Thirteen-week oral toxicity study of difluoromethylornithine in combination with tamoxifen citrate in female dogs |
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| Authors: | Alan P Brown Robert L Morrissey James A Crowell Barry S Levine |
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| Institution: | (1) Toxicology Research Laboratory, Department of Pharmacology, University of Illinois at Chicago, 1940 West Taylor Street, Chicago, IL 60612-7353, USA Tel.: +1-312-996-5543; Fax: +1-312-996-7755, US;(2) Pathology Associates International, Chicago, IL, USA, US;(3) Division of Cancer Prevention and Control, National Cancer Institute, National Institutes of Health, Rockville, MD, USA, US |
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| Abstract: | 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.
Received: 1 July 1998 / Accepted: 25 September 1998 |
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| Keywords: | Tamoxifen Difluoromethylornithine Dogs Reproductive system toxicity GI toxicity |
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