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

Purpose: Cancer chemoprevention is the use of pharmacologic or natural agen ts to inhibit the development of cancer. Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase, the rate-limiting enz yme in the biosynthesis of polyamines. DFMO has demonstrated chemopreventiv e efficacy in animal models of tumorigenesis. Tamoxifen (TAM), a nonsteroid al 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 ca rcinoma. Methods: The toxicity of DFMO in combination with TAM was evaluate d 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 reticu locyte counts and TAM increased counts of mature neutrophils. DFMO alone re sulted in lesions to the intestines and ovaries, and cornified epithelium o f vagina and cervix. TAM produced cornified epithelium of vagina and cervix , and numerous lesions in the ovaries, fallopian tube, uterus, cervix and v agina which were likely due to an estrogen agonist effect. Coadministration of DFMO increased the incidence and/or severity of these reproductive trac t lesions. Each compound alone produced ovarian atrophy, and antral follicl es and corpora lutea were completely absent in the 1.0 TAM + 100 DFMO group . Conclusions: Coadministration of DFMO and TAM resulted in additive toxici ty involving the female reproductive system.