Thirteen-week oral toxicity study of difluoromethylornithine in combination with tamoxifen citrate in female dogs

被引:5
作者
Brown, AP
Morrissey, RL
Crowell, JA
Levine, BS
机构
[1] Univ Illinois, Dept Pharmacol, Toxicol Res Lab, Chicago, IL 60612 USA
[2] Pathol Assoc Int, Chicago, IL USA
[3] NCI, Div Canc Prevent & Control, NIH, Rockville, MD USA
关键词
tamoxifen; difluoromethylornithine; dogs; reproductive system toxicity; GI toxicity;
D O I
10.1007/s002800050927
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Cancer chemoprevention is the use of pharmacologic or natural agents to inhibit the development of cancer. Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in the biosynthesis of polyamines. DFMO has demonstrated chemopreventive efficacy in animal models of tumorigenesis. Tamoxifen (TAM), a nonsteroidal antiestrogen, is approved for use in the treatment of estrogen receptor-positive breast carcinoma and has demonstrated efficacy in chemoprevention of breast cancer in women at high risk for the disease. The administration of TAM with DFMO is being considered for development by the National Cancer Institute as a potential drug regimen for the chemoprevention of breast carcinoma. Methods: The toxicity of DFMO in combination with TAM was evaluated in female Beagle dogs following 13 weeks of daily oral administration by capsule. Dose levels in milligrams per kilogram body weight per day were: 0 (vehicle control), 100 DFMO, 0.1 TAM, 1.0 TAM, 0.1 TAM + 100 DFMO and 1.0 TAM + 100 DFMO. Results: No mortalities occurred. Diarrhea was produced by TAM and vaginal discharge, due to reproductive tract lesions, was produced by both DFMO and TAM, either alone or in combination. DFMO decreased reticulocyte counts and TAM increased counts of mature neutrophils. DFMO alone resulted in lesions to the intestines and ovaries, and cornified epithelium of vagina and cervix. TAM produced cornified epithelium of vagina and cervix, and numerous lesions in the ovaries, fallopian tube, uterus, cervix and vagina which were likely due to an estrogen agonist effect. Coadministration of DFMO increased the incidence and/or severity of these reproductive tract lesions. Each compound alone produced ovarian atrophy, and antral follicles and corpora lutea were completely absent in the 1.0 TAM + 100 DFMO group. Conclusions: Coadministration of DFMO and TAM resulted in additive toxicity involving the female reproductive system.
引用
收藏
页码:479 / 488
页数:10
相关论文
共 27 条
[1]   PHASE-I TRIAL AND PHARMACOKINETIC STUDIES OF ALPHA-DIFLUOROMETHYLORNITHINE - AN INHIBITOR OF POLYAMINE BIOSYNTHESIS [J].
ABELOFF, MD ;
SLAVIK, M ;
LUK, GD ;
GRIFFIN, CA ;
HERMANN, J ;
BLANC, O ;
SJOERDSMA, A ;
BAYLIN, SB .
JOURNAL OF CLINICAL ONCOLOGY, 1984, 2 (02) :124-130
[2]   Cell transformation, invasion, and angiogenesis: A regulatory role for ornithine decarboxylase and polyamines? [J].
Auvinen, M .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1997, 89 (08) :533-537
[3]  
BANAN A, 1996, AM J PHYSIOL, V34, pG893
[4]  
Boiko IV, 1997, CANCER EPIDEM BIOMAR, V6, P849
[5]  
BREAZILE JE, 1971, TXB VET PHYSL, P524
[6]   TAMOXIFEN - A REAPPRAISAL OF ITS PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES, AND THERAPEUTIC USE [J].
BUCKLEY, MMT ;
GOA, KL .
DRUGS, 1989, 37 (04) :451-490
[7]  
Chabner B., 1996, GOODMAN GILMANS PHAR, P1233
[8]   CHRONIC TOXICITY STUDIES OF THE POTENTIAL CANCER PREVENTIVE 2-(DIFLUOROMETHYL)-DL-ORNITHINE [J].
CROWELL, JA ;
GOLDENTHAL, EI ;
KELLOFF, GJ ;
MALONE, WF ;
BOONE, CW .
FUNDAMENTAL AND APPLIED TOXICOLOGY, 1994, 22 (03) :341-354
[9]  
Fong L. Y. Y., 1998, Proceedings of the American Association for Cancer Research Annual Meeting, V39, P193
[10]  
Goel V, 1998, CAN MED ASSOC J, V158, P1615