EFFECT OF EARLY VS. LATE ADMINISTRATION OF 4-HYDROXYPHENYLRETINAMIDE (4-HPR) ON N-METHYL-N-NITROSOUREA (MNU)-INDUCED MAMMARY TUMORIGENESIS

Mammary tumors were induced in 48-52-day-old female Sprague-Dawley rat s in metestrus or diestrus with a single jugular injection of MNU (50 mg/kg). Control rats received the saline vehicle (Group 4 n = 9). Rats were fed 4% Teklad diet containing either 0 (Group 3, n = 20) or 782 mg 4-HPR/kg diet. 4-HPR supplementation was initiated either 1 week pr ior to (Group 1, n = 14) or 4 weeks following MNU administration (Grou p 2, n = 19). Neither body weight nor food intake differed significant ly between treatment groups. Feeding of 4-HPR 1 week prior to tumor in duction reduced the number of tumors (0.8+/-.2) when compared to MNU c ontrol rats (2.1+/-.4). Immunohistochemical staining of mammary tumor sections for PCNA was quantitated by microdensitometry and expressed a s an HSCORE. No differences in HSCORE were observed between tumor grou ps although the percentage of nuclear area occupied by intermediate an d darkly stained nuclei was reduced in the late 4-HPR group. GC-->AT t ransitions in codon 12 of the H-ras gene were detected in 50% (12/24) of MNU control tumors, 60% (6/10) of early 4-HPR tumors, and 38% (6/16 ) of late 4-HPR tumors. Mutation rates did not differ significantly be tween groups. 4-HPR appears to be a more effective chemopreventive whe n fed during the initiation period. (C) 1908 Wiley-Liss, Inc.