Effect of reduced body weight gain on the evaluation of chemopreventive agents in the methylnitrosourea-induced mammary cancer model.

These studies examined whether the small to moderate reductions in body weight gain (< or = 15%) affect mammary carcinogenesis. Beginning 1 week prior to methylnitrosourea (MNU) administration (experiment 1), rats received diets supplemented with 4-hydroxyphenylretinamide (4-HPR) (782 mg/kg of diet) and retinyl acetate (328 mg/kg of diet) or underwent food restrictions. Rats were administered an i.v. dose of MNU (50 mg/kg body wt) at 50 days of age. Although the final body weights were similarly depressed by 4-HPR (8%) and by retinyl acetate (11%) from rats fed ad libitum, the kinetics of inhibition were quite different. Whereas 4-HPR caused an acute decrease in body weight at the time it was administered, the effect of retinyl acetate was more chronic. At 110 days after the administration of MNU, the average number of mammary cancers per rat was 4.9 for rats fed ad libitum, 1.3 for rats fed 4-HPR, 3.1 when body weights were matched to 4-HPR-treated rats, 1.9 for retinyl acetate and 3.2 when body weights were matched to retinyl acetate. Experiment II was performed to determine the minimal degree of acute body weight gain reduction that would alter MNU-induced mammary carcinogenesis. Body weight gain depressions of 3, 6, 9, 12 and 15% were initiated at 43 days of age by dietary restrictions and MNU was administered at 50 days of age. At 120 days after MNU, the percentage decreases in mammary cancer multiplicity in the various groups were 14, 15, 41, 44 and 55%, respectively. These data demonstrate that moderate reductions (9-15%) in body weight gain, in particular when occurring during the initiation and early promotion stages can greatly affect cancer multiplicity.