The general objective of this project is to develop a chemical induction model in rats for prostatic carcinogenesis.
The specific aims are: 1) To adapt an existing experimental approach for induction of adenocarcinomas of the rat dorsolateral prostate prostatic carcinogenesis for use in a generally available rat strain (LEW-strain). The approach consists of sequential treatment with cyproterone acetate (CA) and testosterone propionate (TP) which leads to a wave of cell proliferation in the prostate. This is followed by a single treatment with methylnitrosourea (NMU) or ethylnitrosourea (ENU) during the maximum of the cell proliferative activity. 2) To optimize the protocol for induction of prostatic cancer by determining the conditions needed for optimal cell proliferative response to CA and TP (measured by 3H-thymidine incorporation followed by autoradiography). 3) To study the correlation between time of carcinogen injection and time of maximal cell proliferation, in terms of (a) the final tumor response, and (b) the formation and disappearance of major fluorescent DNA adducts (7-alkylguanine and O6-alkylguanine) as measured by HPLC separation and fluorescence detection. 4) To study the morphology of preneoplastic and early neoplastic lesions in the prostate upon CA-TP-E/MNU treatment in serial-killing experiments. 5) To study the behaviour of the induced prostatic carcinomas upon transplantation into syngeneic rats, in particular their androgen-dependance. For this purpose, tumors will be transplanted into intact, castrated and androgen-treated rats.
