Induction of proliferative lesions of ventral prostate, seminal vesicle, and other accessory sex glands in rats by N-methyl-N-nitrosourea: effect of castration, pretreatment with cyproterone acetate and testosterone propionate and rat strain.
Wistar (Cpb:WU), F344 or Sprague-Dawley rats were sequentially treated with cyproterone acetate (CA) for 21 days, testosterone propionate (TP) for 3 days, followed by a single i.v. injection of N-methyl-N-nitrosourea (MNU). One group of Wistar rats was castrated 4 weeks after MNU injection, and another group 58 weeks after MNU, when the first prostatic carcinoma was detected. Control groups received only CA + TP, CA, MNU, or they remained untreated. Early or late castration inhibited the development of atypical hyperplasia of the ventral prostate in Wistar rats. This lesion was induced by the CA + TP + MNU treatment in F344 rats, but not Sprague-Dawley rats; in Wistar rats, it was induced by CA + TP treatment, irrespective of whether MNU was given. Hypertrophic-hyperplastic lesions of the seminal vesicle were induced by MNU, irrespective of pretreatment, and their development was prevented by early castration and inhibited by late orchiectomy. Dorsolateral prostate carcinomas and preneoplasia occurred only in low incidence in Wistar and Sprague-Dawley rats. These lesions were absent in F344 rats that had received treatment with CA + TP + MNU. No dorsolateral prostate (pre)neoplasia was found in Wistar rats subjected to early orchiectomy, but rats castrated at 58 weeks had an incidence similar to that for the intact group treated with CA + TP + MNU. This finding supports the contention that androgens are required for the development of MNU-induced prostatic cancer in rats but that advanced carcinomas are androgen insensitive. Differences in incidence and localization of prostatic proliferative lesions between F344 and Wistar rats and between dorsolateral and ventral prostate could not be explained by differences in epithelial cell proliferative responses to CA + TP treatment at the time of MNU injection, since they were similar in ventral and dorsolateral prostate and were more prominent in F344 rats than in Wistar rats. DNA damage as estimated by MNU-induced unscheduled DNA synthesis also did not differ between dorsolateral and ventral prostate.
Bosland
M C
MC
Department of Biological Toxicology, TNO-CIVO Toxicology and Nutrition Institute, Zeist, The Netherlands.
Prinsen
M K
MK
Rivenson
A
A
Silverman
J
J
Fiala
E
E
Williams
G M
GM
Kroes
R
R
Weisburger
J H
JH
D000728:Androgens / Q000502:physiology; D000818:Animals; D003534:Cyproterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D017373:Cyproterone Acetate; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005834:Genital Neoplasms, Male / Q000139:chemically induced*; D008297:Male; D008770:Methylnitrosourea; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains / Q000502:physiology*; D012669:Seminal Vesicles / Q000187:drug effects* / Q000473:pathology; D013737:Testis / Q000502:physiology*; D013739:Testosterone / Q000494:pharmacology*; D013997:Time Factors
D000728:Androgens; D004273:DNA, Neoplasm; D013739:Testosterone; D017373:Cyproterone Acetate; D008770:Methylnitrosourea; D003534:Cyproterone