Combination of melatonin and tamoxifen as a chemoprophylaxis against N-nitroso-N-methylurea-induced rat mammary tumors

The effect of melatonin (Mel) and or tamoxifen (Tam) was evaluated on a mammary tumor model induced in 50 day old female Sprague-Dawley rats by a single intraperitoneal (i.p.) injection of a direct carcinogen, N-nitroso-N-methylurea (NMU) (50 mg/kg b.wt./rat). These animals were treated with either Mel 200 mu g/rat per day, orally in drinking water and/or Tam (s.c.) 60 mu g/rat per week or 180 mu g/rat per week. The total observation period was 300 days post-NMU administration in all the animals. The mean latency period of tumor appearance and tumor incidence was recorded. The mean latency period was significantly lengthened in all the treated groups as compared to that in the only NMU-administered rats (P < 0.001). Highly significant suppression of tumor incidence was observed in Mel + Tam(180) group (P < 0.001). The other two groups i.e. Mel + Tam(60), and Tam(180) also showed significant suppression of tumor incidence (P < 0.01). Eight weeks after the initiation of treatment regimen, we observed marked reduction in [H-3]thymidine incorporation into mammary gland DNA of Mel- and/or Tam-treated groups of animals as compared to the age-matched controls and NMU-administered rats, which correlated positively with the sparse mammary gland development seen in the whole mount preparations. The result of the combined therapy is highly promising and warrants clinical evaluation in the prophylaxis of breast carcinogenesis in humans. (C) 1997 Elsevier Science Ireland Ltd.