Mechanistic analysis of multistage carcinogenesis in the rat prostate.

A new rat model of prostatic carcinomas has been developed using F344 rats and 3,2'-dimethyl-4-aminobiphenyl (DMAB). Immunohistochemical and biochemical investigation using polyclonal antibodies against DMAB-modified DNA showed DMAB-DNA adducts to be formed in all parts of the prostate including the seminal vesicles. DMAB normally induces in situ carcinomas limited to the ventral prostate. However, when it is given together with and followed by testosterone propionate (TP), invasive adenocarcinomas, some of which demonstrated metastatic growth in other organs, arose from the dorsolateral and anterior prostate and seminal vesicles, indicating that exogenous testosterone can exert strong enhancing effects on chemically induced carcinogenesis in these lobes of the rat prostate. Sequential observation has indicated that atypical hyperplasias are premalignant lesions and that testosterone plays a key role in the promotion and progression stages of prostate tumor development. By analogy, it is suggested that testosterone may exert equivalent influence on progression of prostate neoplasia in man. In the present studies low incidences of mutations were detected in p53 or K-ras genes in noninvasive and invasive rat prostate carcinomas induced by DMAB.