Skip to main content
SpringerLink
Log in

Chemoprevention of Colon Cancer: Current Status and Future Prospects

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Colorectal cancer is an important public health problem in the western world. Although some progress has been made in the prevention and management of this disease, colon cancer still remains one of the most common types of epithelial malignancies in both genders and is essentially incurable when it reaches the most advanced stages. Given the substantial morbidity and mortality associated with colorectal malignancies and their treatment, cancer prevention in its many forms emerges as a very attractive approach. Colorectal cancer chemoprevention refers to the administration of natural or synthetic compounds to block, reverse, delay or prevent the development of invasive large bowel neoplasms. The ultimate goal of implementing a chemopreventive intervention in the general, or alternatively, in an at-risk population is to decrease the incidence rate of the specific cancer being targeted. This article reviews the present status of colorectal cancer chemoprevention. Current insights into the molecular and genetic models of human colorectal carcinogenesis, preclinical models for efficacy testing as well as into promising biomarkers for colorectal chemoprevention are provided. The developmental status of many promising agents is also discussed emphasizing the epidemiological evidence, preclinical information substantiating an anticarcinogenic effect, their postulated mechanism of action and the status of human clinical development. Our perspective of the future prospects in this scientific area is also provided and has been predicated primarily on the firm belief that the proper integration of advances in the biology of colon carcinogenesis, experimental therapeutics and clinical trial methodology will be critical for the success of this promising field.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Greenlee RT, Murray T, Bolden S, Wingo PA: Cancer statistics. CA Cancer J Clin 50: 7–33, 2000

    Google Scholar 

  2. Osborne M, Boyle P, Lipkin M: Cancer prevention. Lancet 349(Suppl II): 27–30, 1997

    Google Scholar 

  3. Verno SW: Participation in colorectal cancer screening: A review. J Natl Cancer Inst 89: 1406–1422, 1997

    Google Scholar 

  4. Wattenberg LW: An overview of chemoprevention: Current status and future prospects. Proceedings of the Society for Experimental Biology and Medicine 216: 133–141, 1997

    Google Scholar 

  5. Lippman S, Lee J, Sabini A: Cancer chemoprevention: Progress and promise. J Natl Cancer Inst 90(20): 1514–1518, 1998

    Google Scholar 

  6. Heinonen O, Albanes D: The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330: 1029–1035, 1994

    Google Scholar 

  7. Omen G, Goodman G, Thornquist M, Balmes J, Cullen M, Glass AK, et al.: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334(18): 1150–1155, 1996

    Google Scholar 

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

    Google Scholar 

  9. Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Maziarz FR, et al.: Association of the APC gene product with β-catenin. Science 262: 1731–1734, 1993

    Google Scholar 

  10. Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, et al.: Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253: 665–669, 1991

    Google Scholar 

  11. Groden J, Thliveris A, Samowitz W, Carlson M, Gilbert L, Albertsen H, et al.: Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66: 589–600, 1991

    Google Scholar 

  12. Fearnhead NS, Britton MP, Bodmer WF: The ABC of APC. Human Molec Genet 10(7): 721–733, 2001

    Google Scholar 

  13. Hiltunen MO, Alhonen L, Koistinaho J, Myohanen S, Paakkonen M, Marin S, Kosma VM, Janne J: Hypermethylation of the APC (Adenomatous Polyposis Coli) gene promoter region in human colorectal carcinoma. Int J Cancer 70: 644–648, 1997

    Google Scholar 

  14. Munemitsu S, Albert I, Souza B, Rubinfeld B, Polakis P: Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor suppressor protein. Proc Natl Acad Sci USA 92: 3046–3050, 1995

    Google Scholar 

  15. Hulsken J, Birchmeier W, Behrens J: E-cadherin and APC compete for the interaction with beta-catenin and the cytoskeleton. J Cell Biol 127: 2061–2069, 1995

    Google Scholar 

  16. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, et al.: Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-1-colon carcinoma. Science 275: 1784–1787, 1997

    Google Scholar 

  17. Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kuzler KW: Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275: 1787–1790, 1997

    Google Scholar 

  18. Funk CD, Funk LB, Kennedy ME, Pong AS, Fitzgerald GA: Human platelet/erythroleukemia prostaglandin synthase: cDNA cloning, expression, and gene chromosomal assignment. FASEB J 5: 2304–2312, 1991

    Google Scholar 

  19. Sigal E: The molecular biology of mammalian arachidonic acid metabolism. Am J Physiol 260: L13–L28, 1991

    Google Scholar 

  20. Sirois J, Richards J: Purification and characterization of a novel, distinct isoform of prostaglandin endoperoxide synthase induced by human chorionic gonadotrophin in granulosa cells of rat preovulatory follicles. J Biol Chem 267: 6382–6388, 1992

    Google Scholar 

  21. Herschman H: Prostaglandin synthase 2. Biochim Biophys Acta 1299: 125–140, 1996

    Google Scholar 

  22. Sano H, Kawahito Y, Wilder R, Hashiramoto A, Mukai S, Asai K, et al.: Expression of cyclooxygenase-1 and-2 in human colorectal cancer. Cancer Res 55: 3785–3789, 1995

    Google Scholar 

  23. Kargman S, O'Neill S, Vickers P, Evans J, Mancini J, Jothy S: Expression of prostaglandin G/H synthase-1 and-2 protein in human colon cancer. Proc AACR 36: 601, 1995

    Google Scholar 

  24. Hecht J, Rovai L, Herschman H: Cyclooxygenase-2 expression and regulation in colonic mucosa, cancer, and cell lines. Proc AACR 36: 598, 1995

    Google Scholar 

  25. Eberhart C, Coffey R, Radhika A, Giardiello F, Ferrenbach S, DuBois R: Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107: 1183–1188, 1994

    Google Scholar 

  26. Subbaramaiah K, Telang N, Ramonetti J, Araki R, DeVito B, Weksler B, et al.: Transcription of cyclooxygenase-2 is enhanced in transformed mammary epithelial cells. Cancer Res 56: 4424–4429, 1996

    Google Scholar 

  27. Boolbol S, Dannenberg A, Chadburn A, Martucci C, Guo X, Ramonetti J, et al.: Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res 56: 2556–2560, 1996

    Google Scholar 

  28. Oshima M, Dinchuk J, Kargman S, Oshima H, Hancock B, Kwong E, et al.: Suppression of intestinal polyposis in Apc-716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87: 803–809, 1996

    Google Scholar 

  29. DuBois R, Awad J, Morrow J, Roberts L, Bishop P: Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor–alpha and phorbol ester. J Clin Invest 93: 493–498, 1994

    Google Scholar 

  30. Tsujii M, DuBois R: Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 83: 493–501, 1995

    Google Scholar 

  31. Thiagalingam S, Lengauer C, Leach FS, Schutte M, Hahn SA, Overhauser J, et al.: Evaluation of candidate tumor suppressor genes on chromosome 18 in colorectal cancers. Nat Genet 13: 343–346, 1996

    Google Scholar 

  32. Fazeli A, Dickinson SL, Hermiston ML, Tighe RV, Steen RG, Small CG, et al.: Phenotype of mice lacking functional deleted in colorectal cancer (Dcc) gene. Nature 386: 796–804, 1997

    Google Scholar 

  33. Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, et al.: The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75: 1027–1038, 1993

    Google Scholar 

  34. Leach FS, Nicolaides NC, Papadopoulos N, Liv B, Jen J, Parsons R, et al.: Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75: 1215–1225, 1993

    Google Scholar 

  35. Brenner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, et al.: Mutation in the DNA mismatch repair gene homologuehMLH1is associated with hereditary nonpolyposis colon cancer. Nature 368: 258–261, 1994

    Google Scholar 

  36. Thibodeau SN, French AJ, Cunningham JM, Tester D, Burgart LJ, Roche PC, et al.: Microsatellite instability in colorectal cancer: Different mutator phenotypes and the principal involvement of hMLH1. Cancer Res 58: 1713–1718, 1998

    Google Scholar 

  37. Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, et al.: Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268: 1336–1338, 1995

    Google Scholar 

  38. Souza RF, Lei J, Yin J, Appel R, Zon TT, Zhou X, et al.: A transforming growth factor beta 1 receptor type II mutation in ulcerative colitis associated neoplasms. Gastroenterology 112: 40–45, 1997

    Google Scholar 

  39. Massague J: The transforming growth factor beta family. Annu Rev Cell Biol 6: 597–641, 1990

    Google Scholar 

  40. Massague J, Polyak K: Mammalian antiproliferative signals and their targets. Curr Opin Genet Dev 5(1): 91–96, 1995

    Google Scholar 

  41. Alexandrow M, Moses H: Transforming growth factor beta and cell cycle regulation. Cancer Res 55: 1452–1457, 1995

    Google Scholar 

  42. Oberhammer F, Pavelka M, Sharma S, Tiefenbacher R, Purchio A, Bursch W, Shulte-Hermann R: Induction of apoptosis in cultured hepatocytes and in regressing liver by transforming growth factor beta 1. Proc Natl Acad Sci USA 89: 5408–5412, 1992

    Google Scholar 

  43. Rorke E, Jacobberger J: Transforming growth factor-beta 1 (TGF beta 1) enhances apoptosis in human papillomavirus type 16-immortalized human ectocervical epithelial cells. Exp Cell Res 216: 65–72, 1995

    Google Scholar 

  44. Lin H, Wang XF, Ng-Eaton E, Weinberg R, Lodish H: Expression cloning of the TGF-beta type II receptor, a functional transmembrane serine/threonine kinase. Cell 68: 775–785, 1992

    Google Scholar 

  45. Wrana J, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M, Wang X-F, Massague J: TGF-beta signals through a heteromeric protein kinase receptor complex. Cell 71: 1003–1014, 1992

    Google Scholar 

  46. Moustakas A, Lin H, Henis Y, Plamondon J, O'connor-McCourt M, Lodish H: The transforming growth factor beta receptors types I, II and III form hetero-oligomeric complexes in the presence of ligand. J Biol Chem 268: 22215–22218

  47. Boyd F, Massague J: Transforming growth factor beta inhibition of epithelial cell proliferation linked to the expression of a 53-kDa membrane receptor. J Biol Chem 264: 2272–2278, 1989

    Google Scholar 

  48. Laiho M, Weis F, Boyd F, Ignotz R, Massague J: Responsiveness to transforming growth factor-beta (TGF-beta) restored by genetic complementation between cells defective in TGF-beta receptor I and II. J Biol Chem 266: 9108–9112, 1991

    Google Scholar 

  49. Laiho M, Weis M, Massague J: Concomitant loss of transforming growth factor (TGF) – beta receptor types I and II in TGF-beta-resistant cell mutants implicates both receptor types in signal transduction. J Biol Chem 265: 18518–18524, 1990

    Google Scholar 

  50. Wrana J, Attisano L, Wieser R, Ventura F, Massague J: Mechanism of activation of the TGF-β receptor. Nature 370: 341–347, 1994

    Google Scholar 

  51. Grady W, Myeroff L, Swinker S, Rajput A, Thiagalingam J, Lutterbaugh J, Neumann A, Brattain M, Chang J, Kim S-J, Kinzler K, Vogelstein B, Willson J, Markowitz S: Mutational inactivation transforming growth factor beta receptor type II in microsatellite stable colon cancers. Cancer Res 59: 320–324, 1999

    Google Scholar 

  52. Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan R, Zborowska E, Kinzler K, Vogelstein B, Brattain M, Willson JKV: Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268: 1336–1338, 1995

    Google Scholar 

  53. Parsons R, Myeroff L, Liu B, Willson JKV, Markowitz S, Kinzler K, Vogelstein B: Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res 55: 5548–5550, 1995

    Google Scholar 

  54. Thibodeau S, Bren G, Schaid D: Microsatellite instability in cancer of the proximal colon. Science 260: 816–819, 1993

    Google Scholar 

  55. Ionov Y, Peinado M, Malkhosyan S, Shibata D, Perucho M: Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363: 558–561, 1993

    Google Scholar 

  56. Markowitz S: TGF-β receptors andDNArepair genes, coupled targets in a pathway of human colon carcinogenesis. Biochim et Biophys Acta 1470: M13–M20, 2000

    Google Scholar 

  57. Bird R: Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: Preliminary findings. Cancer Lett 37: 147–151, 1987

    Google Scholar 

  58. Siu I, Pretlow T, Amini S, Pretlow T: Identification of dysplasia in human colonic aberrant crypt foci. Am J Pathol 150: 1805–1813, 1997

    Google Scholar 

  59. Polyak K, Hamilton S, Vogelstein B, Kinzler K: Early alteration of cell-cycle-regulated gene expression in colorectal neoplasia. Am J Pathol 149: 381–387, 1996

    Google Scholar 

  60. Takayama T, Katsuki S, Takahashi Y, Ohi M, Nojiri S, Sakamaki S, et al.: Aberrant crypt foci of the colon as precursors of adenoma and cancer. N Engl J Med 339: 1277–1284, 1998

    Google Scholar 

  61. Jen J, Powell S, Papadopoulos N, Smith K, Hamilton S, Vogelstein B, et al.: Molecular determinants of dysplasia in colorectal lesions. Cancer Res 54: 5523–5526, 1994

    Google Scholar 

  62. Pretlow T, Brasitus T, Fulton N, Cheyer C, Kaplan E: K-ras mutations in putative preneoplastic lesions in human colon. J Natl Cancer Inst 85: 2004–2007, 1993

    Google Scholar 

  63. Smith A, Stern H, Penner M, Hay K, Mitri A, Bapat B, et al.: Somatic APC and K-ras codon 12 mutations in aberrant crypt foci from human colons. Cancer Res 54: 5527–5530, 1994

    Google Scholar 

  64. Hamilton S: Pathogenesis of polyps (adenomas). Dis Colon Rectum 26: 413–414, 1983

    Google Scholar 

  65. Wargovich MJ, Chen CD, Harris C, Yang E, Velasco M: Inhibition of aberrant crypt growth by non-steroidal anti-inflammatory agents and differentiation agents in the rat colon. Int J Cancer 60(4): 515–519, 1995

    Google Scholar 

  66. Reddy B, Rao C, Seibert K: Evaluation of a cyclooxygenase-2 inhibitor for potential chemopreventive properties in colon carcinogenesis. Cancer Res 56: 4566–4569, 1996

    Google Scholar 

  67. Kawamori T, Rao C, Seibert K, Reddy B: Chemopreventive effect of celecoxib, a specific cyclooxygenase-2 inhibitor on colon carcinogenesis. Cancer Res 58: 409–412, 1998

    Google Scholar 

  68. Konstantakos A, Siu I, Pretlow T, Stellato T, Pretlow T: Human aberrant crypt foci with carcinoma in situ from a patient with sporadic colon cancer. Gastroenterology 111: 772–777, 1996

    Google Scholar 

  69. Thurnherr N, Deschner EE, Stonehill EH, Lipkin M: Induction of adenocarcinomas of the colon in mice by weekly injections of 1,2-dimethylhydrazine. Cancer Res 33: 940–945, 1973

    Google Scholar 

  70. Narisawa T, Sato T, Hayakawa M, Sakuma A, Nakano H: Carcinoma of the colon and rectum of rats by rectal infusion ofN-methyl-N-nitro-N-nitroguanidine. Gann 62: 231–234, 1971

    Google Scholar 

  71. Rogers KJ, Pegg AE: Formation of o6-methylguanine by alkylation of rat liver, colon and kidney DNA following administration of 1,2-dimethylhydrazine. Cancer Res 37: 4082–4087, 1977

    Google Scholar 

  72. Moon RC, Fricks CM, Schiff LJ: Effects of age and sex on colon carcinogenesis. Proc Am Assoc Cancer Res 17: 23–28, 1976

    Google Scholar 

  73. Winneker RC, Tompkins M, Westenberger P, Harris J: Morphological studies of chemically induced colon tumours in hamsters. Exp Mol Pathol 27: 19–34, 1977

    Google Scholar 

  74. Pozharisski KM, Kapustin YM, Likhachev AJ, Shaposhnicov JD: The mechanism of carcinogenic action of 1,2-dimethylhydrazine in rats. Int J Cancer 15: 673–683, 1975

    Google Scholar 

  75. Ward JM, Yamamoto RS, Brown CA: Pathology of intestinal neoplasm and other lesions in rats exposed to azoxymethane. J Natl Cancer Inst 51: 1029–1039, 1973

    Google Scholar 

  76. De Filippo C, Caderni G, Bazzicalupo M, Briani C, Giannini A, Fazi M, Dolara P: Mutations of the Apc gene in experimental colorectal carcinogenesis induced by azoxymethane in F344 rats. Br J Cancer 77: 2148–2151, 1998

    Google Scholar 

  77. Maltzman T, Whittington J, Driggers L, Stephens J, Ahnen D: AOM-induced mouse colon tumors do not express full-length APC protein. Carcinogenesis 18(12): 2435–2439, 1997

    Google Scholar 

  78. Bissonnette M, Khare S, von Lintig FC, Wali RK, Nguyen L, Zhang Y, Hart J, Skarosi S, Varki N, Boss GR, Brasitus TA: Mutational and nonmutational activation of p21ras in rat colonic azoxymethane-induced tumors: Effects on mitogen-activated protein kinase, cyclooxygenase-2 and cyclin D1. Cancer Res 60(16): 4602–4609, 2000

    Google Scholar 

  79. Singh J, Kulkarni N, Kelloff G, Reddy BS: Modulation of azoxymethane-induced mutational activation of ras protooncogenes by chemopreventive agents in colon carcinogenesis. Carcinogenesis 15(7): 1317–1323, 1994

    Google Scholar 

  80. Shivapurkar N, Tang Z, Ferreira A, Nasim S, Garett C, Alabaster O: Sequential analysis of K-ras mutations in aberrant crypt foci and colonic tumors induced by azoxymethane in Fischer-344 rats on high-risk diet. Carcinogenesis 15(4): 775–778, 1994

    Google Scholar 

  81. Vivona AA, Shpitz B, Medline A, Bruce WR, Hay K, Ward MA, Stern HS, Gallinger S: K-ras mutations in aberrant crypt foci, adenomas and adenocarcinomas during azoxymethane-induced colon carcinogenesis. Carcinogenesis 14(9): 1777–1781, 1993

    Google Scholar 

  82. Shivapurkar N, Belinsky SA, Wolf DC, Tang Z, Alabaster O: Absence of p53 gene mutations in rat colon carcinomas induced by azoxymethane. Cancer Lett 96(1): 63–70, 1995

    Google Scholar 

  83. Erdman SH, Wu HD, Hixson LJ, Ahnen DJ, Gerner EW: Assessment of mutations in Ki-ras and p53 in colon cancers from azoxymethane-and dimethylhydrazine-treated rats. Mol Carcinog 19(2): 137–144, 1997

    Google Scholar 

  84. Koesters R, Hans MA, Benner A, Prosst R, Boehm J, Gahlen J, Doeberitz MK: Predominant mutation of codon 41 of the beta-catenin proto-oncogene in rat colon tumors induced by 1,2-dimethylhydrazine using a complete carcinogenic protocol. Carcinogenesis 22(11): 1885–1890, 2001

    Google Scholar 

  85. Wang QS, Papanikolau A, Sabourin CL, Rosenberg DW: Altered expression of cyclin D1 and cyclin-dependent kinase 4 in azoxymethane-induced mouse colon tumorigenesis. Carcinogenesis 19(11): 2001–2006, 1998

    Google Scholar 

  86. Luceri C, De Filippo C, Caderni G, Gambacciani L, Salvatori M, Giannini A, Dolara P: Detection of somatic DNA alterations in azoxymethane-induced F344 rat colon tumors by random amplified polymorphic DNA analysis. Carcinogenesis 21(9): 1753–1756, 2000

    Google Scholar 

  87. Luongo C, Gould KA, Su LK, et al.: Mapping of multiple intestinal neoplasia (Min) to proximal chromosome 18 of the mouse. Genomics 15: 3–8, 1993

    Google Scholar 

  88. Moser AR, Pitot HC, Dove WF: A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247: 322–324, 1990

    Google Scholar 

  89. Dietrich WF, Lander ES, Smith JS, et al.: Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 75: 631–639, 1993

    Google Scholar 

  90. Oshima M, Dinchuk JE, Kargman SL, et al.: Suppression of intestinal polyposis in Apc delta 716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87: 803–809, 1996

    Google Scholar 

  91. Fodde R, Edelmann W, Yang K, et al.: A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc Natl Acad Sci USA 91: 8969–8973, 1994

    Google Scholar 

  92. Smits R, Kartheuser A, Jagmohan-Changur S, et al.: Loss of Apc and the entire chromosome 18 but absence of mutations at the Ras and Tp53 genes in intestinal tumors from Apc 1638N, a mouse model for Apc-driven carcinogenesis. Carcinogenesis 18: 321–327, 1997

    Google Scholar 

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

    Google Scholar 

  94. Lippman S, Lec J, Lotan R, et al.: Biomarkers as intermediate endpoints in chemoprevention trials. J Natl Cancer Inst 82: 555, 1990

    Google Scholar 

  95. Einspahr JG, Alberts DS, Gapstur SM, et al.: Surrogate end-point biomarkers as measures of colon cancer risk and their use in cancer chemoprevention trials. Cancer Epidemiol Biomarkers Prev 6: 37–48, 1997

    Google Scholar 

  96. O'Brien MJ, Winauer SJ, Zauber AG, et al.: The national polyp study: Patient and polyp characteristics associated with high-grade dysplasia in adenomas. Gastroenterology 98: 371–379, 1990

    Google Scholar 

  97. Hixson LJ, Fennerty MB, Sampliner RE, et al.: Two-year incidence of colonic adenomas developing after tandem colonoscopy. Am J Gastroenterol 89: 687–691, 1994

    Google Scholar 

  98. Kelloff GJ, Sigman CC, Johnson KM, Boone CW, Greenwald P, Crowell JA, Hawk ET, Doody LA: Perspectives on surrogate end points in the development of drugs that reduce the risk of cancer. Cancer Epidemiol Biomarkers Prev 9(2): 127–137, 2000

    Google Scholar 

  99. Fujii T, Rembacken BJ, Dixon MF, Yoshida S, Axon AT: Flat adenomas in the United Kingdom: Are treatable cancers being missed? Endoscopy 30(5): 437–443, 1998

    Google Scholar 

  100. Kudo S, Kashida H, Tamura T, Kogure E, Imai Y, Yamano H, et al.: Colonoscopic diagnosis and management of nonpolypoid early colorectal cancer. World J Surg 24(9): 1081–1090, 2000

    Google Scholar 

  101. Muto T, Kamiya J, Sawada T, Konishi F, Sugihara K, Kubota Y, et al.: Small 'flat adenoma' of the large bowel with special reference to its clinicopathologic features. Dis Colon Rectum 28(11): 847–851, 1985

    Google Scholar 

  102. Saitoh Y, Waxman I, West AB, Popnikolov NK, Gatalica Z, Watari J, et al.: Prevalence and distinctive biologic features of flat colorectal adenomas in a North American population. Gastroenterology 120(7): 1657–1665, 2001

    Google Scholar 

  103. Yashiro M, Carethers JM, Laghi L, Saito K, Slezak P, Jaramillo E, et al.: Genetic pathways in the evolution of morphologically distinct colorectal neoplasms. Cancer Res 61(6): 2676–2683, 2001

    Google Scholar 

  104. Shiff SJ, Basil R: The role of cyclooxygenase inhbition in the antineoplastic effects of nonsteroidal antiinflammatory drugs (NSAIDs). J Exp Med 190(4): 445–450, 1999

    Google Scholar 

  105. Shureiqui I, Lippman SM: Lipooxygenase modulation to reverse carcinogenesis. Cancer Res 61: 6307–6312, 2001

    Google Scholar 

  106. Pegg AE: Polyamine metabolism and its importance in neoplastic growth and as target for chemotherapy. Cancer Res 48: 759–774, 1988

    Google Scholar 

  107. Hixson LJ, Garewal HS, McGee DL, Sloan D, Fennerty MB, Sampliner RE, Gener EW: Ornithine decarboxylase and polyamines in colorectal neoplasia and mucosa. Cancer Epidemiol Biomarkers Prev 2: 369–374, 1993

    Google Scholar 

  108. Goodman G: The clinical evaluation of chemoprevention agents: Defining and contrasting phase I, II, III objectives. Cancer Res 52: 2752–2758, 1992

    Google Scholar 

  109. Einspahr J, Alberts D, Xie T, et al.: Comparison of proliferating cell nuclear antigen versus the more standard measures of rectal mucosal proliferation rates in subjects with a history of colorectal cancer and normal age-matched controls. Cancer Epidemiol Biomarkers Prev 4: 359–366, 1995

    Google Scholar 

  110. Boland CR, Montgomery CK, Kim YS: Alterations in human colonic mucin occurring with cellular differentiation and malignant transformation. Proc Natl Acad Sci USA 79: 2051–2055, 1988

    Google Scholar 

  111. Sam JS, Lynch HT, Burt RW, et al.: Abnormalities of lectin histochemistry in familial polyposis coli and hereditary nonpolyposis colorectal cancer. Cancer 66: 502–508, 1990

    Google Scholar 

  112. Hall PA, Coates PJ, Ansari B, Hopwood D: Regulation of cell number in the mammalian gastrointestinal tract: The importance of apoptosis. J Cell Sci 107: 3569–3577, 1994

    Google Scholar 

  113. Bedi A, Pasricha PJ, Akhtar AJ, et al.: Inhibition of apoptosis during development of colorectal cancer. Cancer Res 55: 1811–1816, 1995

    Google Scholar 

  114. Piazza G, Rahm A, Krutzsch M, et al.: Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res 55: 3110–3116, 1995

    Google Scholar 

  115. Barnes C, Cameron I, Hardman W, Lee M: Non-steroidal anti-inflammatory drug effect on crypt cell proliferation and apoptosis during initiation of rat colon carcinogenesis. Br J Cancer 77: 573–580, 1998

    Google Scholar 

  116. Stoner GD, Budd GT, Ganapathu R, DeYoung B, Kresty LA, Nitert M, Fryer B, Church JM, Provencher K, Pamucku R, Piazza G, Hawk E, Kelloff G, Elson P, van Stolk RU: Sulindac sulfone induced regression of rectal polyps in patients with familial adenomatous polyposis. Adv Exp Med Biol 470: 45–53, 1999

    Google Scholar 

  117. DuBois RN, Shao J, Tsujii M, et al.: G1 delay in cells over-expressing prostaglandin endoperoxide synthase-2. Cancer Res 56: 733–737, 1996

    Google Scholar 

  118. Shureiqui I, Lippman SM: Lipoxygenase modulation to reverse carcinogenesis. Cancer Res 61: 6307–6312, 2001

    Google Scholar 

  119. Narumiya S, Fitzgerald GA: Genetic and pharmacological analysis of prostanoid receptor function. J Clin Invest 108(1): 25–30, 2001

    Google Scholar 

  120. Watanabe K, et al.: Role of prostaglandin E receptor subtype EP1 in colon carcinogenesis. Cancer Res 59: 5093–5096, 1999

    Google Scholar 

  121. Crist K, Wang Y, Lubet R, et al.: P 53 accumulation and K-ras mutations as surrogate endpoint biomarkers (SEBs) for chemoprevention in a rat colon tumor model. Proc Am Assoc Cancer Res 36: A591, 1995

    Google Scholar 

  122. Singh J, Kelloff G, Reddy BS: Intermediate biomarkers of colon cancer: Modulation of expression of ras oncogene by chemopreventive agents during azoxymethane induced colon carcinogenesis. Carcinogenesis 14: 699–704, 1993

    Google Scholar 

  123. Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP: Alterations in DNA methylation: A fundamental aspect of neoplasia. Adv Cancer Res 72: 141–196, 1998

    Google Scholar 

  124. Bird AP: CpG-rich islands and the function of DNA methylation. Nature 321: 206–213, 1986

    Google Scholar 

  125. Bird A: The essentials of NA methylation. Cell 70: 5–8, 1992

    Google Scholar 

  126. Sakai T, Toguchida J, Ohtani N, Yandell DW, Rapaport JM, Dryja TP: Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am J Hum Genet 48: 880–888, 1991

    Google Scholar 

  127. Bird AP, Wolffe AP: Methylation-induced repression: Belts, braces and chromatin. Cell 99: 451–454, 1999

    Google Scholar 

  128. Jones PL, Wolffe AP: Relationships between chromatin organization an DNA methylation in determining gene expression. Semin Cancer Biol 9: 339–347, 1999

    Google Scholar 

  129. Herman JG, Merlo A, Mao L, et al.: Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 55: 4525–4530, 1995

    Google Scholar 

  130. Herman JG, Umar A, Polyak K, et al.: Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95: 6870–6875, 1998

    Google Scholar 

  131. Esteller M, Sparks A, Toyota M, et al.: Analysis of adenomatous polyposis coli promoter hypermethylation in human cancer. Cancer Res 60: 4366–4371, 2000

    Google Scholar 

  132. Jubb AM, Bell SM, Quirke P: Methylation and colorectal cancer. J Pathol 195: 111–134, 2001

    Google Scholar 

  133. Issa JP: CpG-island methylation in aging and cancer. Curr Top Microbiol Immunol 249: 101–118, 2000

    Google Scholar 

  134. Logan RFA, Little J, Hawtin PG, Hardcastle JD: Effect of aspirin and non-steroidal anti-inflammatory drugs on colorectal adenomas: Case-control study of subjects participating in the Nottingham faecal occult blood screening programme. BMJ 307: 285–289, 1993

    Google Scholar 

  135. Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Ascherio A, Willett WC: Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med 121: 241–246, 1994

    Google Scholar 

  136. Kune G, Kune S, Watson L: Colorectal cancer risk, chronic illnesses, operations and medications: Case control results from the Melbourne Colorectal Cancer Study. Cancer Res 48: 4399–4404, 1988

    Google Scholar 

  137. Thun MJ, Namboodiri MM, Heath CW Jr.: Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 328: 1593–1596, 1991

    Google Scholar 

  138. Paganini-Hill A, Hsu G, Ross RK, Henderson BE: Aspirin use and incidence of large bowel cancer in a California retirement community. J Natl Cancer Inst 83: 1182–1183, 1991

    Google Scholar 

  139. Moorghen M, Ince P, Finney KJ, Suhnter JP, Watson AJ, Appleton DR: The effect of sulindac on colonic tumour formation in dimethylhydrazine-treated mice. Acta Histochemica 34(Suppl): 195–199, 1990

    Google Scholar 

  140. Pollard M, Luckert PH: Treatment of chemically-induced intestinal cancer with indomethacin. Proc Soc Exp Biol Med 167: 161–164, 1981

    Google Scholar 

  141. Pollard M, Luckert PH: Effect of indomethacin on intestinal tumor induced in rats by the acetate derivative of dimethylnitrosamine. Science 214: 558–559, 1981

    Google Scholar 

  142. Pollard M, Luckert PH, Schmidt MA: The suppressive effect of piroxicam on autochronous intestinal tumors in the rat. Cancer Lett 21: 57–61, 1983

    Google Scholar 

  143. Reddy BS, Maruyama H, Kelloff G: Dose-related inhibition of colon carcinogenesis by dietary piroxicam, a nonsteriodal anti-inflammatory drug, during different stages of rat colon tumor development. Cancer Res 47: 5340–5346, 1987

    Google Scholar 

  144. Baron J, Tosteson T, Wargovich M, Sandler R, Mandel J, Bond J, et al.: Calcium supplementation and rectal mucosal proliferation: A randomized controlled trial. J Natl Cancer Inst 87: 1303–1307, 1995

    Google Scholar 

  145. Reddy BS, Rao CV, Rivenson A, Kelloff G: Inhibitory effect of aspirin on azoxymethane-induced colon carcinogenesis in F344 rats. Carcinogenesis 14: 1493–1497, 1993

    Google Scholar 

  146. Kawamori T, Rao C, Seibert K, Reddy B: Chemopreventive effect of celecoxib, a specific cyclooxygenase-2 inhibitor on colon carcinogenesis. Cancer Res 58: 409–412, 1998

    Google Scholar 

  147. Oshima M, Dinchuk J, Kargman S, Oshima H, Hancock B, Kwong E, et al.: Suppression of intestinal polyposis in Apc delta 716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87: 803–809, 1996

    Google Scholar 

  148. Laboyle D, Fischer D, Vielh P, et al.: Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology 101: 635–639, 1991

    Google Scholar 

  149. Nugent KP, Farmer KCR, Spigelman AD, Williams CB, Phillips RKS: Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br J Surg 80: 1618–1619, 1993

    Google Scholar 

  150. Giardiello FM, Hamilton SR, Krush AJ, et al.: Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 328: 1313–1316, 1993

    Google Scholar 

  151. Steinbach G, Lynch PM, Phillips RKS, et al.: The effect of celecoxib a cyclooxygenase-2 inhibitor in familial adenomatous polyposis. N Engl J Med 342: 1946–1952, 2000

    Google Scholar 

  152. Keller JJ, Offerhaus GJ, Polak M, et al.: Rectal epithelial apoptosis in familial adenomatous polyposis patients treated with sulindac. Gut 45: 822–828, 1999

    Google Scholar 

  153. Spagnesi M, Tonelli F, Dolara P, et al.: Rectal proliferation and polyp recurrence in patients with familial adenomatous polyposis after sulindac treatment. Gastroenterology 106: 362–366, 1994

    Google Scholar 

  154. Block G, Patterson B, Subar A: Fruit, vegetables and cancer prevention:Areviewof the epidemiological evidence. Nutr Cancer 18(1): 1–29, 1992

    Google Scholar 

  155. Leclercq C, Valsta LM, Turrini A: Food composition issues – implications for the development of food-based dietary guidelines. Public Health Nutr 4(2B): 677–682, 2001

    Google Scholar 

  156. Bostick RM, Potter JD, Sellers TA, McKenzie DR, Kushi LH, Folsom AR: Relation of calcium, vitamin D, and dairy food intake to incidence of colon cancer among older women. The IowaWomen's Health Study. Am J Epidemiol 137: 1302–1317, 1993

    Google Scholar 

  157. Tseng M, Murray SC, Kuper LL, Sandler RS: Micronutrients and the risk of colorectal adenomas. Am J Epidemiol 144(11): 1026–1027, 1996

    Google Scholar 

  158. Kampman E, Goldbohm RA, van den Brandt PA, Van't Veer P: Fermented dairy products, calcium and colorectal cancer in the Netherlands Cohort Study. Cancer Res 54(12): 3186–3190, 1994

    Google Scholar 

  159. Little J, Logan RF, Hawtin PG, Hardcastle JD, Turner ID: Colorectal adenomas and diet:Acase-control study of subjects participating in the Nottingham faecal occult blood screening programme. Br J Cancer 67: 177–184, 1993

    Google Scholar 

  160. Neugut AI, Horvath K, Whelan RL, Terry MB, Garbowski GC, Bertram A, Forde KA, Treat MR, Waye J: The effect of calcium and vitamin supplements on the incidence and recurrence of colorectal adenomatous polyps. Cancer 78(4): 723–728, 1996

    Google Scholar 

  161. Bergma-Kadijk JA, van't Veer P, Kampman E, Burema J: Calcium does not protect against colorectal neoplasia. Epidemiology 7(6): 590–597, 1996

    Google Scholar 

  162. Bostick RM, Potter JD, Fosdick L, et al.: Calcium and colorectal epithelial cell proliferation. A preliminary randomized, double-blind, placebo-controlled clinical trial. J Natl Cancer Inst 85: 132–141, 1993

    Google Scholar 

  163. Newmark HL, Wargovich MJ, Bruce WR: Colon cancer and dietary fat, phosphate, and calcium: A hypothesis. J Natl Cancer Inst 72: 1323–1325, 1984

    Google Scholar 

  164. Pence BC: Role of calcium in colon cancer prevention: Experimental and clinical studies. Mutat Res 290: 87–95, 1993

    Google Scholar 

  165. Lipkin M, Newmark H: Effect of added dietary calcium on colonic epithelial-cell proliferation in subjects at high risk for familial colonic cancer. N Engl J Med 313(22): 1381–1384, 1985

    Google Scholar 

  166. Wargovich MJ, Isbell G, Shabot M, Winn R, Lanza F, Hochman L, Larson E, Lynch P, Roubein L, Levin B: Calcium supplementation decreases rectal epithelial cell proliferation in subjects with sporadic adenoma. Gastroenterology 103(6): 1994–1995, 1992

    Google Scholar 

  167. Cats A, Kleibeuker JH, van der Meer R, Kuipers F, Sluiter WJ, Hardonk MJ, Oremus ET, Mulder NH, de Vries EG: Randomized, double-blinded, placebo-controlled intervention study with supplemental calcium in families with hereditary nonpolyposis colorectal cancer. J Natl Cancer Inst 87: 598–603, 1995

    Google Scholar 

  168. Stern HS, Gregoire RC, Kashtan H, Stadler J, Bruce RW: Long-term effects of dietary calcium on risk markers for colon cancer in patients with familial polyposis. Surgery 108(3): 528–533, 1990

    Google Scholar 

  169. Baron JA, Tosteson TD, Wargovich MJ, Sandler R, Mandel J, Bond J, Haile R, Summers R, van Stolk R, Rothstein R: Calcium supplementation and rectal mucosal proliferation: A randomized controlled trial. J Natl Cancer Inst 87(17): 1303–1307, 1995

    Google Scholar 

  170. Lupton JR, Steibach G, Chang WC, O'brien BC, Wiese S, Stoltzfus CL, Glober GA, Wargovich MJ, McPherson RS, Winn RJ: Calcium supplementation modifies the relative amounts of bile acids in bile and affects key aspects of human colon physiology. J Nutr 126(5): 1421–1428, 1996

    Google Scholar 

  171. Alberts DS, Ritenbaugh C, Story JA, Aickin M, Rees-McGee S, Buller MK, Atwood J, Phelps J, Ramanujam PS, Bellapravalu S, Patel J, Bextinger L, Clark L: Randomized, double-blinded, placebo-controlled study of effect of wheat bran fiber and calcium on fecal bile acids in patients with resected adenomatous colon polyps. J Natl Cancer Inst 88(2): 81–92, 1996

    Google Scholar 

  172. Baron JA, Beach M, Mandel JS, van Stolk RU, Haile RW, Sandler RS, Rothstein R, Summers RW, Snover DC, Beck GJ, Frankl H, Pearson L, Bond JH, Greenberg ER: Calcium supplements and colorectal adenomas. Ann NY Acad Sci 889: 138–145, 1999

    Google Scholar 

  173. Burkitt DP: Epidemiology of cancer of the colon and rectum. Cancer 28: 3–13, 1971

    Google Scholar 

  174. Reddy BS, Hedges AR, Laaskso K, et al.: Metabolic epidemiology of large bowel cancer: Fecal bulk and constituents of high-risk North American and low-risk Finnish population. Cancer 42: 2832–2838, 1978

    Google Scholar 

  175. Hill MJ: Dietary fibre and human cancer: Epidemiological data. Adv Exp Med Biol 427: 27–34, 1997

    Google Scholar 

  176. Lupton JR: Is fiber protective against colon cancer? Where the research is leading us. Nutrition 16(7–8): 558–561, 2000

    Google Scholar 

  177. Eastwood MA, Hamilton D: Studies on the absorption of bile salts to non-adsorbed components of diet. Biochim Biophys Acta 152(1): 165–173, 1968

    Google Scholar 

  178. Kritchevsky D: Epidemiology of fibre, resistant starch and colorectal cancer. Eur J Cancer Prev 4: 345–352, 1995

    Google Scholar 

  179. D'Argenio G, Cosenza V, Cave MD, et al.: Butyrate production from dietary fibre and protection against large bowel cancer in a rat model. Gastroenterology 110: 1727–1734, 1996

    Google Scholar 

  180. Hill MJ: Cereals, cereal fibre and colorectal cancer risk: A review of the epidemiological literature. Eur J Cancer Prev 7(Suppl 2): S5–S10, 1998

    Google Scholar 

  181. Alberts DS, Martinez ME, Roe DJ, et al.: Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. N Engl J Med 342: 1156–1162, 2000

    Google Scholar 

  182. Schatzkin A, Lanza E, Corle D, et al.: Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. N Engl J Med 342: 1149–1155, 2000

    Google Scholar 

  183. Glynn SA, Albanes D, Pietinen P, Brown CC, Rautalahti M, Tangrea JA, Gunter EW, Barrett MJ, Virtamo J, Taylor PR: Colorectal cancer and folate status: A nested case-control study among male smokers. Cancer Epidemiol Biomarkers Prev 5: 487–494, 1996

    Google Scholar 

  184. White E, Shannon JS, Patterson RE: Relationship between vitamin and calcium supplement use and colon cancer. Cancer Epidemiol Biomarkers Prev 6(10): 769–774, 1997

    Google Scholar 

  185. Su LJ, Arab L: Eating patterns and risk of colon cancer. Am J Epidemiol 148(1): 4–16, 1998

    Google Scholar 

  186. Freudeheim JL, Graham S, Marshall JR, Haugey BP, Cholewinski S, Wilkinson G: Folate intake and carcinogenesis of the colon and rectum. Int J Epidemiol 20(2): 368–374, 1991

    Google Scholar 

  187. Lashner BA, Heidenreich PA, Su GL, Kane SV, Hanauer SB: Gastroenterology 97(2): 255–259, 1989

    Google Scholar 

  188. Lashner BA: Red blood cell folate is associated with the development of dysplasia and cancer in ulcerative colitis. J Cancer Res Clin Oncol 119(9): 549–554, 1993

    Google Scholar 

  189. Ma J, Stampfer NJ, Giovanucci E, et al.: Methylenetetrahydrofolate reductase polymorphism, detary interactions, and risk of colorectal cancer. Cancer Res 57: 1098–1102, 1997

    Google Scholar 

  190. Chen J, Giovanucci E, Hankinson SE, et al.: A prospective study of methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms, and risk of colorectal adenoma. Carcinogenesis 19: 2129–2132, 1998

    Google Scholar 

  191. Giovannucci E, Stampfer MJ, Colditz GA, et al.: Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 85: 875–883, 1993

    Google Scholar 

  192. Cravo M, Fidalgo P, Pereira A, et al.: DNA methylation as an intermediate biomarker in colorectal cancer: Modulation by folic acid supplementation. Eur J Cancer Prev 3: 473–479, 1994

    Google Scholar 

  193. Giovannucci E, Rimm EB, Ascherio A, Stampfer MJ, Colditz GA, Willett WC: Alcohol, low-methionine – low folate diets, and risk of colon cancer in men. J Natl Cancer Inst 86(4): 265–273, 1995

    Google Scholar 

  194. Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C, Rosner BA, Speizer FE, Willett WC: Multivitamin use, folate and colon cancer in women in the Nurses' Health Study. Ann Intern Med 129(7): 517–524, 1998

    Google Scholar 

  195. Kim YI, Baik HW, Fawaz K, Knox T, Lee YM, Norton R, Libby E, Mason JB: Effects of folate supplementation on two provisional molecular markers of colon cancer: A prospective randomized trial. Am J Gastroenterol 96(1): 184–195, 2001

    Google Scholar 

  196. Reddy B, Rivenson A, El-Bayoumy K, Upadhyaya P, Pittman B, Rao C: Chemoprevention of colon cancer by organoselenium compounds and impact of high-and low-fat diets. J Natl Cancer Inst 89: 506–512, 1997

    Google Scholar 

  197. Reddy B, Xan C, Samaha H, Lubet R, Steele V, Kelloff G, Rao S: Chemoprevention of colon carcinogenesis by dietary perillyl alcohol. Cancer Res 57: 420–425, 1997

    Google Scholar 

  198. Tanaka T, Kawata K, Kakumoto M, Hara A, Murakami A, Kuki W, et al.: Citrus auraptene exerts dose-dependent chemopreventive activity in rat large bowel tumorigenesis: The inhibition correlates with suppression of cell proliferation and lipid peroxidation and with induction of Phase II drug metabolizing enzymes. Cancer Res 58: 2550–2556, 1998

    Google Scholar 

  199. Tanaka T, Kawabata K, Kakumoto M, Makita H, Matsunaga K, Mori H, et al.: Chemoprevention of azoxymethane-induced rat colon carcinogenesis by a xanthine oxidase inhibitor, 1´-acetoxychavicol acetate. Jpn J Cancer Res 88: 821–830, 1997

    Google Scholar 

  200. Tanaka T, Makita H, Satoh K, et al.: Chemoprevention of azoxymethane-induced rat colon carcinogenesis by the naturally-occurring flavonoids, diosmin and hesperidin. Carcinogenesis 18: 957–965, 1997

    Google Scholar 

  201. Rao CV, Rivenson A, Simi, B, Reddy BS: Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res 55: 259–266, 1995

    Google Scholar 

  202. Huang MT, Lou YR, Ma W, Newmark HL, Reuhl KR, Conney AH: Inhibitory effects of dietary curcumin on forestomach, duodenal and colon carcinogenesis in mice. Cancer Res 54: 5841–5847, 1994

    Google Scholar 

  203. Hanif R, Qiao L, Shiff S, Rigas B: Curcumin, a natural plant phenolic food additive inhibits cell proliferation and induces cell cycle changes in colon adenocarcinoma cell lines by a prostaglandin-independent pathway. J Lab Clin Med 130: 576–584, 1997

    Google Scholar 

  204. Cheng AL, Lin JK, Hsu MM, Shen TS, Ko JY, Lin JT, Wu MS, Yu HS, Jee SH, Chen GS, Chen TM, Chen CA, Lai MK, Pu YS, Pan MH, Wang UJ, Tsai CC, Hsieh CY: Phase I chemoprevention clinical trial of curcumin. Proc Am Soc Clin Oncol 17: 558a, 1998

    Google Scholar 

  205. Grodstein F, Newcomb PA, Stampler MJ: Postmenopausal hormone therapy and the risk of colorectal cancer: A review and meta-analysis. Am J Med 106(5): 574–582, 1999

    Google Scholar 

  206. Wysowski DK, Golden L, Burke L: Use of menopausal estrogens and medroxyprogesterone in the United States, 1982–1992. Obstet Gynecol 85: 6–10, 1995

    Google Scholar 

  207. Fernandez E, La Vecchia C, Braga C, et al.: Hormone replacement therapy and risk fo colon and rectal cancer. Cancer Epidemiol Biomarkers Prev 7: 329–333, 1998

    Google Scholar 

  208. Calle EE, Miracle-McMahill HL, Thun MJ, Heath CW Jr.: Estrogen replacement therapy and risk of fatal colon cancer in a prospective cohort of postmenopausal women. J Natl Cancer Inst 87: 517–523, 1995

    Google Scholar 

  209. Grodstein F, Platz EA, Giovannucci E, Colditz GA, Kantzky M, Fuchs C, Stampfer MJ: Postmenopausal hormone use and risk of colorectal cancer and adenoma. Ann Intern Med 128: 705–712, 1998

    Google Scholar 

  210. McMichael AJ, Potter JD: Reproduction, endogenous and exogenous sex hormones, and colon cancer: A review and hypothesis. J Natl Cancer Inst 65: 1201–1207, 1980

    Google Scholar 

  211. Ma J, Pollak MN, Giovannucci E, et al.: Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 91: 620–625, 1999

    Google Scholar 

  212. Slattery ML, Potter JD, Curtin K, Edwards S, Ma KN, Anderson K, Schaffer D, Samowitz WS: Estrogens reduce and withdrawal of estrogens increase risk of microsatellite instability-positive colon cancer. Cancer Res 61(1): 126–130, 2001

    Google Scholar 

  213. Arai N, Strom A, Rafter JJ, Gustafsson JA: Estrogen receptor beta mRNA in colon cancer cells: Growth effects of estrogen and genistein. Biochem Biophys Res Com 270(2): 425–431, 2000

    Google Scholar 

  214. Fiorelli G, Picariello L, Martineti V, Tonelli F, Brandi ML: Functional estrogen receptor beta in colon cancer cells. Biochem Biophys Res Com 261(2): 521–527, 1999

    Google Scholar 

  215. Alford TC, Do HM, Geelhoed GW, Tsangaris NT, Lippman ME: Steroid hormone receptors in human colon cancers. Cancer 43(3): 980–984, 1979

    Google Scholar 

  216. Lointier P, Wildrick DM, Boman BM: The effects of steroid hormones on a human colon cancer cell line in vitro. Anticancer Res 12(4): 1327–1330, 1992

    Google Scholar 

  217. Ziv Y, Gupta MK, Milsom JW, Vladisavljevic A, Kitago K, Fazio VW: The effect of tamoxifen on established human colorectal cancer cell lines in vitro. Anticancer Res 16(6B): 3767–3771, 1996

    Google Scholar 

  218. Picariello L, Fiorelli G, Brandi ML, Galli G, Malentacchi C, Montali E, Bigozzi U, Ficari F, Tonelli F: In vitro bioeffects of the antiestrogen LY117018 on desmoid tumor and colon cancer cells. Anticancer Res 17(3C): 2099–2104, 1997

    Google Scholar 

  219. Nakayama Y, Sakamoto H, Satoh K, Yamamoto T: Tamoxifen and gonadal steroids inhibit colon cancer growth in association with inhibition of thymidylate synthase, survivin and telomerase expression through estrogen receptor beta mediated system. Cancer Lett 161(1): 63–71, 2000

    Google Scholar 

  220. Ranelletti FO, Ricci R, Larocca LM, Maggiano N, Capelli A, Scambia G, Benedetti-Panici P, Mancuso S, Rumi C, Piantelli M: Growth-inhibitory effect of quercetin and presence of type-II estrogen-binding sites in human colon-cancer cell lines and primary colorectal tumors. Int J Cancer 50(3): 486–492, 1992

    Google Scholar 

  221. Ziv Y, Fazio VW, Kitago K, Gupta MK, Sawady J, Nishioka K: Effect of tamoxifen on 1,2-dimethylhydrazine-HCl-induced colon carcinogenesis in rats. Anticancer Res 17(2A): 803–810, 1997

    Google Scholar 

  222. Smirnoff P, Liel Y, Gnainsky J, Shany S, Schwartz B: The protective effect of estrogen against chemical induced murine colon carcinogenesis is associated with decreased CpG island methylation and increased mRNA and protein expression of the colonic vitamin D receptor. Oncol Res 11(6): 255–264, 1999

    Google Scholar 

  223. Gamet I, Cazenave Y, Trocheris V, et al.: Involvement of ornithine decarboxylase in the control of proliferation of the HT29 human colon cancer cell line. Int J Cancer 47: 633–638, 1991

    Google Scholar 

  224. Luk GD, Baylin SB: Ornithine decarboxylase as a biologic marker in familial colonic polyposis. N Engl J Med 311: 80–83, 1984

    Google Scholar 

  225. Thompson H, Ronan A: Effect of D,L-2-difluoromethylornithine and endocrine manipulation of the induction of mammary carcinogenesis by 1-methyl-1-nitrosurea. Carcinogenesis 7: 2003–2006, 1986

    Google Scholar 

  226. Boyle JO, Meyskens FL Jr., Garewal HS, Gerner EW: Polyamine contents in rectal and buccal mucosa in humans treated with oral difluoromethylornithine. Cancer Epidemiol Biomarkers Prev 1: 131–135, 1992

    Google Scholar 

  227. Love R, Carbone P, Verma A, et al.: Randomized phase I chemoprevention dose seeking study of α-difluoromethylornithine. J Natl Cancer Inst 85: 732–737, 1993

    Google Scholar 

  228. Love RR, Jacoby R, Newton MA, Tutsch KD, Simon K, Pomplun M, Verma AK: A randomized, placebo-controlled trial of low-dose alpha-difluoromethylornithine in individuals at risk for colorectal cancer. Cancer Epidemiol Bio Prev 7(11): 989–992, 1998

    Google Scholar 

  229. Meyskens FL, Emerson SS, Pelot D, Meshkinpour H, Shassetz LR, Einspaar J, et al.: Dose de-escalation chemoprevention trial of α-difluoromethylornithine in patients with colon polyps. J Natl Cancer Inst 85: 732–736, 1994

    Google Scholar 

  230. Meyskens FL, Gerner EW, Emerson S, Pelot D, Durbin T, Doyle K, Lagerberg W: Effects of α-difluoromethylornithine on rectal mucosal levels of polyamines in a randomized, double-blinded trial for colon cancer prevention. J Natl Cancer Inst 90(16): 1212–1218

  231. O'Dwyer ME, Druker BJ: STI571: An inhibitor of the BCR-ABL tyrosine kinase for the treatment of chronic myelogenous leukaemia. Lancer Oncol 1: 207–211, 2000

    Google Scholar 

  232. Meyskens F: Principles of human chemoprevention. Hematol Oncol Clin North Am 12(5): 1–7, 1998

    Google Scholar 

  233. Coffey R, Hawkey C, Damstrup L, Graves-Deal R, Daniel V, Dempsey P, et al.: Epidermal growth factor receptor activation induces nuclear targeting of cyclooxygenase-2, basolateral release of prostaglandins, and mitogenetis in polarizing colon cancer cells. Proc Natl Acad Sci USA 94: 657–662, 1997

    Google Scholar 

  234. Sheng H, Shao J, Dixon DA, Williams CS, Prescott SM, DuBois RN, et al.: Transforming growth factor-beta1 enhances Ha-ras-induced expression of cyclooxygenase-2 in intestinal epithelial cells via stabilization of mRNA. J Biol Chem 275(9): 6628–6635, 2000

    Google Scholar 

  235. Sheng H, Shao J, Hooton EB, Tsujii M, DuBois RN, Beauchamp RD: Cyclooxygenase-2 induction and transforming growth factor beta growth inhibition in rat intestinal epithelial cells. Cell Growth Differ 8(4): 463–470, 1997

    Google Scholar 

  236. Torrance CJ, Jackson PE, Montgomery E, Kunzler KW, Vogelstein B, Wissner A, Nunes M, Frost P, Discafani CM: Combinatorial chemoprevention of intestinal neoplasia. Nat Med 6(9): 1024–1028, 2000

    Google Scholar 

  237. Gupta RS, DuBois RN: Combinations for cancer prevention. Nat Med 6(9): 974–975, 2000

    Google Scholar 

  238. Jacoby RF, Cole CE, Tetsch K, Newton MA, Kelloff G, Hawk ET, Lubet RA: Chemoprevention efficacy of combined piroxicam and difluoromethylornithine treatment of Apc mutant Min mouse adenomas, and selective toxicity against Apc mutant embryos. Cancer Res 60(7): 1864–1870, 2000

    Google Scholar 

  239. Carbone PP, Douglas JA, Larson PO, Verma AK, Blair IA, Pomplun M, Tutsch KD: Phase I chemoprevention study of piroxicam and alpha-difluoromethylornithine. Cancer Epidemiol Biomarkers Prev 7(10): 907–912, 1998

    Google Scholar 

  240. Harris G, Gupta A, Nines R, Kresty L, Habib S, Frankel W, et al.: The effects of lyophilized black raspberries on azoxymethane-induced colon cancer and 8-hydroxy-2´-deoxyguanosine levels in the Fischer 344 rat. Nutr Cancer 40(2): 125–133, 2001

    Google Scholar 

  241. Li H, Kramer P, Lubet R, Steele V, Kelloff G, Pereira M: Effects of calcium on azoxymethane-induced aberrant crypt foci and cell proliferation in the colon of rats. Cancer Lett 124: 39–46, 1998

    Google Scholar 

  242. Deschner EE, Cohen BI, Raicht RF: The kinetics of the protective effect of beta-sitosterol against MNU-induced colonic neoplasia. J Cancer Res Clin Oncol 103(1): 49–54, 1982

    Google Scholar 

  243. Rao C, Tokumo K, Rigotty J, Zang E, Kelloff G, Reddy B: Chemoprevention of colon carcinogenesis by dietary administration of piroxicam, a-difluoromethylornithine, 16-a-fluoro-5-androsten-17-one, and ellagic acid individually and in combination. Cancer Res 51: 4528–4534, 1991

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL

    David M. Gustin

  2. Department of Internal Medicine, Pharmacology and Family Practice, University of Michigan Medical School and Ann Arbor Veterans' Affairs Medical Center, Ann Arbor, MI, USA

    Dean E. Brenner

Authors
  1. David M. Gustin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dean E. Brenner
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gustin, D.M., Brenner, D.E. Chemoprevention of Colon Cancer: Current Status and Future Prospects. Cancer Metastasis Rev 21, 323–348 (2002). https://doi.org/10.1023/A:1021271229476

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1021271229476

Search

Navigation