薬理と治療

Abstract

Background　It is known that 7,12-dimethylbenz（a）anthracene（DMBA）induces mammary tumors in rats, and SHN strain mice have a high potential for mammary carcinogenesis. Medroxyprogesterone acetate（MPA）has antiestrogenic and antigonadotropic activities, and tamoxifen（TAM）has agonistic and antagonistic activities for estrogen. The 5-fluorouracil derivative, UFT has been used as an oral anticancer drug. Thymidylate synthase（TS）and thymidine kinase（TK）, key enzymes in the de novo and salvage pathways for pyrimidine nucleotide synthesis, are highly active in rapidly proliferating tissues. Methods　We investigated the effects of MPA and TAM on DMBA-induced rat mammary tumors, and the effects of MPA and UFT on mammary carcinogenesis in SHN virgin mice. Results　MPA and TAM reduced the number of rat mammary tumors with reduction of plasma levels of estradiol and tissue TS and TK activities. However, MPA with estrogen slightly shortened the latent period of mouse mammary carcinogenesis. Long-term administrations of low-dose UFT lowered the number of hyperplastic alveolar nodules, which were representative preneoplastic states in mammary glands of mice, with decrease in both TS and TK activities, and high-dose UFT decreased total volume of mammary tumors with diminution of TS activity, but not TK, in SHN mice. Conclusions　MPA and TAM could suppress mammary carcinogenesis in rats, but MPA with estrogen might slightly hasten mammary carcinogenesis in mice. UFT might inhibit mammary carcinogenesis via the de novo pathway for pyrimidine nucleotide synthesis in mice.