Skip to main content
SpringerLink
Log in

Rationale and Mechanisms of Cancer Chemoprevention

  • Conference paper
Chemoprevention of Cancer

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 151))

Abstract

Chronic degenerative diseases, including cancer, have a multifactorial origin. An intricate network connects each disease with multiple risk factors and also with multiple protective factors. From the point of view of preventive medicine, this implies that removal of a single risk factor will have a beneficial impact on the epidemiology of several diseases. However, in contrast to the situation in infectious diseases, it will never be possible to eradicate any chronic degenerative disease in this way, because each of them is associated with other risk factors at the same time. Similarly, a single protective factor can decrease the risk of contracting different diseases, and the risk of developing a single disease can be attenuated by different protective factors, often in a coordinated fashion. It is thus evident that cancer can be prevented not only by avoiding exposure to recognized risk factors, but also, as a complementary approach referred to as chemoprevention, by favouring the intake of protective factors and by fortifying the physiological defences of the host organism. Chemoprevention can be applied in a primary prevention setting when it is addressed to healthy individuals with the goal of inhibiting occurrence of the disease. Conversely, it is applied in a secondary prevention setting when it is addressed to individuals affected by premalignant tumours, with the goal of reversing the carcinogenesis process. A rational use of chemopreventive agents is based not only on the assessment of their efficacy and safety but also on understanding of their mechanisms of action. A detailed classification is proposed, which covers a variety of mechanisms interfering with different phases of mutagenesis and carcinogenesis. However, this sequence of events does not fit in with a rigid scheme, and several mechanisms, such as inhibition of genotoxic effects, antioxidant activity and scavenging of free radicals, inhibition of cell proliferation, and signal transduction modulation are reiterated several times throughout evolution of these processes. Some of these mechanisms are also involved in advanced stages of tumour progression towards malignancy, invasion and metastasis, and can therefore conveniently be applied for the tertiary prevention of cancer. Most inhibitors work through multiple mechanisms, examples of which are given for 18 chemopreventive agents.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Albini A, D’Agostini F, Giunciuglio D, Paglieri I, Balansky R, De Flora S (1995) Inhibition of invasion, gelatinase activity, tumor take and metastasis of malignant cells by N-acetyl- cysteine. Int J Cancer 61:121–129.

    Article  PubMed  CAS  Google Scholar 

  • Arimoto S, Kan-yama K, Rai H, Hayatsu H (1995) Inhibitory effect of hemin, clorophyllin and related pyrrole pigments on the mutagenicity of benzo[a]pyrene and its metabolites. Mutat Res 345:127–135.

    Article  PubMed  CAS  Google Scholar 

  • Bartsch H, Ohshima H, Pignatelli B (1988) Inhibitors of endogenous nitrosation. Mechanisms and implications in human cancer prevention. Mutat Res 202:307–324.

    CAS  Google Scholar 

  • Bergelson S, Pinkus R, Daniel V (1994) Intracellular glutathione levels regulate fos/jun induction and activation of glutathione S -transferase gene expression. Cancer Res 54:36–40.

    PubMed  CAS  Google Scholar 

  • Bertram JS, Kolonel LN, Meyskens FL Jr (1987) Rationale and strategies for chemoprevention of cancer in humans. Cancer Res 47:3012–3031.

    PubMed  CAS  Google Scholar 

  • Boone CW, Kelloff GJ, Steele VE (1992) Natural history of intraepithelial neoplasia in humans with implications for cancer chemopreventive strategy. Cancer Res 52:1651–1659.

    PubMed  CAS  Google Scholar 

  • Conaway CC, Jiao D, Chung FL (1996) Inhibition of rat liver cytochrome P450 isozymes by isothiocyanates and their conjugates: a structure-activity relationship study. Carcinogenesis 17:2423–2427.

    Article  PubMed  CAS  Google Scholar 

  • De Flora S (1987) Proposed classification of inhibitors of mutagenesis and carcinogenesis according to their mechanisms (abstract). 2nd International Conference on Anticarcino-genesis and Radiation Protection, Gaithersburg, Md, 8–12 March 1987.

    Google Scholar 

  • De Flora S (1990) Mechanisms of inhibitors of genotoxicity. Relevance in preventive medicine. In: Mendelsohn ML, Albertini RJ (eds) Mutation and the environment, part E. Wi-ley-Liss, New York, pp 307–318.

    Google Scholar 

  • De Flora S (1994) Cancer prevention strategies and mechanisms of chemopreventive agents. Eur J Cancer Prev 3:364–366.

    Article  PubMed  Google Scholar 

  • De Flora S (1998) Mechanisms of inhibitors of mutagenesis and carcinogenesis. Mutat Res 402:151–158.

    PubMed  Google Scholar 

  • De Flora S, Ramel C (1988) Mechanisms of inhibitors of mutagenesis and carcinogenesis. Classification and overview. Mutat Res 202:285–306.

    Google Scholar 

  • De Flora S, Zanacchi P, Izzotti A, Hayatsu H (1991) Mechanisms of food-borne inhibitors of genotoxicity relevant to cancer prevention. In: Hayatsu H (ed) Mutagens in food. Detection and prevention. CRC Press, Boca Raton, Fl, pp 157–180.

    Google Scholar 

  • De Flora S, Bronzetti G, Sobels FH (eds) (1992) Assessment of antimutagenicity and anticar-cinogenicity. End-points and systems. Mutat Res 267:153–295.

    Google Scholar 

  • De Flora S, Izzotti A, Bennicelli C (1993) Mechanisms if antimutagenesis and anticarcino-genesis. Role in primary prevention. In: Bronzetti G, Hayatsu H, De Flora S, Waters MD, Shankel DM (eds) Antimutagenesis and anticarcinogenesis mechanisms, vol III. Plenum Press, New York, pp 1–16.

    Google Scholar 

  • De Flora S, Balansky R, Bennicelli C, Camoirano A, D’Agostini F, Izzotti A, Cesarone CF (1995 a) Mechanisms of anticarcinogenesis: the example of N-acetylcysteine. In: Loan-nides C, Lewis DFV (eds) Drugs, diet and disease, vol 1: Mechanistic approaches to cancer. Ellis Horwood, Hemel Hempstead, UK, pp 151–203.

    Google Scholar 

  • De Flora S, Cesarone CF, Balansky RM, Albini A, D’Agostini F, Bennicelli C, Bagnasco M, Camoirano A, Scatolini L, Rovida A, Izzotti A (1995 b) Chemopreventive properties and mechanisms of N-acetylcysteine. The experimental background. J Cell Biochem 58 [Suppl 22]:33–41.

    Article  Google Scholar 

  • De Flora S, Balansky R, Scatolini L, Di Marco C, Gasparini L, Orlando M, Izzotti A (1996 a) Adducts to nuclear DNA and mitochondrial DNA as biomarkers in chemoprevention. In: Stewart BW, McGregor D, Kleihues P (eds) Principles of chemoprevention. (IARC scientific publication no 139) International Agency for Research on Cancer, Lyon, pp 291–301.

    Google Scholar 

  • De Flora S, Izzotti A, Randerath K, Randerath E, Bartsch H, Nair J, Balansky R, van Schoo-ten F, Degan P, Fronza G, Walsh D, Lewtas J (1996 b) DNA adducts and chronic degenerative diseases. Pathogenetic relevance and implications in preventive medicine. Mutat Res 366:197–238.

    Google Scholar 

  • Egner PA, Kensler TW, Prestera T, Talalay P, Libby AH, Curphey TJ (1994) Regulation of phase 2 enzyme induction by otipraz and other dithiolethiones. Carcinogenesis 15:177–181.

    Article  PubMed  CAS  Google Scholar 

  • El-Bayoumy K, Upadhyaya P, Chae Y-H, Sohn O-S, Rao CV, Fiala E, Reddy BS (1995) Chemoprevention of cancer by organoselenium compounds. J Cell Biochem Suppl 22:92–100.

    Article  PubMed  CAS  Google Scholar 

  • Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767.

    Article  PubMed  CAS  Google Scholar 

  • Feo F, Pirisi L, Pascale R, Daino L, Frassetto S, Garcea R, Gaspa L (1984) Modulatory effect of glucose-6-phosphate dehydrogenase deficiency on benzo(a)pyrene toxicity and transforming activity for in vitro-cultured human skin fibroblasts. Cancer Res 44:3419–3425.

    PubMed  CAS  Google Scholar 

  • Fong AT, Swanson HI, Dashwood RH, Williams DE, Hendricks JD, Bailey GS (1990) Mechanisms of anti-carcinogenesis by indole-3-carbinol: studies of enzyme induction, electro-phile-scavenging, and inhibition of aflatoxin Bx activation. Biochem Pharmacol 39:19–26.

    Article  PubMed  CAS  Google Scholar 

  • Giunciuglio D, Cai T, Masiello L, De Flora S, Albini A (1996) N-Acetylcysteine. A possible inhibitor of tumor angiogenesis (abstract). Presented at the Meeting on Oxidative Stress and Redox Regulation, Paris, France, 21–24 May 1996.

    Google Scholar 

  • Govers MJAP, Termont DSML, van der Meer R (1994) Mechanisms of the antiproliferative effect of milk mineral and other calcium supplements on colonic epithelium. Cancer Res 54:95–100.

    PubMed  CAS  Google Scholar 

  • Greenwald P, Kelloff GJ, Boone CW, McDonald SS (1995) Genetic and cellular changes in colorectal cancer: proposed targets of chemopreventive agents. Cancer Epidemiol Biomarkers Prev 4:691–702.

    PubMed  CAS  Google Scholar 

  • Hartman PE, Shankel DM (1990) Antimutagens anticarcinogens: a survey of putative interceptor molecules. Environ Mol Mutagen 15:145–182.

    Article  PubMed  CAS  Google Scholar 

  • Hecht SS (1995) Chemoprevention by isothiocyanates. J Cell Biochem Suppl 22:195–209.

    Article  PubMed  CAS  Google Scholar 

  • Huang T-S, Lee S-C, Lin J-K (1991) Suppression of c-Jun/AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells. Proc Natl Acad Sei USA 88:5292–5296.

    Article  CAS  Google Scholar 

  • International Agency for Research on Cancer (1996) Some pharmaceutical drugs. IARC Monogr Eval Carcinog Risks Hum 66:253–365.

    Google Scholar 

  • lp C, Ganther HE (1992) Relationship between the chemical form of selenium and anticarci-nogenic activity. In: Wattenberg, Lipkin M, Boone CW, Kelloff GJ (eds) Cancer chemoprevention. CRC Press, Boca Raton, Fl, pp 479–488.

    Google Scholar 

  • Jiang M-C, Yang-Yen H-F, Jong-Young Yen J, Lin J-K (1996) Curcumin induces apoptosis in immortalized NIH 3T3 and malignant cancer cell lines. Nutr Cancer 26:111–120.

    Article  PubMed  CAS  Google Scholar 

  • Jordan VC, Murphy CS (1990) Endocrine pharmacology of antiestrogens as antitumor agents. Endocr Rev 11:578–610.

    Article  PubMed  CAS  Google Scholar 

  • Kada T, Inoue T, Namiki N (1982) Environmental desmutagens and antimutagens. In: Klekowski EJ (ed) Environmental mutagenesis and plant biology. Praeger, New York, pp 137–151.

    Google Scholar 

  • KeHoff GJ, Boone CW (eds) (1994) Cancer chemopreventive agents. Drug development status and future prospects. J Cell Biochem Suppl 20:1–303.

    Google Scholar 

  • Kelloff GJ, Boone CW, Steele VE, Crowell JA, Lubet R, Sigman CC (1994) Progress in cancer chemoprevention: perspectives on agent selection and short-term clinical intervention trials. Cancer Res 54 [Suppl]:2015s–2024s.

    PubMed  CAS  Google Scholar 

  • Kelloff GJ, Boone CW, Steele VE, Crowell JA, Lubet RA, Greenwald P, Hawk ET, Fay JR, Sigman CC (1996) Mechanistic considerations in the evaluation of chemopreventive data.In: Stewart BW, McGregor D, Kleihues P (eds) Principles of chemoprevention. (IARC scientific publication no 139). International Agency for Research on Cancer, Lyon, pp 203–219.

    Google Scholar 

  • Kennedy AR (1993) Overview: anticarcinogenic activity of protease inhibitors. In: Troll W, Kennedy AR (eds) Protease inhibitors as cancer chemopreventive agents. Plenum, New York, pp 9–64.

    Google Scholar 

  • Kensler TW, Helzlsouer KJ (1995) Oltipraz: clinical opportunities for cancer chemoprevention. J Cell Biochem Suppl 22:101–107.

    Article  PubMed  CAS  Google Scholar 

  • Kensler TW, Egner PA, Dolan PM, Groopman JD, Roebuck BD (1987) Mechanism of protection against aflatoxin tumorigenicity in rats fed 5-(2-pyrazinyl)-4-methyl-l,2-dithiol-3-thione (oltipraz) and related l,2-dithiol-3-thione and l,2-dithiol-3-ones. Cancer Res 47:4271–4277.

    PubMed  CAS  Google Scholar 

  • Krinsky NI (1993) Actions of carotenoids in biological systems. Annu Rev Nutr 13:561–587.

    Article  PubMed  CAS  Google Scholar 

  • Last JM (1986) Scope and methods of prevention. In: Last JM, Chin J, Fielding JE, Frank AL, Lashof JC, Wallace RB (eds) Maxcy-Rosenau. Public health and preventive meclicine. Appleton-Century-Crofts, Norwalk, Ct, pp 3–7.

    Google Scholar 

  • Lepley DM, Li B, Birt DF, Pelling JC (1996) The chemopreventive flavonoid apigenin induces G2/M arrest in keratinocytes. Carcinogenesis 17:2367–2375.

    Article  PubMed  CAS  Google Scholar 

  • Lertratanangkoon K, Orkiszewski RS, Scimeca JM (1996) Methyl-donors deficiency due to chemically induced glutathione depletion. Cancer Res 56:995–1005.

    PubMed  CAS  Google Scholar 

  • Lipkin M, Newmark H (1995) Calcium and the prevention of colon cancer. J Cell Biochem Suppl 22:65–73.

    Article  PubMed  CAS  Google Scholar 

  • Lippman SM, Heyman RA, Kurie JM, Benner SE, Hong WK (1995) Retinoids and chemoprevention: clinical and basic studies. J Cell Biochem Suppl 22:1–10.

    Article  PubMed  CAS  Google Scholar 

  • Morse MA, Stoner GD (1993) Cancer chemoprevention: principles and prospects. Carcinogenesis 14:1737–1746.

    Article  PubMed  CAS  Google Scholar 

  • Nayfield SG, Karp JE, Ford LG, Dorr FA, Kramer BS (1991) Potential role of tamoxifen in prevention of breast cancer. J Natl Cancer Inst 83:1450–1459.

    Article  PubMed  CAS  Google Scholar 

  • Nishino H (1995) Cancer chemoprevention by natural carotenoids and their related compounds. J Cell Biochem Suppl 22:231–235.

    Article  PubMed  CAS  Google Scholar 

  • Norman AW (1995) The vitamin D endocrine system: manipulation of structure-function relationships to provide opportunities for development of new cancer chemopreventive and immunosuppresive agents. J Cell Biochem Suppl 22:218–225.

    Article  PubMed  CAS  Google Scholar 

  • Ramel C, Alekperov UK, Ames BN, Kada T, Wattenberg LW (1986) Inhibitors of mutagenesis and their relevance to carcinogenesis. Mutat Res 168:47–65.

    PubMed  CAS  Google Scholar 

  • Schwartz AG, Pashko LL (1995) Cancer prevention with dehydroepiandrosterone and non-androgenic structural analogs. J Cell Biochem Suppl 22:210–217.

    Article  PubMed  CAS  Google Scholar 

  • Shamberger RJ (1986) Chemoprevention of cancer. In: Reddy BS, Cohen LA (eds) Diet, nutrition, and cancer: a critical evaluation, vol II: Micronutrients, nonnutritive dietary factors, and cancer. CRC Press, Boca Raton, Fl, pp 43–62.

    Google Scholar 

  • Sporn MB, Newton DL (1979) Chemoprevention of cancer with retinoids. Fed Proc 38:2528–2534.

    PubMed  CAS  Google Scholar 

  • Stetler-Stevenson WG, Hewitt R, Corcoran M (1996) Matrix metalloproteinases and tumor invasion: from correlation and causality to the clinic. Semin Cancer Biol 7:147–154.

    Article  PubMed  CAS  Google Scholar 

  • Stoner GD; Mukthar H (1995) Polyphenols as cancer chemopreventive agents. J Cell Biochem Suppl 22:169–180.

    Article  PubMed  CAS  Google Scholar 

  • Stoner GD, Morrissey D, Heur Y-H, Daniel E, Galati A, Wagner SA (1991) Inhibitory effects of phenethyl isothiocyanate on AT-nitrosobenzylmethylamine carcinogenesis in the rat esophagus. Cancer Res 51:2063–2068.

    PubMed  CAS  Google Scholar 

  • Suganuma M, Okabe S, Sueoka E, Iida N, Komori A, Kim S-J, Fujiki H (1996) A new process of cancer prevention mediated through inhibition of tumor necrosis factor a expression. Cancer Res 56:3711–3715.

    PubMed  CAS  Google Scholar 

  • Tachino N, Guo D, Dashwood WM, Yamane S, Larsen R, Dashwood RH (1994) Mechanisms of the in vitro anti-mutagenic action of chlorophyllin against benzo[a]pyrene: studies of enzyme inhibition, molecular complex formation, and degradation of the ultimate carcinogen. Mutat Res 308:191–203.

    PubMed  CAS  Google Scholar 

  • Takahashi N, Dashwood RH, Bjeldanes LF, Bailey GS, Williams DE (1995) Regulation of hepatic CYP1A1 by indol-3-carbinol: transient induction with continuous feeding in rainbow trout. Food Chem Toxicol 33:111–120.

    Article  PubMed  CAS  Google Scholar 

  • Trosko J, Chang C (1980) An integrative hypothesis Unking cancer, diabetes, and atherosclerosis: The role of mutations and epigenetic changes. Med Hypotheses 6:455–468.

    Article  PubMed  CAS  Google Scholar 

  • van Zandwijk N (1995) N-Acetylcysteine (NAC) and glutathione (GSH): antioxidant and chemopreventive properties, with special reference to lung cancer. J Cell Biochem Suppl 22:24–32.

    Article  PubMed  Google Scholar 

  • Wargovich MJ, Eng VWS, Newmark HL, Bruce WR (1983) Calcium ameliorates the toxic effect of deoxycholic acid on colonic epithelium. Carcinogenesis 4:1205–1207.

    Article  PubMed  CAS  Google Scholar 

  • Wattenberg LW (1977) Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate and related compounds. J Natl Cancer Inst 58:395–398.

    PubMed  CAS  Google Scholar 

  • Wattenberg LW (1981) Inhibitors of chemical carcinogens. In: Burchenal JH, Oetfgen HF (eds) Cancer: achievements, challenges and prospects for the 1980s. Grune and Stratton, New York, pp 517–540.

    Google Scholar 

  • Wattenberg LW, Bueding E (1986) Inhibitory effects of 5-(2-pyranizyl)-4-methyl-l,2-dithiol- 3-thione (oltipraz) on carcinogenesis induced by benzo[a]pyrene, diethylnitrosamine and uracil mustard. Carcinogenesis 7:1379–1381.

    Article  PubMed  CAS  Google Scholar 

  • Weinstein IB (1988) Strategies for inhibiting multistage carcinogenesis based on signal transduction pathways. Mutat Res 202:413–420.

    PubMed  CAS  Google Scholar 

  • Yu R, Jiao J-J, Duh J-L, Tan T-H, Tony Kong A-N (1996) Phenethyl isothiocyanate, a natural chemopreventive agent, activates c-Jun N-terminal kinase 1. Cancer Res 56:2954–2955.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Hygiene and Preventive Medicine, University of Genoa, Via A. Pastore 1, I-16132, Genoa, Italy

    C. Bennicelli & M. Bagnasco

Authors
  1. S. De Flora
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Bennicelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Bagnasco
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Center for Tumordetection and Prevention, Rorschacherstrasse 150, CH-9006, St. Gallen, Switzerland

    Hans-Jörg Senn

  2. European Institute of Oncology, Via Ripamonti, I-20141, Milan, Italy

    Alberto Costa M.D.

  3. Robert H. Lurie Cancer Center Breast Cancer Research Program, Olson Pavilion, Northwest-University Medical School, 503 E. Chicago Ave., 60611, Chicago, IL, USA

    V. Craig Jordan

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer-Verlag Berlin · Heidelberg

About this paper

Cite this paper

De Flora, S., Bennicelli, C., Bagnasco, M. (1999). Rationale and Mechanisms of Cancer Chemoprevention. In: Senn, HJ., Costa, A., Jordan, V.C. (eds) Chemoprevention of Cancer. Recent Results in Cancer Research, vol 151. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59945-3_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-59945-3_3

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-64192-3

  • Online ISBN: 978-3-642-59945-3

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation