Meyskens, FL

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UC IrvineUC Irvine Previously Published WorksTitleThinking about cancer causality and chemoprevention.Permalinkhttps://escholarship.org/uc/item/2hs308pjJournalJournal of the National Cancer Institute, 80(16)ISSN0027-8874AuthorMeyskens, FLPublication Date1988-10-19DOI10.1093/jnci/80.16.1278Copyright InformationThis work is made available under the terms of a Creative Commons Attribution License, availalbe at https://creativecommons.org/licenses/by/4.0/ Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaCommentaryThinking About Cancer Causality andChemoprevention^Frank L Meyskens, Jr.3,4,*Chemoprevention is a strategy used to block the devel-opment of cancers in humans. Necessarily, the approachdraws its rationale from a multitude of disciplines. The in-terdisciplinary milieu necessary to conduct chemopreventionresearch has muddied, if not obscured to nonaficionados,the scientific basis of chemoprevention and its relationshipto more established scientific endeavors. Figure 1 presentschemoprevention in terms of the relationship of cancer etiol-ogy and biology to prevention and evaluation of diesase endpoints.Chemoprevention interfaces with biology, epidemiology,and behavioral sciences, with clinical trials serving as the tac-tical arm of experimental implementation in humans (7). Inthis commentary, the implications of concepts and relation-ships associated with these interfaces are elucidated througha series of questions. The answers to these questions will im-pact on the scientific development of chemoprevention overthe next decade.QuestionsWhat will be the contribution of genetic background todesigning chemoprevention trials?To date, cancer intervention trials have been based onrisk characteristics of individuals in a population, and subse-quent trials have measured the outcome for the populationof individuals in the arms of the trial. Consequently, trialsare designed to include large numbers of individuals withrelatively long-term exposure to the intervention. This ap-proach has been used to assure that trial data are adequate todemonstrate the significance and power necessary to provethe validity of study conclusions. There is increasing evi-dence that cancer risk is intimately associated with geneticstructure at the molecular level (2). Advances in analysisof the molecular genotype using restriction fragment-lengthpolymorphisms and other approaches have made identifica-tion of hereditary diseases at the molecular level possible;the same approach is likely to be used in the study of mostcancers soon. Investigators have identified genetic polymor-phisms that appear to give individuals substantially increasedrisk for particular cancers. Almost certainly, with continuedadvances in molecular biology, epidemiologic studies willfurther establish actual baseline risks for most diseases. Phe-notypic expression of the disease will be shown to rangefrom absolute (e.g., bilateral retinoblastoma) to unlikely, de-pending largely on susceptibility of the underlying molecularstructure to permanent mutagenic damage by any particularinitiator.On the basis of these findings, individuals with a highgenetic risk should be identifiable, and the required samplesize for any particular trial should be markedly reduced.Individuals at high risk for a disease would be excellentcandidates for a specific primary prevention trial. In addition,advances in detection of DNA damage (e.g., DNA adductformation) may allow identification of individuals who haveboth high risk and mutagenic changes in the relevant tissue.What is the role of epidemiology in a biological model ofdisease prevention?Epidemiologic approaches have identified major dietarycomponents and cultural practices that affect the phenotypicexpression of many cancers. Additional study of these fac-tors in individuals at risk, or perhaps in vitro at the cellularlevel, may allow new insights into the fundamental processesand influences operative at the phenotypic level. A betterunderstanding of the interaction of risk factors and specificgenes should result in a new mechanistic epidemiology atthe molecular level. For example, certain genetic changes'Received August 18, 1988; accepted August 18, 1988.^Supported in part by Public Health Service grants CA-23074, CA-41108,and CA-27502 from the National Cancer Institute, National Institutes ofHealth, Department of Health and Human Services.'Department of Internal Medicine, Section of Hematology/Medical On-cology, and The Arizona Cancer Center, University of Arizona Health Sci-ences Center, Tucson, AZ.••I thank R. Goldman and M. Humphrey for excellent secretarial andadministrative assistance.* Correspondence to: Frank L. Meyskens, Jr., MD., Department of InternalMedicine, Section of Hematology/Medical Oncology, University of ArizonaHealth Sciences Center, 1501 N. Campbell Ave^ Tucson, AZ 85724.1278 Journal of the National Cancer Instituter A I I O A l I T V .EVENTBIOLOGICLEVEL OF •EFFECTTYPES OFPREVENTIONEVALUATIONMODESGENETIC PROMOTION PROGRESSION PRENEOPLASIAINTRINSIC EXTRINSIC(INITIATION)IMMUNERESPONSEtMOLECULAR BIOCHEMICAL HI8TOLOGICPRIMARY SECONDARYSCREENINGTERTIARYEARLY DETECTIONNEOPLASIA£ARLY LATETREATMENTFigure 1. Relation-ship of cancer causal-ity and biology toprevention and eval-uation of disease endpoints.may result in functioning proteins that exhibit subtle differ-ences from the normal and interact differentially in particularphenotypes to produce an enhanced risk for abnormal pro-liferation (3).Another unexplored area is the epidemiology of preneo-plastic growth, which offers a rich opportunity for novel re-search. Little is known about what causes preneoplastic ormetaplastic lesions to form or to evolve into frank malignan-cies. It is known, however, that cigarette smoking, exposureto ultraviolet light, and use of alcohol enhance the progres-sion of promoted and preneoplastic cells to the malignantphenotype in appropriate tissues.What new approaches shook! be explored for inhibitingcarcinogenesis?New approaches to the inhibition of carcinogenesis includethe use of anti- initiators, antipromoters, and antiproliferativeagents that show promise for chemoprevention in humans(1,4). Another approach is the interaction of early immuneresponse with phenotypically altered cells, an area of studythat has been almost totally neglected. The results of so-phisticated experimental studies using ultraviolet irradiationof skin and analysis of host immune and nonimmune celldistribution in skin lesions indicate that complex interactionsoccur between immune cells and damaged normal cells (5,6).Undoubtedly, subtle changes in host immune status occur inresponse to the first biochemical membrane lesion or alteredcytokine release, and crude pharmacologic approaches canbe used to interfere with these processes. It is likely that withmore detailed understanding of the biological battlefield,specific pharmacologic or biologic agents will be developedto interfere with the escape of early precancerous growthfrom host immune control without producing irreversibleeffects on the host immune system.What is the natural history of premalignant conditions?An understanding of the biology of preneoplastic lesionsshould provide important information about carcinogenesisin humans. The study of the progression of carcinogenesis isrelatively new and is essentially confined to animal cutaneousmodels. Except for cervical dysplasia (7), very little is knownabout the biology of premalignant conditions in humans.Investigators have begun to study the precursive biologyof cutaneous melanoma (8), esophageal cancer (9), and toa lesser extent, colon cancer (70), but virtually nothing isknown about the biology of these lesions or of such lesionsas oral leukoplakia, bronchial metaplasia, gastric metaplasia,and actinic keratosis.Are there good intermediate markers for cancer orcancer risk?The extensive time required for progression from the dam-aged cell to cancer in humans has made the study of inter-mediate biochemical markers attractive. However, a majorproblem is that we do not know if any of them are valid in-dicators of cancer risk or development Most investigatorshave used markers to measure abnormalities by analysis ofDNA content or cytogenetic study or by indirect [(ornithinedecarboxylase or protein kinase C (PKC)] or direct (Ki67antibody, thymidine labeling, or mitotic index) estimation ofproliferation. Chromosomal abnormalities have been predic-tive of malignant outcome, but in general, they have beenidentified at late stages of the disease (11,12). Although sev-eral complex studies have used intermediate markers forcolonic cell proliferation, including favorable modulation bycalcium, it has not been demonstrated that these changes areindicators of cancer risk or development (10,13,14). Theconcept of intermediate markers is valuable for the study ofhuman neoplasia and of the modulating effects of chemo-prevention agents, but more detailed investigations in animalmodels and in human disease are needed to validate theapproach.What are desirable properties of a chemopreventionagent in humans?The optimal chemoprevention agent would be nontoxic,highly efficacious, easily measurable in serum and tissue, andreadily available. For the most part, dietary components suchas 0-carotene, a-tocopherol, and vitamin C fill this bill. Otherdietary elements such as selenium appear to have a steep ef-ficacy/toxicity ratio. With few exceptions-, the pharmacolog-ical compounds proposed as chemopreventive agents haveside effects that are dose related. The acceptability of sideeffects depends on the nature of the condition being stud-ied. An individual with familial polyposis may be willingto accept considerable side effects from a chemopreventionagent In contrast, a person 55 years of age who has hadone polyp removed in the past year and is asked to join aVol. 80, No. 16, October 19, 1988 COMMENTARY 1279chemoprevention trial to prevent polyp recurrence may ex-press considerable reservations if any side effects from a drugare expected. One way to reduce side effects is to determinethe lowest dose at which an agent will produce a significantand relevant biochemical or biological effect Careful phaseI studies with modulation of biological or biochemical endpoints in relevant tissues are needed to provide the basis forplanning future chemoprevention trials.What is the biological rationale for development ofchemoprevention agents?There are a number of ways in which chemopreventionagents can be viewed. One possible unified approach isshown in figure 2. The common strategy for chemopreven-tion at the cellular level is modulation of the key regula-tory pathways, most notably, signal transduction and controlmediated by the phosphatidylinositol cascade, the cyclic nu-cleotide pathway, and polyamine regulation. The intricaciesof these regulatory controls have been described in detail(15-IT). The purpose of this discussion is to point out newpossibilities for chemoprevention strategies in the future.A multitude of growth factors mediate the effects of theseregulatory controls by signal transduction via the phosphatidyl-inositol (fig. 2, Al) cascade or the cyclic nucleotide (fig. 2,A2) pathway. Undoubtedly, abnormalities in growth factorproduction, growth factor receptor function, or integrationof the response will be found to be early changes in ma-lignant transformation. Abundant data indicate that growthfactors can either produce or inhibit proliferation in the samecells, depending on the biochemical and cellular milieu (75).The development of signal analogs or inhibitors that differen-tially affect receptor function should lead to the availabilityof new chemoprevention agents as well. Propagation of thesignal via the phosphatidylinositol pathway requires a steadysource of inositol (fig. 2B). The regeneration of inositolfrom inositol-1-phosphate is selectively inhibited by lithiumand results in abrogation of signal responses (19). Lithiumcarbonate (Eskalith) has been widely used as a drug formanic-depressive illness; the pharmacology is well known,and side effects closely correlate to serum levels. Conse-quently, further exploration of lithium as a potential chemo-prevention agent is warranted.The role of PKC in modulating cellular responses hasbeen extensively studied, and the enzyme has a multiplic-ity of secondary modifications via phosphorylation. Withthe recent identification of these numerous subtypes ofPKC, the possibility of interactions and modifications ofkey enzymes and receptors is nearly limitless. Because12-0-tetradecanoylphorbol-13-acetate (TPA) has been iden-tified as the ligand for PKC, the design of specific inhibitorsseems possible and likely. Recent studies with the nonphor-bol tumor promoter bryostatin suggest that the control of theenzyme is complex and the opportunity to develop specificmodulators extensive (20). A number of nonspecific regu-lators (anti-inflammatory steroids) and selective regulators[H-series derivative (isoquinolinesulfonamides) and palmi-toyl carnitine] of PKC have been identified and studied. Itmay be useful to study the effects of carnitine (fig. 2C),since the action of this natural substrate for palmitoyl carni-tine and lipid biosynthesis has been well studied (21). Addi-tionally, carnitine is commercially available for the treatmentof inherited carnitine deficiencies.An important intermediate in the phosphatidylinositol cas-cade, arachidonic acid, is the source of prostanoids, whichare major stimulators of cellular proliferation in the cellsof many tissues. Many nonsteroidal anti-inflammatory com-pounds inhibit prostaglandin synthesis. A particularly usefulcompound is proxicam (fig. 2D), which has been active asa chemoprevention agent in animal systems (22). The clin-ical experience with this drug has been extensive, and thespectrum of side effects at different doses is well defined.One of the sentinel regulatory enzymes that undergoesSIONAL SIOHALC Y C L A 8 E S | 8 - PROTEIN PHOSPHOUPASE C PHOSPHATIOTL INOSITOL | «•>*- ®©CAMP C«MP ORNITHINE© ' OltNITHINEDECANBOXYLA8EDAS-ARACHIDONICLIPA8EIITPP0LYAUINE8A - PROTEIN KINASE •PROTEINKINASE0A0 ARACHIDONIC.PROTEIN KINASE C pas CA-PKCELLULAR RESPONSESFigure 2. Diagramof a biological strat-egy for chemopre-vention. Some po-tential inhibitors ofcarcinogenesis: Aland A2, signal ana-logs; B, lithium; C,carnitine; D, piroxi-cam; E, DFMO; andF, theophylline. PD= phosphodiesterase;DAG = diacylglyc-erol; FTP = inosinetriphosphate; PGS =prostaglandins; andCA-PK = caJcium-activated protein ki-nase.1280 Journal of the National Cancer Institutemodification by PKC is ornithine decarboxylase, an impor-tant key enzyme in the polyamine synthesis pathway. Therole of polyamine synthesis in cellular regulation has beenextensively studied and recently reviewed (76). An impor-tant step in understanding the role of polyamines in cellulargrowth was the synthesis of an enzyme-activated irreversibleinhibitor of ornithine decarboxylase activity, difluoromethyl-ornithine (DFMO). This compound has been shown to bean inhibitor in all of the animal systems tested, whether itwas applied topically or administered systemically. It hasalso been demonstrated that low doses of DFMO inhibitTPA-promoted human skin ornithine decarboxylase (23).Since this compound is almost nontoxic at low concentra-tions, its use as a chemoprevention agent in humans shouldbe widely explored (fig. 2E). We have just started studieswith DFMO (Eflornithine) in patients with oral leukoplakiaand Barrett's esophagus and eagerly await the results.The cyclic nucleotide pathway has been a rich target forstudy of differentiation and proliferation in normal and ab-normal cells (7 7). In some systems, merely raising the cAMPlevels by using theophylline (or derivatives) to inhibit thebreakdown of cyclic nucleotide produces profound changes,with marked inhibition of growth and terminal differentia-tion. In other systems, no such effect is seen. Perturbation ofthis critical pathway as a strategy for chemoprevention hasnot been well studied at the experimental level. In view ofthe rigid controls evidenced by the study of this pathway,the development of modulators appears to be an importantchemoprevention strategy (fig. 2F). The real possibilitiesfor new and novel chemoprevention strategies based on anappreciation of key regulatory events in the cell should beevidentIn the past decade, the results of epidemiologic studies andclinical trials have provided the basis for a reliable scientificstrategy for early intervention against human cancers. In thenext decade, modern biology should also contribute informa-tion critical to the success of that endeavor. Epidemiologyand biology as complementary underpinnings for chemopre-vention in humans should become the order of the day.References1. BERTRAM JS, KOLONEL LN, MEYSKENS FL JR. Rationale and strategiesfor chemoprevention of cancer in humans. Cancer Res 1987;47:3012-3031.2. DENEL TF. Polypeptide growth factors: role in normal and abnormalcell growth. Annu Rev Cell Biol 1987;3:443-492.3. HANSEN MF, CAVENCE WK. Genetics of cancer predisposition. CancerRes 1987;47:5518-5527.4. WATTENBERO LW. Chemoprevention of cancer. Cancer Res 1976;45:1-8.5. KJUPKE ML, FISHER MS. Immunologic parameters of ultraviolet car-cinogenesis. J Natl Cancer lust 1976;57:211-215.6. DAYNES RA, SPIKES JD. Experimental and clinical photoimmunology,vols 1-3. Boca Raton, FL: CRC Press, 1983.7. SYRJANEN KJ. Human papillomavirus infection as a possible etiologicalfactor in cervical squamous cell carcinogenesis. Contraception FertilSuppl 1987;15:963-973.8. HERLYN M, CLARK W, RODECK V, et al. Biology of tumor progressionin human melanocytes. Lab Invest 1987^6:461-474.9. GAREWAL H, SAMPUNER R, GERNER E, et al. Omithine decarboxylaseactivity in Barrett's esophagus: a potential marker for dysplasia. Gas-troenterology 1988. In press.10. LJPKIN M. Biomarkers of increased susceptibility to gastrointestinalcancer, a new application to studies of cancer prevention in humansubjects. Cancer Res 1988;48:235-245.11. ROWLEY JD. Chromosome abnormalities in leukemia. J Clin Oncol1988;6:194-202.12. SANDBERG AA, TURC-CAVEL C, GEMMILL RM. Chromosomes in solidrumors and beyond. Cancer Res 1988;48:1049-1059.13. LUK GD, BAYLJN SB. Omithine decarboxylase as a biologic marker infamilial colonic polyposis. New Engl J Med 1984;311:80-83.14. WARGOVICH MJ, ENG VWS, NEWMARK HL, et al. Calcium modificationof the promoting stimulus of fatty acids to the colonic epithelium.Cancer Lett 1984^3:256-261.15. NISHEUKA J. Studies and perspectives of protein kinase C. Nature1986^33:305-312.16. MCCANN PP, PEGG AE, SJOERDSMA A. Inhibition of polyaminemetabolism: biological significance and basis for new therapies. NewYork: Academic Press, 1987.17. WHITFIELD JF, DURKIN JP, FRANKS DJ, et al. Calcium, cyclic AMPand protein kinase C—partners in mitogenesis. Cancer Metastasis Rev1987^:205-250.18. SPORN MB, ROBERTS AB. Peptide growth factors are multifunctional.. Nature 1988332:217-219.19. RASMUSSEN H. The calcium messenger system (part II). New Engl J Med1986;314:1164-1170.20. DELL AQUILA ML, NGUYEN HT, HERALD CL, et al. Inhibition bybryostatin 1 of the phorbol ester-induced blockage of differentiationin hexamethylene-bisacetamide-treated Friend erythroleukemic cells.Cancer Res 1987;47:6006-6009.21. BAHL JJ, BRESSLER R. The pharmacology of camitine. Annu Rev Phar-macol Toxicol 1987^7:257-277.22. REDDY BS, MARUYAMA H, KELLOFF G. Dose related inhibition of coloncarcinogenesis by dietary piroxicam, a nonsteroidal anti-inflammatorydrug, during different stages of rat colon tumor development Cancer Res1987;47:5340-5346.23. VERMA AK, LOPRINZI CL, BOUTWELL RK, et al. In vitro inductionof human skin ornithine decarboxylase by the tumor promoter 12-0-tetradecanoylphorbol-13-acetate. JNCI 1985;75:85-90.Vol. 80, No. 16, October 19, 1988 COMMENTARY 1281

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Thinking about cancer causality and chemoprevention.

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