Effect of D,L-2-difluoromethylornithine and endocrine manipulation on the induction of mammary carcinogenesis by 1-methyl-1-nitrosourea.

The purpose of this investigation was to establish an efficient route and dose regime for the long-term administration of tamoxifen in the study of mammary tumorigenesis in the rat. The second objective of this work was to determine whether treatment with D,L-2-difluoromethylornithine (DFMO), a synthetic inhibitor of the enzyme ornithine decarboxylase, would reduce the occurrence of mammary cancers in tamoxifen-treated or ovariectomized rats. A total of 265 female Sprague-Dawley rats were assigned to one of two experimental protocols. All animals were injected with 50 mg 1-methyl-1-nitrosourea (MNU) per kg body wt at 50 days of age. In experiment 1, beginning 7 days after the injection of the carcinogen, animals were assigned to one of six groups which received either 0, 1 or 5 mg tamoxifen citrate per kg AIN-76A purified diet in addition to either no DFMO or a 0.125% w/v solution of DFMO as the drinking water. The experiment was terminated 180 days following carcinogen treatment. Treatment with tamoxifen resulted in a dose-dependent reduction in cancer incidence, and the number of cancers induced and significantly prolonged the median cancer-free time. This effect was also accompanied by a decrease in the rate of body weight gain. Treatment with DFMO delayed latency and reduced tumor number. DFMO in addition to tamoxifen (1 mg/kg diet) further prolonged latency. In experiment 2 each animal was assigned to one or four treatment groups when its first palpable mammary tumor was detected. At that time each was either ovariectomized or sham-operated. In addition, the rats were either provided no DFMO or a 0.5% w/v solution of DFMO as the drinking water. The study was terminated 35 weeks following carcinogen injection. Ovariectomy significantly inhibited the occurrence of additional mammary tumors. Ovariectomy plus DFMO was more effective than ovariectomy alone in reducing tumor number. Collectively, these observations indicate that suppression of polyamine biosynthesis via the systemic administration of DFMO inhibits the development of ovarian hormone insensitive mammary tumors.