposis and Gardner’s syndrome (1 1 2, weight, respectively, with minimal toxic effects present at 60 1 1 3). In one of these studies, regression was seen in 9 pa- mg/kg body weight (the highest dosage tested). Observation tients with familial adenornatous polyposis in less than 4 of schistosomiasis patients in clinical trials also indicated months of treatment (1 i 3). A recent major epiderniological that oltipnaz is tolerated on p.o. administration (1 25, 1 26). study also suggests that NSAIDs have promise in the clinic Despite these encouraging results, much work remains to be as chemopreventives. Regular aspirin use (1 6 times/month done to determine the appropriate chronic clinical dosage or more often) has been reported to reduce the relative risk regimen for chemoprevention studies. The agent has shown of death from colon cancer by 40% (79). For clinical use as significant toxicity in certain clinical settings. For example, chemopreventives, the goal is to identify dosages/regimens acute administration at high doses (up to 2 g) in schistoso- which are efficacious in cyclooxygenase inhibition and non- miasis therapy was discontinued due to delayed side effects, toxic with respect to the gastrointestinal upset, ulcers, and especially phototoxicity (1 27). In a 6-month Phase I clinical nephropathy which limit NSAID usage in other applications. trial at 125 and 250 mg/day, side effects included photo- Oltipraz is a synthetic dithiolthione related to naturally sensitivity, heat intolerance, gastrointestinal discomfort, occurring i ,2-dithiolthiones found in crucifenous veg- neurological abnormalities, and an altered taste; the lower etables. It is a schistosomicidal drug that has demonstrated dose was considered to be in excess of the MTD (128). chernopreventive efficacy in many animal model systems. In animal screens cited in Table 3, N-acetyl-!-cysteine Oltipnaz inhibited the induction offonestornach and pulmo- had chemopneventive activity in the hamster trachea, nat co- nary tumors in mice by B(a)P, N,N’-diethylnitrosamine and Ion, nat mammary, and mouse bladder models. Published uracil mustard (i 1 4). It also protected against AFB-induced studies indicate that N-acetyl-/-cysteine prevented urethane- liver cancer (1 1 5), azasenine-induced pancreatic cancer,3 induced lung tumors in mice (1 29) and DMH-induced colon and spontaneous hernatopoietic tumors (i 1 3) in rats. As tumors in rats (1 30). Like oltipraz, N-acetyl-/-cysteine stirnu- shown in Table 3, oltipnaz has been highly effective in ani- lates intracellular production of GSH and activity of GSH mal screens carried out under the NCI chemopreventive S-transfenases; it is readily deacetylated to form cysteine in drug development program; positive results have been seen the body, which enhances GSH synthesis (1 31). These ac- in hamster lung and trachea, mouse and mat colon, rat marn- tivities may be the basis of its chemopreventive potential. mary, mouse bladder, and mouse skin. The activity against Toxicity is considered low and the drug has been marketed azoxymethane-induced colon cancer in rats has been me- for years as a mucolytic agent (Mucomyst) and for treatment ported in the literature (1 1 7). of acetaminophen poisoning. Chronic toxicity studies in rats Although the mechanism ofthis activity is not fully un- and dogs at dosages up to i g/kg body weight/day and 300 denstood, the anticancinogenic potential of oltipraz was first mg/kg body weight/day, respectively, did not show any sig- suggested by its chernoprotective, radioprotective, and an- nificant toxicities (1 32). Phase I cancer prevention trials are tirnutagenic properties. Anshen eta!. (1 1 8) demonstrated that currently planned for 1 .6 g/m2/day, possibly escalating to oltipraz protected against hepatotoxicity in mice induced by 6.4 g/m2/day (on 42 to 1 69 mg/kg body weight/day). acetarninophen and carbon tetnachlonide. The agent also in- 18f3-Glycynnhetinic acid is found in licorice root and hibited AFB1-induced hepatotoxicity and DNA adduct for- has antimnflarnrnatory effects by mechanisms that appear to mation in rat liven (1 i 9). Oltipraz administered p.o. in- differ from the NSAIDs. It has been used at concentrations creases liven GSH levels and induces enzymes involved in up to 2% in ointments for the treatment of various skin dis- electrophile detoxification, i.e., GSH S-tnansferases, epoxide eases (1 33). Canbenoxolone is the succinic acid ester of 1 8f3- hydnolase, and NAD(P)H:quinone oxidoneductase (i i 8- glycynnhetinic acid and is also a potent antiinflamrnatory; it i 20). GSH is present in high concentrations in most cells, is used in the treatment of peptic ulcers. It appears to act where it functions to inactivate electrophilic carcinogens locally on the stomach, possibly by stimulating the produc- and scavenge oxygen-free radicals. It also reacts with hy- tion of protective mucus (1 33). drogen peroxide catalyzed by glutathione peroxidase and Both 1 8f3-glycynrhetinic acid and its saponin parent, prevents the formation of other more reactive oxygen corn- glycynrhizin, have shown chemopreventive activity in van- pounds (1 21 ). The chernopreventive and chemoprotective ous animal models. Glycymrhizin inhibited the development efficacy of oltipnaz in liver has been attributed to these ac- of liven tumors in mice and rats (reviewed by Nishino in Ref. tivities (1 i 5, i 1 8, i 22). There also is some evidence that i 34) and 1 8-glycyrrhetinic acid inhibited tumor promotion oltipraz may have antipnolifemative effects that may on may in mouse skin (134, 135). In studies cited in Table 3, i8j3- not be directly related to modulation of GSH and the Phase glycymnhetinic acid exhibited chemopneventive efficacy in II metabolic enzymes. For example, in efficacy studies in mat the mouse colon, mouse skin, and rat mammary models. colon (i 23) and mammary cited in Table 3, the agent was Carbenoxolone was efficacious in the mat mammary model. effective even when it was administered only after treatment The mechanism of chernopneventive activity of these agents with the carcinogen had been completed. is not well understood, but is believed to be related to their Besides the wide spectrum of its efficacy, oltipnaz is an antiinflammatory potential, as evidenced by the inhibition interesting candidate for further development as a cancer by 1 83-glycynrhetinic acid of the inflammation associated chemopreventive agent because of its apparent low toxicity. with tumor promotion in mouse skin (1 34). 1 83- Early studies of acute and subacute toxicity of oltipnaz in Glycyrnhetinic acid also inhibits numerous other biological animals demonstrated that the drug is well tolerated on p.o. activities associated with tumor promotion, especially those mediated by signal transduction via protein kinase C [me- viewed by Nishino (134)]. Although Phase I clinical trials with 1 8-glycymrhetinic i B. D. Roebuck, unpublished results (116). acid are still underway and those for carbenoxolone are still

in the planning stages, previous studies with canbenoxolone are therefore of high interest. Arylalkyl isothiocyanates, and indicate that these two agents will be well tolerated in a phenhexyl isothiocyanate in particular, may be such agents chemoprevention dosage regimen. As an antiulcen and an- in the lung. A series of anylalkyl isothiocyanates with alkyl tiinflammatory agent, canbenoxolone has undergone exten- chains ranging from two (phenethyl isothiocyanate) to six sive clinical testing at doses up to 300 mg/day (i 36). At doses (phenhexyl isothiocyanate) carbons inhibited lung tumors above 1 00 mg/day, severe side effects have been observed, induced in mice by the tobacco-specific carcinogen NNK consisting mainly of diastolic hypertension, edema, and hy- (1 52, 1 53). In these studies, the length of the alkyl chain in pokalemia. Although these side effects were still present at the isothiocyanates proved to be an important determinant 1 00 mg/day, they were seen in only a few percent of patients. of the potency of chemopreventive activity. Chernopreven- Therefore, it appears that 1 00 mg/day would be the MTD for tive efficacy increased as the alkyl chain was elongated. carbenoxolone in the context of cancer chemoprevention. Thus, phenhexyl isothiocyanate, the most potent of the This dosage is still much higher than the estimated chemo- agents tested, was SO-i 00 times more potent than phenethyl preventive dose in humans. The dose for humans equivalent isothiocyanate (1 54, 1 56). Although the reasons for this to the chernopreventive dose in the rat mammary model, structure-activity relationship have not been elucidated, in- calculated on the basis of relative surface area, is only 10 creased lipophilicity and stability have been suggested mg/day. For 1 8(3-glycyrrhetinic acid, our chronic toxicity (157). studies in rats and dogs established NOELs in the rat at 1000 The available evidence indicates that a primary mecha- mg/kg body weight/day and in the dog at 300 mg/kg body nism of the inhibition of NNK cancinogenesis by arylalkyl weight/day. Phase I clinical trials are evaluating doses up to isothiocyanates is prevention of NNK-DNA adduct fonma- 500 mg/rn2/day (approximately 1 3 mg/kg body weight/day). tion (i57). Preliminary results of toxicology testing in rats S-Allyl-/-cysteine is a water soluble onganosulfun corn- indicate low toxicity. Anticipated toxicities include minor pound found in garlic. For many years, there has been a high weight loss and fatty changes in the liven, as seen in F344 mats level of interest in the potential chernopreventive effects of fed phenethyl isothiocyanate at doses of 3 or 6 pmol/g (ap- garlic, onion, and their components. Studies of these corn- proximately 490 on 980 mg/kg) diet for 1 3 weeks (i 53, 1 58). pounds have been reviewed recently (1 37). Epiderniological Curcurnin is the major yellow pigment in turmeric and studies have shown inverse correlations between gastric curry and is obtained from the rhizome ofthe plant Curcuma cancer incidence and consumption of vegetables in the A!- !onga. It is of high interest both because of its potential for !ium genus (1 38, 1 39). Garlic oil has shown chernopreven- chernopreventive activity and its apparent low toxicity; i.e., tive activity in mouse skin (1 40) and cervix (1 41 ), and several it is already a common dietary component. In animal cancer of its volatile, lipophilic components (particularly, diallyl screens cited in Table 3, curcumin had chernopreventive sulfide) have shown chemopreventive activity in mouse co- activity in mouse colon and MNU rat mammary models. In Ion and stomach (142-144). Diallyl sulfide also inhibited other studies, the agent had tumor inhibitory activity in the skin cancer induced in mice by DMBA (1 45), esophageal two-stage DMBATFPA mouse skin model (1 59-1 61 ) and in cancer induced in rats by N-nitrosobenzylmethylamine the induction of skin tumors by B(a)P (1 62). (146), glandular stomach cancer induced in mats by Curcumin may have chemopreventive activity via mul- N-rnethyl-N’-nitrosoguanidine (1 47). In an NCI-sponsoned tiple mechanisms. It is a potent antiinflamrnatory agent study in hamsters, diallyl disulfide strongly inhibited the in- (162-165). It inhibited arachidonic acid metabolism in duction of tracheal tumors in hamsters by MNU (data not CD-i mouse skin by blocking both the lipoxygenase and shown). cyclooxygenase pathways (1 62, 1 66). There is also evidence The volatility and pungency of the lipophilic garlic that it inhibits phospholipase A2 (162). Cuncumin exhibits compounds make them difficult to test and unpalatable. strong antioxidant activity (167, 168), being an effective These disadvantages have led recently to interest in the water scavenger of supenoxide radicals (i69). On topical appli- soluble, less aromatic components such as S-allyl-!-cystemne. cation, cuncurnin inhibited TPA-induced DNA synthesis in On p.o. administration the compound inhibited DMH- mouse skin as measured by tnitiated thymidmne incorpona- induced colon tumors in female C57BL mice (i48). tion, demonstrating the inhibitory effect of cuncumin on pro- The mechanism of action of the garlic sulfur corn- lifemation (1 60). It also may inhibit the metabolic activation pounds is not well understood but appears to be related to and DNA binding of PAH carcinogens (1 62, 1 70, i 71 ). As electrophile detoxification. Like oltipraz and N-acetyl-!- noted above, cuncurnin is not expected to exhibit much tox- cysteine, S-allyl-!-cysteine (1 48) and other garlic sulfur corn- icity in humans. Toxic effects ofchmonic exposure in humans pounds (143) enhance the activity of GSH S-tnansferases. have not been characterized apart from respiratory symp- Also, diallyl sulfide and, probably, other garlic sulfides in- torns and allergic dermatitis in spice factory workers (1 72). hibit cytochnome P45OIIE1 which is involved in metabolic Ulcerogenic effects have been reported in rats (1 73). In our activation of carcinogens such as DMH and N-methyl-N’- acutetoxicity study in rats,curcurnin was nottoxic; i.e., 50% nitnosoguanidine (137, 149). Preclinical acute and sub- lethal dose >3.5 g/kg body weight, the highest dose that chronic (90-day) toxicity evaluations of S-allyl-!-cysteine in reasonably could be administered p.o. An acute toxicity rats and dogs are currently underway. Human toxicity of the study in dogs and subchronic (90-day) toxicity evaluations agent has not been characterized but is anticipated to be very in mats and dogs are currently underway. low. Ellagic acid represents the naturally occurring polyphe- Several arylalkyl isothiocyanates have been shown to nols which have recently received much attention as po- inhibit mammary, forestomach, and lung tumors induced by tential chemopreventives (e.g., Refs. i 74-i 81 ). Besides el- PAHs and nitmosamines in mats and mice (1 50-i 54). Tobacco lagic acid, this class of agents includes the green tea smoking is a significant risk for several major human cancers catechins and various flavonoids. Ellagic acid itself is found including those in the lung, other sites in the upper aemo- in a number offnuits and vegetables, including grapes, straw- digestive tract, and bladder (e.g., Ref. 1 55). Chemopreven- berries, raspberries, and nuts (1 82). Conney et a!. (i 83) first tive agents that potentially can counter the effects of smoking demonstrated its potential chernopreventive activity by its

inhibition of the mutagenicity of PAHs. In animal studies it be noted that the high dose tolerance might be related to has shown chemopreventive activity againsttumors induced poor absorption from the gastrointestinal tract (cited in Ref. by PAHs in mouse skin on topical administration (184-188) 205). Additional preclinical acute and subchronic toxicity and in mouse lung on i.p. administration (1 84, 1 87, 1 88). It evaluations are scheduled in rats and dogs. also inhibited nitnosarnine-induced esophageal papillomas Schwartz eta!. (206-21 6), as well as other investigators, on p.o. administration (189). In animal screens cited in Table have demonstrated the chemopreventive activity of the an- 3, ellagic acid reduced tumor multiplicity in rat colon and drogen DHEA in numerous animal models. DHEA is a potent carcinoma incidence in mouse bladder when fed in the diet. inhibitor of G6PDH. The primary function ofthis enzyme is The chemopreventive activity of ellagic acid may be catalysis of the formation of extnamitochondnial NAD(P)H related generally to its antioxidant potential, but it also ap- and nibose 5-phosphate. Schwartz has hypothesized two pears to be related specifically to its ability to prevent meta- ways in which inhibition of G6PDH may mediate the che- bolic activation of carcinogens and binding ofthe activated mopneventive activity of DHEA (21 6). First, DHEA inhibits carcinogens to DNA. For PAHs, its chemopreventive activity the activity of carcinogens such as B(a)P, AFB1 , and DMBA has been attributed to inhibition of mixed function oxidases which require metabolic activation via mixed function oxi- involved in activating the carcinogens and to binding to the dases (21 6-21 9). Mixed function oxidases require NAD(P)H activated form ofthe carcinogens (1 90). For nitrosarnine can- as a cofacton. Thus, since inhibition of G6PDH reduces the cinogens, its activity has been attributed to site-specific bind- formation of NAD(P)H, it consequently reduces the activity ing to DNA, thereby preventing reaction of the carcinogens of mixed function oxidases and the activation of certain can- with DNA (i9i). As is likely the case for all polyphenols, cinogens. Secondly, DHEA also inhibits tumor promotion chernopreventive activity of ellagic acid at sites other than and proliferative activity induced by TPA (210, 220). Cell colon may be limited by its poor absorption on p.o. admin- proliferation requires NAD(P)H-dependent DNA synthesis, istnation (i 90, 1 92). Uses in cancer prevention might require and DNA synthesis in mouse epidermis and mammary tissue formulations facilitating absorption (i 93). Oral toxicity stud- also is inhibited by DHEA (221). Accordingly, reduction of ies have not been completed; however, in chernoprevention the NAD(P)H pool by inhibition of G6PDH could inhibit studies cited in Table 3, no significant toxicity was seen at carcinogen-induced cell proliferation. dose levels up to 6 g/kg diet/day. Ellagic acid is known to be Unfortunately, the chernopreventive potential of DHEA pharmacologically active by other routes of administration. is compromised by some undesirable pharmacological ef- For example, at low iv. dosages (0.22 mg/kg body weight) fects: potent hormonal (222), liver-enlarging (223), and to human cancer patients, ellagic acid activated the intrinsic pemoxisome-prolifenating activities (223, 224). To eliminate blood coagulation system (194). these side effects while preserving chemopreventive activity, Fumanic acid has good potential for further develop- Schwartz designed several analogues (2i6, 223, 225). One ment because of its lack of toxicity, as well as its chemo- of these analogues, fluasterone (1 6a-fluomo-DHEA; DHEA preventive activity. It is a metabolic intermediate in mam- analogue 8354) is particularly promising and is being de- malian tissues (citric acid and urea cycles) and is a generally veloped in the NCI chemopreventive drug program. Flu- recognized as safe substance used commercially in food and asterone does not have the androgenic or liver toxicity of beverages as an antioxidant, acidulant, flavoring agent, feed DHEA (223). It was a more potent inhibitor of tumor initia- additive, and cure accelerator (i9S, 196). The chernopre- tion and promotion in the DMBAIIPA mouse skin model than DHEA (220), and, in animal studies cited in Table 3, it ventive efficacy of furnanic acid was shown first by Kuroda was effective in the rat mammary gland against MNU- and associates. They identified fumanic acid as the component of the herb Capsella bursa-pastoris responsible for its induced cancers (226) and in rat colon against azoxymethane-induced tumors (1 2). antipnolifenative and antimnflammatory properties by which Subchmonic studies in rats (up to 1 g/kg body weight/ the herb inhibited the growth oftmansplanted tumors in mice (1 97) and gastric ulcers in rats (1 98). It also reduced the liver day) and dogs (up to 250 mg/kg body weight/day) have es- toxicity of the carcinogens mitomycin C and AFB1 (1 99). In tablished a NOEL of 250 mg/kg body weight for fluasterone in both species; no target organs with histopathology were a series of studies, they showed that fumanic acid had che- identified in either study. Effects seen at the high doses tested mopreventive activity in mouse fonestornach (200), rat liven included dose-related weight loss (>10% at 1 g/kg body (201 , 202), and mouse lung (200). Subsequently, the agent weight/day) and hypocholesterolemia (at 500 mg/kg body demonstrated chernopreventive effects in studies in MNU hamster trachea and MNU rat mammary models (see weight/day and 1 g/kg body weight/day) in the male mats. The Table 3). relevance of these effects to the potential of fluastemone for clinical use has not yet been evaluated. Particularly, the The mechanism of the chemopreventive action of fumanic acid has not been elucidated, but may be related to minimal effective doses of fluasterone have not been determined. Phanmacokinetic evaluations are currently under- its antioxidative potential. On the basis of the studies cited way and chronic toxicity studies are planned. Like some of above, fumanic acid appears to be active in later stages of cancinogenesis. For example, in the studies in mouse fore- the other compounds discussed, fluastenone may require for- stomach, rat liven, and mouse lung cited above, it was active mulations designed to augment bioavailability. when given after treatment with the carcinogen was corn- pleted. Also, in the mat mammary study cited in Table 3, Future Diredions furnanic acid significantly increased tumor latency but did The progress that has been made to date indicates that che- not decrease tumor incidence on multiplicity. moprevention research will soon begin to yield practical From studies reported in the literature, fumanic acid ap- applications for the reduction of cancer incidence. None- pears to have little toxicity (1 96, 203-205). In 6-week dose theless, the time and resources required to carry out a full tolerance studies preparatory to the chernoprevention clinical evaluation of a chernopreventive agent in a cancer screens cited in Table 3, no toxicity was observed at the incidence reduction study is of great concern. As stated doses tested, which ranged from 0.4 to 20 g/kg diet. It should above, the success of chemoprevention rests on the ability

to limit the progression of neoplasms before they become and mutagenesis: the role of DNA base damage. Mol. Carcinogen, 3: frank cancers. To address this goal, as well as the concern 188-197, 1990. for time and resources, the role of Phase II clinical studies has 10. Kensler, T. W., and Taffe, B. G. Free radicals in tumor promotion. Free Rad. Biol. Med., 2: 347, 1986. been expanding to evaluate markers in predysplastic and 1 1 . Reddy, B. S., Nayini, J., Tokumo, K., Rigotty, )., Zang, E., and Kelloff, C. dysplastic tissue as endpoints for evaluation of chernopre- Chemoprevention of colon carcinogenesis by concurrent administration of ventive agents. Studies in patients with dysplastic lesions- piroxicam, a nonsteroidal antiinflammatory drug with ut-a- cervical dysplasia, oral leukoplakia, superficial bladder can- difluoromethylornithine, an ornithine decarboxylase inhibitor, in diet. Cancer cens, and actinic keratoses-have been initiated recently. Res., 50:2562-2568, 1990. These and other Phase II studies will be used to search for 12. Rao, C. V., Tokumo, K., Rigotty, )., Zang, E., Kelloff, C., and Reddy, B. S. Chemoprevention of colon carcinogenesis by dietary administration of and validate earlier markers that are endpoints for chemo- piroxicam, a-difluoromethylornithine, 1 6-a-fluoro-5-androsten-i 7-one, and prevention. In these studies, various potential markers of ab- ellagic acid individually and in combination. Cancer Res., 51: 4528-4534, normal cellular proliferation and differentiation and genetic 1991.

changes such as abnormal gene expression (including on- 1 3. Ratko, T. A., Detnisac, C. )., Dinger, N. M., Thomas, C. F., Kelloff, C. )., cogenes and tumor suppressors), altered DNA content, and and Moon, R. C. Chemopreventiveefficacyofcombined retinoid and tamoxifen treatment following surgical excision of a primary mammary cancer in chromosome structural changes may be evaluated. More ex- female rats. Cancer Res., 49: 4472-4476, 1989. penimentation in animal models related to the validation of 1 4. Moon, R. C., Kelloff, C. J., Detnisac, C. J., Steele, V. E., Thomas, C. F., and markers also has begun. Recently, in the NCI chemopre- Sigman, C. C. Chemoprevention of MNU-induced mammary tumors in the vention drug development program, studies of potential mature rat by 4-HPR and tamoxifen. Anticancer Res., 12: 1 1 47-i 1 54, 1992. markers have been initiated in mouse and rat colon, hamster 1 5. Moon, R. C., McCormick, D. L., and Mehta, R. C. Inhibition of carci- buccal pouch, hamster pancreas, hamster and mouse lung, nogenesis by retinoids. Cancer Res. (Suppl.), 43: 2469s-2475s, 1983. and rat bladder. 1 6. Moon, R. C., and Mehta, R. C. Chemoprevention of experimental car- New technologies are also expected to benefit cherno- cinogenesis in animals. Prey. Med., 18: 576-591, 1989. prevention research, especially detection and validation of 1 7. Willett, W. C., Polk, B. F., Underwood, B. A., Stampfer, M. j., Pressel, S., Rosner, B., Taylor, J. 0., Schneider, K., and Hames, C. C. Relation of serum early markers. Particularly interesting are techniques, such vitamins A and E and carotenoids to the risk of cancer. N. EngI. J. Med., 310: as fine needle aspiration and the polyrnerase chain reaction, 430-434, 1984. that will allow early and rare lesions to be detected relatively 18. Wald, N. J., Boreham, )., Hayward, J. L., and Bulbrook, R. D. Plasma noninvasively. Likewise, as knowledge in molecular biology retinol, f3-carotene and vitamin E levels in relation to the future risk of breast and the basic cellular processes in carcinogenesis increases, cancer. Br. ). Cancer, 49: 321-324, 1984. chemopreventive agents that are directed to repair or sup- 19. Nomura, A. M. Y., Stemmermann, C. N., Heilbrun, L. K., Salkeld, R. M., and Vuilleumier, J. P. Serum vitamin levels and the risk of cancer of specific press early genetic lesions and control cellular growth sites in men of Japanese ancestry in Hawaii. Cancer Res., 45: 2369-2372, mechanisms (e.g., programmed cell death, angiogenesis) 1985. may be possible. 20. Salonen, J. T., Salonen, R., Lappetelainen, R., Maenpaa, P. H., Alfthan, To date, chemoprevention research efforts have fo- C., and Puska, P. Risk of cancer in relation to serum concentrations of se- cused primarily on cancers of the colon, lung, breast, and lenium and vitamins A and E: matched case-control analysis of prospective data. Br. Med. J., 290:417-420, 1985. bladder. In the NCI drug development program, models for 21 . Menkes, M. S., Comstock, C. W., Vuillemier, J. P., Helsing, K. )., Rider, evaluating potential chemopreventive agents in prostate and A. A., and Brookmeyer, R. Serum n-carotene, vitamins A and E, selenium, and pancreas are being investigated. Other cancers with high the risk of lung cancer. N. Engl. J. Med., 315: 1250-1254, 1986.

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G J Kelloff, C W Boone, J A Crowell, et al.

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