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Tumor Biology |
716 Mouse by Rofecoxib, a Specific Cyclooxygenase-2 Inhibitor
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd. (Merck), Tsukuba 300-2611, Japan [M. O., N. M. H.]; Merck Frosst Center for Therapeutic Research, Pointe-Claire Dorval, Quebec, Canada H9R 4P8 [S. K., M. A., P. L., E. K.]; University of Tokyo, Graduate School of Pharmaceutical Sciences, Laboratory of Biomedical Genetics, Tokyo 113-0033 Japan [M. M. T.]; and Merck & Co., Inc., West Point, Pennsylvania 19486 [J. F. E.]
Mutations in the human adenomatous
polyposis (APC) gene are causative for familial
adenomatous polyposis (FAP), a rare condition in which numerous colonic
polyps arise during puberty and, if left untreated, lead to colon
cancer. The APC gene is a tumor suppressor that has been
termed the "gatekeeper gene" for colon cancer. In addition to the
100% mutation rate in FAP patients, the APC gene is
mutated in >80% of sporadic colon and intestinal cancers. The
Apc gene in mice has been mutated either by chemical
carcinogenesis, resulting in the Min mouse
Apc
850, or by heterologous
recombination, resulting in the
Apc716 or
Apc1368 mice (M. Oshima
et al., Proc. Natl. Acad. Sci. USA, 92:
4482–4486, 1995). Although homozygote
Apc-/- mice are embryonically lethal, the
heterozygotes are viable but develop numerous intestinal polyps with
loss of Apc heterozygosity within the polyps (M. Oshima
et al., Proc. Natl. Acad. Sci. USA, 92:
4482–4486, 1995). The proinflammatory, prooncogenic protein
cyclooxygenase (COX)-2 has been shown to be markedly induced in
the Apc716 polyps at an early
stage of polyp development (M. Oshima et al., Cell,
87: 803–809, 1996). We demonstrate here that treatment
with the specific COX-2 inhibitor rofecoxib results in a dose-dependent
reduction in the number and size of intestinal and colonic polyps in
the Apc716 mouse. The plasma
concentration of rofecoxib that resulted in a 55% inhibition of polyp
number and an 80% inhibition of polyps >1 mm in size is comparable
with the human clinical steady-state concentration of 25 mg rofecoxib
(Vioxx) taken once daily (A. Porras et al., Clin. Pharm.
Ther., 67: 137, 2000). Polyps from both untreated
and rofecoxib- or sulindac-treated
Apc716 mice expressed COX-1
and -2, whereas normal epithelium from all mice expressed COX-1 but
minimal amounts of COX-2. Polyps from either rofecoxib- or
sulindac-treated mice had lower rates of DNA replication, expressed
less proangiogenic vascular endothelial-derived growth factor
and more membrane-bound ß-catenin, but showed unchanged
nuclear localization of this transcription factor. This study showing
the inhibition of polyposis in the
Apc716 mouse suggests that
the specific COX-2 inhibitor rofecoxib (Vioxx) has potential as a
chemopreventive agent in human intestinal and colon cancer.
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K. Yang, K. Fan, N. Kurihara, H. Shinozaki, B. Rigas, L. Augenlicht, L. Kopelovich, W. Edelmann, R. Kucherlapati, and M. Lipkin Regional response leading to tumorigenesis after sulindac in small and large intestine of mice with Apc mutations Carcinogenesis, March 1, 2003; 24(3): 605 - 611. [Abstract] [Full Text] [PDF]
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M. Yao, S. Kargman, E. C. Lam, C. R. Kelly, Y. Zheng, P. Luk, E. Kwong, J. F. Evans, and M. M. Wolfe Inhibition of Cyclooxygenase-2 by Rofecoxib Attenuates the Growth and Metastatic Potential of Colorectal Carcinoma in Mice Cancer Res., February 1, 2003; 63(3): 586 - 592. [Abstract] [Full Text] [PDF]
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S. Arico, S. Pattingre, C. Bauvy, P. Gane, A. Barbat, P. Codogno, and E. Ogier-Denis Celecoxib Induces Apoptosis by Inhibiting 3-Phosphoinositide-dependent Protein Kinase-1 Activity in the Human Colon Cancer HT-29 Cell Line J. Biol. Chem., July 26, 2002; 277(31): 27613 - 27621. [Abstract] [Full Text] [PDF]
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J. G. Edwards, S. P. Faux, S. M. Plummer, K. R. Abrams, R. A. Walker, D. A. Waller, and K. J. O'Byrne Cyclooxygenase-2 Expression Is a Novel Prognostic Factor in Malignant Mesothelioma Clin. Cancer Res., June 1, 2002; 8(6): 1857 - 1862. [Abstract] [Full Text] [PDF]
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C. Waskewich, R. D. Blumenthal, H. Li, R. Stein, D. M. Goldenberg, and J. Burton Celecoxib Exhibits the Greatest Potency amongst Cyclooxygenase (COX) Inhibitors for Growth Inhibition of COX-2-negative Hematopoietic and Epithelial Cell Lines Cancer Res., April 1, 2002; 62(7): 2029 - 2033. [Abstract] [Full Text] [PDF]
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M. J. Thun, S. J. Henley, and C. Patrono Nonsteroidal Anti-inflammatory Drugs as Anticancer Agents: Mechanistic, Pharmacologic, and Clinical Issues J Natl Cancer Inst, February 20, 2002; 94(4): 252 - 266. [Abstract] [Full Text] [PDF]
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Y. Cao, K. B. Dave, T. P. Doan, and S. M. Prescott Fatty Acid CoA Ligase 4 Is Up-Regulated in Colon Adenocarcinoma Cancer Res., December 1, 2001; 61(23): 8429 - 8434. [Abstract] [Full Text] [PDF]
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G. Lal, C. Ash, K. Hay, M. Redston, E. Kwong, B. Hancock, T. Mak, S. Kargman, J. F. Evans, and S. Gallinger Suppression of Intestinal Polyps in Msh2-deficient and Non-Msh2-deficient Multiple Intestinal Neoplasia Mice by a Specific Cyclooxygenase-2 Inhibitor and by a Dual Cyclooxygenase-1/2 Inhibitor Cancer Res., August 1, 2001; 61(16): 6131 - 6136. [Abstract] [Full Text] [PDF]
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 M. E. Burleigh, V. R. Babaev, J. A. Oates, R. C. Harris, S. Gautam, D. Riendeau, L. J. Marnett, J. D. Morrow, S. Fazio, and M. F. Linton Cyclooxygenase-2 Promotes Early Atherosclerotic Lesion Formation in LDL Receptor-Deficient Mice Circulation, April 16, 2002; 105(15): 1816 - 1823. [Abstract] [Full Text] [PDF]
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