• 1
    Boone CW, Steele VE, Kelloff GJ. Screening for chemopreventive (anticar-cinogenic) compounds in rodents. Mutat Res 1992; 267: 2515.
  • 2
    Olivo S, Wargovich MJ. Inhibition of aberrant crypt foci by chemopreventive agents. In Vivo 1998; 12: 15966.
  • 3
    Hirose Y, Kuno T, Yamada Y, Sakata K, Katayama M, Yoshida K, Qiao Z, Hata K, Yoshimi N, Mori H. Azoxymethane-induced beta-catenin-accumulated crypts in colonic mucosa of rodents as an intermediate biomarker for colon carcinogenesis. Carcinogenesis 2003; 24: 10711.
  • 4
    Carderni G, Femia, AP, Giannini A, Favuzza A, Luceri C, Salvadori M, Dolara P. Identification of mucin-depleted foci in the unsectioned colon of azoxymethane-treated rats: correlation with carcinogenesis. Cancer Res 2003; 63: 238892.
  • 5
    Femia AP, Dolara P, Caderni G. Mucin-depleted foci (MDF) in the colon of rats treated with azoxymethane (AOM) are useful biomarkers for colon carcinogenesis. Carcinogenesis 2004; 25: 27781.
  • 6
    Ichii S, Takeda S, Horii A, Nakatsuru S, Miyoshi Y, Emi M, Fujiwara Y, Koyama K, Furuyama J, Utsunomiya J, Nakamura Y. Detailed analysis of genetic alterations in colorectal tumors from patients with and without familial adenomatous polyposis (FAP). Oncogene 1993; 8: 2399405.
  • 7
    Miyaki M, Konishi M, Kikuchi-Yanoshita R, Enomoto M, Igari T, Tanaka K, Muraoka M, Takahashi H, Amada Y, Fukayama M, Maeda Y, Iwama T, Mishima Y, Mori T, Koike M. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res 1994; 54: 301120.
  • 8
    Konishi M, Kikuchi-Yanoshita R, Tanaka K, Muraoka M, Onda A, Okumura Y, Kishi N, Iwama T, Mori T, Koike M, Ushio K, Chiba M, Nomizu S, Konishi F, Utsunomiya J, Miyaki M. Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology 1996; 111: 30717.
  • 9
    Jen J, Powell SM, Papadopoulos N, Smith KJ, Hamilton SR, Vogelstein B, Kinzler KW. Molecular determinants of dysplasia in colorectal lesions. Cancer Res 1994; 54: 55236.
  • 10
    Smith AJ, Stern HS, Penner M, Hay K, Mitri A, Bapat BV, Gallinger S. Somatic APC and K-ras codon 12 mutations in aberrant crypt foci from human colons. Cancer Res 1994; 54: 552730.
  • 11
    Yamashita N, Minamoto T, Ochiai A, Onda M, Esumi H. Frequent and characteristic K-ras activation and absence of p53 protein accumulation in aberrant crypt foci of the colon. Gastroenterology 1995; 108: 43440.
  • 12
    Otori K, Konishi M, Sugiyama K, Hasebe T, Shimoda T, Kikuchi-Yanoshita R, Mukai K, Fukushima S, Miyaki M, Esumi H. Infrequent somatic mutation of the adenomatous polyposis coli gene in aberrant crypt foci of human colon tissue. Cancer 1998; 83: 896900.
  • 13
    Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61: 75967.
  • 14
    Rubinfeld B, Souza B, Albert I, Müller O, Chamberlain SH, Masiarz FR, Munemitsu S, Polakis P. Association of the APC gene product with β-cate-nin. Science 1993; 262: 17314.
  • 15
    Munemitsu S, Albert I, Souza B, Rubinfeld B, Polakis P. Regulation of intra-cellular β-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci USA 1995; 92: 304650.
  • 16
    Yost C, Torres M, Miller JR, Huang E, Kimelman D, Moon RT. The axis-inducing activity, stability, and subcellular distribution of β-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev 1996; 10: 144354.
  • 17
    Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW. Activation of β-catenin-Tcf signaling in colon cancer by mutations in β-catenin or APC. Science 1997; 275: 178790.
  • 18
    Sparks AB, Morin PJ, Vogelstein B, Kinzler KW. Mutational analysis of the APC/β-catenin/Tcf pathway in colorectal cancer. Cancer Res 1998; 58:11304.
  • 19
    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 1997; 19: 13744.
  • 20
    Caderni G, Filippo D, Luceri C, Fazi M, Dolara P, Bazzicalupo M. Ape mutations in aberrant crypt foci and colonic tumors induced by azoxymethane in rats. Proc Am. Assoc Cancer Res 1997; 38: 467 (3122).
  • 21
    Matsumoto K, Iwase T, Hirono I, Nishida Y, Iwahori Y, Hori T, Asamoto M, Takasuka N, Kim DJ, Ushijima T, Nagao M, Tsuda H. Demonstration of ras and p53 gene mutations in carcinomas in the forestomach and intestine and soft tissue sarcomas induced by N-methyl-N-nitrosourea in the rat. Jpn J Cancer Res 1997; 88: 12936.
  • 22
    Kakiuchi H, Watanabe M, Ushijima T, Toyota M, Imai K, Weisburger JH, Sugimura T, Nagao M. Specific 5“-GGGA-3′[RIGHTWARDS ARROW]5′-GGA-3′ mutation of the Apc gene in rat colon tumors induced by 2-amino-l-methy1-6-phenylimi-dazo[4,5-b]pyridine. Proc Natl Acad Sci USA 1995; 92: 9104.
  • 23
    Kakiuchi H, Ushijima T, Ochiai M, Imai K, Ito N, Yachi A, Sugimura T, Nagao M. Rare frequency of activation of the Ki-ras gene in rat colon tumors induced by heterocyclic amines: possible alternative mechanisms of human colon carcinogenesis. Mol Carcinog 1993; 8: 448.
  • 24
    Stopera SA, Murphy LC, Bird RP. Evidence for a ras gene mutation in azoxymethane-induced colonic aberrant crypts in Sprague-Dawley rats: earliest recognizable precursor lesions of experimental colon cancer. Carcinogenesis 1992; 13: 20815.
  • 25
    Vivona AA, Shpitz B, Medline A, Bruce WR, Ward MA, Stern HS, Gallinger G. K-ras mutations in aberrant crypt foci, adenomas and adenocarcinomas during azoxymethane-induced colon carcinogenesis. Carcinogenesis 1993; 14: 177781.
  • 26
    Fiala ES. Investigations into the metabolism and mode of action of the colon carcinogens 1,2-dimethylhydrazine and azoxymethane. Cancer 1977; 40: 243645.
  • 27
    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 1977; 37: 40827.
  • 28
    Takahashi M, Fukuda K, Sugimura T, Wakabayashi K. β-Catenin is frequently mutated and demonstrates altered cellular location in azoxymethane-induced rat colon tumors. Cancer Res 1998; 58: 426.
  • 29
    Takahashi M, Mutoh M, Kawamori T, Sugimura T, Wakabayashi K. Altered expression of β-catenin, inducible nitric oxide synthase and cyclooxygenase-2 in azoxymethane-induced rat colon carcinogenesis. Carcinogenesis 2000; 21: 131927.
  • 30
    Dashwood RH, Suzui M, Nakagama H, Sugimura T, Nagao M. High frequency of β-catenin (Ctnnbl) mutations in the colon tumors induced by two heterocyclic amines in the F344 rat. Cancer Res 1998; 58: 11279.
  • 31
    Singh J, Kulkarni N, Kelloff G, Reddy BS. Modulation of azoxymethane-induced mutational activation of ras protooncogenes by chemopreventive agents in colon carcinogenesis. Carcinogenesis 1994; 15: 131723.
  • 32
    Takahashi M, Nakatsugi S, Sugimura T, Wakabayashi K. Frequent mutations of the β-catenin gene in mouse tumors induced by azoxymethane. Carcinogenesis 2000; 21: 111720.
  • 33
    Maltzman T, Whittington J, Driggers L, Stephens J, Ahnen D. AOM-induced mouse colon tumors do not express full-length APC protein. Carcinogenesis 1997; 18, 24359.
  • 34
    Jackson PE, Cooper DP, O'Connor PJ, Povey AC. The relationship between 1,2-dimethylhydrazine dose and the induction of colon tumors: tumor development in female SWR mice does not require a K-ras mutational event. Carcinogenesis 1999; 20: 50913.
  • 35
    Ambs S, Merriam WG, Bennett WP, Felley-Bosco E, Ogunfusika MO, Oser SM, Klein S, Shields PG, Billiar TR, Harris CC. Frequent nitric oxide synthase-2 expression in human colon adenomas: implication for tumor angio-genesis and colon cancer progression. Cancer Res 1998; 58: 33441.
  • 36
    Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, Dubois RN. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994; 107: 11838.
  • 37
    Takahashi M, Fukuda K, Ohata T, Sugimura T, Wakabayashi K. Increased expression of inducible and endothelial constitutive nitric oxide synthases in rat colon tumors induced by azoxymethane. Cancer Res 1997; 57: 12337.
  • 38
    Jenkins DC, Charles IG, Baylis SA, Lelchuk R, Radomski MW, Moncada S. Human colon cancer cell lines show a diverse pattern of nitric oxide synthase gene expression and nitric oxide generation. BrJ Cancer 1994; 70: 8479.
  • 39
    Takahashi M, Mutoh M, Shoji Y, Kamanaka K, Naka M, Maruyama T, Sugimura T, Wakabayashi K. Transfection of K-rasAsp12 cDNA markedly elevates IL-1β and lipopolysaccharide-mediated inducible nitric oxide synthase expression in rat intestinal epithelial cells. Oncogene 2003; 22: 766776.
  • 40
    Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 1995; 83: 493501.
  • 41
    DuBois RN, Shao J, Tsujii M, Sheng H, Beauchamp RD. G1, delay in cells overexpressing prostaglandin endoperoxide synthase-2. Cancer Res 1996; 56: 7337.
  • 42
    Tsujii M, Kawano S, Tsujii S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998; 93: 70516.
  • 43
    Prescott SM, White RL. Self-promotion? Intimate connections between APC and prostaglandin H synthese-2. Cell 1996; 87: 7836.
  • 44
    Howe LR, Subbaramaiah K, Chung WJ, Dannenberg AJ, Brown AMC. Transcriptional activation of cyclooxygenase-2 in Wnt-1-transformed mouse mammary epithelial cells. Cancer Res 1999; 59: 15727.
  • 45
    Mei JM, Hord NG, Winterstein DF, Donald SP, Phang JM. Differential expression of prostaglandin endoperoxide H synthase-2 and formation of activated β-catenin-LEF-1 transcription complex in mouse colonic epithelial cells contrasting in Apc. Carcinogenesis 1999; 20: 73740.
  • 46
    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 Dl. Cancer Res 2000; 60: 46029.
  • 47
    Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P. Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci USA 1993; 90:72404.
  • 48
    Corbett JA, Kwon G, Turk J, McDaniel ML. IL-lβ induces the coexpression of both nitric oxide synthase and cyclooxygenase by islets of Langerhans:activation of cyclooxygenase by nitric oxide. Biochemistry 1993; 32: 1376770.
  • 49
    Salvemini D, Seibert K, Masferrer JL, Misko TP, Currie MG, Needleman P. Endogenous nitric oxide enhances prostaglandin production in a model of renal inflammation. J Clin Invest 1994; 93: 19407.
  • 50
    Landino LM, Crews BC, Timmons MD, Morrow JD, Marnett LJ. Peroxynitrite, the coupling product of nitric oxide and superoxide, activates prostaglandin biosynthesis. Proc Natl Acad Sci USA 1996; 93: 1506974.
  • 51
    Rigas B, Goldman IS, Levine L. Altered eicosanoid levels in human colon cancer. J Lab Clin Med 1993; 122: 51823.
  • 52
    Minoura T, Takata T, Sakaguchi M, Takada H, Yamamura M, Hioki K, Yamamoto M. Effect of dietary eicosapentaenoic acid on azoxymethane-induced colon Carcinogenesis in rats. Cancer Res 1988; 48: 47904.
  • 53
    Kawamori T, Uchiya N, Sugimura T, Wakabayashi K. Enhancement of colon Carcinogenesis by prostaglandin E2 administration. Carcinogenesis 2003; 24: 98590.
  • 54
    Watanabe K, Kawamori T, Nakatsugi S, Ohta T, Ohuchida S, Yamamoto H, Maruyama T, Kondo K, Ushikubi F, Narumiya S, Sugimura T, Wakabayashi K. Role of the prostaglandin E receptor subtype EP1, in colon Carcinogenesis. Cancer Res 1999; 59: 50936.
  • 55
    Mutoh M, Watanabe K, Kitamura T, Shoji Y, Takahashi M, Kawamori T, Tani K, Kobayashi M, Maruyama T, Kobayashi K, Ohuchida S, Sugimoto Y, Narumiya S, Sugimura T, Wakabayashi K. Involvement of prostaglandin E receptor subtype EP4 in colon Carcinogenesis. Cancer Res 2002; 62: 2832.
  • 56
    Shoji Y, Takahashi M, Kitamura T, Watanabe K, Kawamori T, Maruyama T, Sugimoto Y, Negishi M, Narumiya S, Sugimura T, Wakabayashi K. Down-regulation of prostaglandin E receptor subtype EP3 during colon cancer development. Gut 2004; in press.
  • 57
    Sonoshita M, Takaku K, Sasaki N, Sugimoto Y, Ushikubi F, Narumiya S, Oshima M, Taketo MM. Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716 knockout mice. Nat Med 2001; 7: 104851.
  • 58
    Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin Dl in colon carcinoma cells. Nature 1999; 398: 4226.
  • 59
    Utsunomiya T, Doki Y, Takemoto H, Shiozaki H, Yano M, Sekimoto M, Tamura S, Yasuda T, Fujiwara Y, Monden M. Correlation of beta-catenin and cyclin Dl expression in colon cancers. Oncology 2001; 61: 22633.
  • 60
    He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW. Identification of c-MYC as a target of the APC pathway. Science 1998; 281: 150912.
  • 61
    Kishimoto Y, Morisawa T, Hosoda A, Shiota G, Kawasaki H, Hasegawa J. Molecular changes in the early stage of colon Carcinogenesis in rats treated with azoxymethane. J Exp Clin Cancer Res 2002; 21: 20311.