Influence of Delayed Administration of Retinyl Acetate on Mammary Carcinogenesis¹

Administration of a dietary retinoid supplement beginning 1 week after carcinogen administration is highly effective in the inhibition of rat mammary carcinogenesis. A study was designed at two carcinogen dose levels to determine to what extent retinoid feeding can be delayed and retain its chemoprotective effect. In the high-dose experiment, groups of 30 virgin female Sprague-Dawley rats received a single i.v. dose of 50 mg N-methyl-N-nitrosourea (MNU) per kg body weight and were fed a dietary supplement of 328 mg retinyl acetate per kg diet beginning at 1, 4, or 8 weeks after MNU administration. In the low-dose experiment, groups of 50 rats received 25 mg MNU per kg, and the retinoid was begun at 1, 4, 8, 12, 16, or 20 weeks post-MNU. Controls at both dose levels received a placebo diet beginning 1 week after carcinogen treatment. At the high MNU dose, retinyl acetate was most effective in inhibition of carcinogenesis when treatment was begun 1 week after MNU administration. Delaying retinyl acetate feeding until 4 weeks post-MNU resulted in slightly reduced chemoprotective efficacy, while an 8-week delay caused a complete loss of anticancer activity. At the low MNU dose, delaying retinyl acetate administration for up to 12 weeks after MNU administration caused no loss of chemopreventive efficacy. A 16-week delay resulted in decreased anticancer activity, while retinoid treatment begun 20 weeks post-MNU had no effect on cancer induction. Retinoid administration can be delayed beyond 1 week and retain its activity against rat mammary carcinogenesis; the length of delay allowable without loss of activity is a function of tumor latency.