Polyamines and hormonal regulation of N-nitrosomethylurea-induced rat mammary tumor growth in vivo

We have observed that polyamines play an essential role in the expression of hormonal action on the growth of the N-nitrosomethylurea-induced mammary tumor cultured in soft agar. Since polyamine levels cannot be measured in this system, we could not determine whether tumor polyamine pools are under endocrine control. To test this hypothesis, the following experiments were conducted in N-nitrosomethylurea tumor-bearing rats in vivo. Both tamoxifen administration (200 micrograms/day) and ovariectomy produced dramatic reductions in tumor growth but neither treatment significantly altered tumor polyamine levels after either 7 or 21 days of treatment. Some decrease in tumor level of putrescine, spermidine, and spermine was observed 21 days after ovariectomy but it was not statistically significant. Exogenous administration of putrescine (300 mg/kg/day) reversed the antitumor effect of tamoxifen but did not prevent tumor regression induced by ovariectomy. This effect of putrescine was, however, variable in magnitude from experiment to experiment. To test whether the reversal of tamoxifen effect by putrescine might simply be due to interference with tamoxifen uptake by the tumor cells, we measured estrogen and progesterone receptors in the tumors of rats chronically treated with tamoxifen and tamoxifen plus putrescine. In both groups estrogen receptors are virtually undetectable, thus suggesting that putrescine had not inhibited tamoxifen entry into the cells and binding to estrogen receptors. Progesterone receptor levels were similarly high in both groups and not significantly different from control. These results indicate that at least under these experimental conditions N-nitrosomethylurea mammary tumor polyamine pools are not under ovarian hormone control. The mechanism by which putrescine reverses tamoxifen's effect remains unclear.