Difluoromethylornithine in combination with tamoxifen in female rats: 13-week oral toxicity study

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) is currently used for treatment of estrogen receptor-positive breast carcinoma and has d emonstrated efficacy in chemoprevention of breast cancer in women at high r isk for the disease. The administration of tamoxifen with DFMO is being con sidered for development by the National Cancer Institute as a potential dru g regimen for the chemoprevention of breast carcinoma. Methods: The toxicit y of DFMO in combination with TAM was evaluated in female rats following 13 weeks of daily administration by gavage. Dose groups were vehicle control, DFMO (1000 mg/kg per day), low TAM (0.25 mg/kg per day), high TAM (2.5 mg/ kg per day), low combination (1000 + 0.25) and high combination (1000 + 2.5 ). Results: No mortalities occurred in the study. Clinical signs of toxicit y were limited to dermal lesions consisting of scab formation and abrasions produced by DFMO. Administration of either DFMO or TAM resulted in decreas ed body weight gains, with coadministration having an additive effect. Seru m albumin, total protein, cholesterol and triglyceride levels were decrease d in all drug-treated dose groups, although histologic evidence of liver le sions were not seen. TAM resulted in increased numbers of red blood cells, whereas DFMO produced a slightly anemic response. DFMO produced lesions in the small intestine consisting of necrosis of crypt epithelium and crypt mi croabscess, which were enhanced by TAM coadministration. Administration of TAM resulted in histologic changes in the ovaries, fallopian tube, vagina, cervix and uterus, indicating that inhibition of ovulation and reproductive cycle arrest in the proestrus stage had occurred. Coadministration with DF MO did not affect the changes to the reproductive system induced by TAM. Co nclusions: Coadministration of DFMO with tamoxifen did not result in toxici ty unique to the combination drug regimen, but rather toxicity resulted fro m administration of each drug. Under the conditions of the study, the overa ll toxicity produced by dual administration of DFMO with tamoxifen was addi tive with respect to the toxicity associated with each agent alone.