Chemoprevention by Nimesulide, a Selective Cyclooxygenase‐2 Inhibitor, of 2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP)‐induced Mammary Gland Carcinogenesis in Rats

Wiley - Tập 91 Số 9 - Trang 886-892 - 2000
Seiichi Nakatsugi1, Toshihisa Ohta, Toshihiko Kawamori, Michihiro Mutoh, Toshiki Tanigawa, Kouji Watanabe, Shigeyuki Sugie, Takashi Sügimura, Keiji Wakabayashi
1Cancer Prevention Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan

Tóm tắt

Breast cancer is common in women all over the world, and exploration of chemopreventive approaches to this cancer is very important. Nimesulide, a selective inhibitor of cyclooxygenase‐2 (COX‐2), is a good candidate as a chemopreventive agent with low toxicity. We examined its effects on mammary tumor development in female Sprague‐Dawley rats induced with the environmental carcinogen 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP). Rats at 7 weeks of age received intragastric intubations of PhIP (85 mg/kg body weight) 4 times weekly for 2 weeks and were maintained on control diet (high fat diet) or experimental diet (high fat diet supplemented with 400 ppm nimesulide) throughout the experiment. COX‐2 protein was over‐expressed in epithelial cancer cells and stromal cells of the PhIP‐induced mammary carcinomas, but was weak or not apparent in normal mammary gland cells. The development of mammary carcinomas was clearly suppressed by administration of nimesulide. The carcinoma incidence was 51% as compared to 71% for the control diet group. The average multiplicity of carcinomas in the experimental diet group was 1.2±0.2 (P < 0.05), significantly smaller than the control diet group value (2.6±0.5). The size of carcinomas was also clearly decreased; 1.1±0.4 cm3/rat in experimental diet group (P < 0.05), 4.1±1.3 cm3/rat in the control diet group. The results therefore provide evidence that the selective COX‐2 inhibitor, nimesulide, possesses chemopreventive activity against PhIP‐induced mammary carcinogenesis in rats.

Từ khóa


Tài liệu tham khảo

10.1038/newbio231232a0

10.1016/0005-2760(95)00194-8

10.1053/gast.1996.v110.pm8613017

Sano H., 1995, Expression of cyclooxygenase‐1 and ‐2 in human colorectal cancer, Cancer Res., 55, 3785

10.1056/NEJM199112053252301

Rao C. V., 1995, Chemoprevention of colon carcinogenesis by sulindac, a nonsteroidal anti‐inflammatory agent, Cancer Res., 55, 1464

10.1093/carcin/14.8.1493

Noguchi M., 1991, Effects of the prostaglandin synthetase inhibitor indomethacin on tumorigenesis, tumor proliferation, cell kinetics, and receptor contents of 7,12‐ dimethylbenz[α]anthracene‐induced mammary carcinoma in Sprague‐Dawley rats fed a high‐ or low‐fat diet, Cancer Res., 51, 2683

10.1111/j.1349-7006.1997.tb00440.x

Taniguchi Y., 1995, Selective inhibition by nimesulide, a novel non‐steroidal anti‐inflammatory drug, with prostaglandin endoperoxide synthase‐2 activity in‐vitro, Pharm. Sci., 1, 173

10.1016/S0952-3278(96)90122-2

Cullen L., 1998, Selective cyclooxygenase‐2 inhibition by nimesulide in man, J. Pharmacol. Exp. Ther., 287, 578

Parrett M. L., 1997, Cyclooxygenase‐2 gene expression in human breast cancer, Int. J. Oncol., 10, 503

10.1093/jnci/90.6.455

10.1006/pmed.1995.1022

10.1097/00001648-199603000-00017

Thun M. J., 1993, Aspirin use and risk of fatal cancer, Cancer Res., 53, 1322

10.1093/jnci/88.14.988

10.1136/bmj.299.6710.1247

10.1006/pmed.1995.1018

10.1093/carcin/12.8.1503

Nagao M., 1999, “Carcinogenicity: Testing, Predicting, and Interpreting Chemical Effects, 563

10.1111/j.1349-7006.1997.tb00337.x

10.1093/carcin/19.11.1939

Okajima E., 1998, Chemopreventive effects of nimesulide, a selective cyclooxygenase‐2 inhibitor, on the development of rat urinary bladder carcinomas initiated by N‐butyl‐N‐(4‐ hydroxybutyl)nitrosoamine, Cancer Res., 58, 3028

Russo J., 1990, “Pathology of Tumours in Laboratory Animals, 47

Takahashi M., 1997, Increased expression of inducible and endothelial constitutive nitric oxide synthases in rat colon tumors induced by azoxymethane, Cancer Res., 57, 1233

10.1007/BF01209649

10.1016/S0092-8674(00)81988-1

10.1111/j.1349-7006.1997.tb00328.x

Kawamori T., 1998, Chemopreventive activity of celecoxib, a specific cyclooxygenase‐2 inhibitor, against colon carcinogenesis, Cancer Res., 58, 409

10.1016/S0952-3278(96)90130-1

10.1016/S0092-8674(00)81433-6

10.1006/bbrc.1993.1358

Kujubu D. A., 1992, Dexamethasone inhibits mitogen induction of the TIS10 prostaglandin synthase/cyclooxygenase gene, J. Biol. Chem., 267, 7991, 10.1016/S0021-9258(18)42398-8

10.1016/0092-8674(95)90127-2

Thông tin
Thông tin xuất bản

Wiley

Tập 91 Số 9

886-892

Thông tin tác giả