Induction of dorsolateral prostate adenocarcinomas and other accessory sex gland lesions in male Wistar rats by a single administration of N-methyl-N-nitrosourea, 7,12-dimethylbenz(a)anthracene, and 3,2'-dimethyl-4-aminobiphenyl after sequential treatment with cyproterone acetate and testosterone propionate.
Groups of 20-25 male Wistar rats (Cpb:WU), nine groups of 4-week-old rats, and nine groups of 8-week-old rats, were given cyproterone acetate (CA) s.c. or by gavage daily for 18 days at a dose of 50 mg/kg/day. Directly following CA treatment, the rats received 3 daily s.c. injections with testosterone propionate (TP) at a dose of 100 mg/kg/day. On the day after the last TP administration, a single dose of one of the following carcinogens was given to 3 groups: N-methyl-N-nitrosourea (MNU), 50 mg/kg i.v.; 7,12-dimethylbenz(a)anthracene, 30 mg/kg i.v.; 3,2'-dimethyl-4-aminobiphenyl, 250 mg/kg s.c. Three other groups received the same carcinogen treatments after 7 days of recovery from the CA administration. The last 3 groups received carcinogen without TP treatment, but immediately after CA pretreatment was stopped. A 25% incidence of invasively growing, metastasizing adenocarcinomas was found in the dorsolateral prostate region of 8-week-old rats that had received MNU after treatment with CA plus TP. In addition, this group had a 5% incidence of carcinoma in situ and a 5% incidence of atypical hyperplasia in the dorsolateral prostate. Lower incidences of adenocarcinoma of the dorsolateral prostate region and of carcinoma in situ and atypical hyperplasia of the dorsolateral prostate were found in other groups that were treated with MNU or 7,12-dimethylbenz(a)anthracene after pretreatment with CA, followed by TP or recovery, but never in rats that had been treated with CA only. In the groups treated with 3,2'-dimethyl-4-aminobiphenyl, which is slowly metabolized, these lesions were also found in groups that were pretreated with only CA. The carcinomas seemed to originate from the dorsolateral prostate and their average latency time was approximately 61 weeks. The 8-week-old rat given a MNU injection after sequential treatment with CA and TP may provide a relevant animal model for human prostatic cancer.
Bosland
M C
MC
Department of Biological Toxicology, TNO-CIVO Toxicology and Nutrition Institute, Zeist, The Netherlands.
Prinsen
M K
MK
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000008:administration & dosage*; D000230:Adenocarcinoma / Q000139:chemically induced*; D000611:Aminobiphenyl Compounds / Q000008:administration & dosage*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003534:Cyproterone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D017373:Cyproterone Acetate; D005837:Genitalia, Male / Q000033:anatomy & histology; D008297:Male; D008770:Methylnitrosourea / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000139:chemically induced*; D051381:Rats; D011919:Rats, Inbred Strains; D012513:Sarcoma, Experimental / Q000139:chemically induced; D016019:Survival Analysis; D013739:Testosterone / Q000008:administration & dosage*
D000611:Aminobiphenyl Compounds; C001042:2',3-dimethyl-4-aminobiphenyl; D013739:Testosterone; D017373:Cyproterone Acetate; D015127:9,10-Dimethyl-1,2-benzanthracene; D008770:Methylnitrosourea; D003534:Cyproterone