Retinoid-tamoxifen interaction in mammary cancer chemoprevention

The synthetic retinoid, N-(4-hydroxyphenyl)retinamide (4-HPR), and bilateral ovariectomy act synergistically to inhibit mammary cancer induction in female rats. Two parallel studies were conducted to determine if a similar interaction would be obtained with 4-HPR and the anti-estrogen, tamoxifen. Fifty-day-old, virgin, female Sprague-Dawley rats were given a single i.v. injection of 50 mg N-methyl-N-nitrosourea/kg body weight. Beginning 7 days post-carcinogen, groups of 30 rats were administered 4-HPR (391 or 782 mg/kg diet) and/or tamoxifen (2.5, 5, 10 or 100 micrograms s.c. three times per week); controls received a placebo diet and injections of vehicle only. Exposure to 4-HPR alone or tamoxifen alone reduced mammary cancer multiplicity and increased tumor latent period compared with the control. Combined administration of 4-HPR plus tamoxifen resulted in an enhanced inhibition of mammary carcinogenesis and caused a significant reduction in tumor-related mortality. These data suggest that retinoid administration may provide a means to increase the efficacy of hormonal manipulation in cancer prevention and therapy.