The MNU Plus Testosterone Rat Model of Prostate Carcinogenesis

Abstract

Animal models of prostate cancer are essential to identify chemopreventive treatments against this major male malignancy. The N-methyl- N-nitrosourea (MNU) plus testosterone rat model of prostate carcinogenesis is a reliable animal model that recapitulates human prostate cancer in many respects and has been used extensively in chemoprevention studies with good predictive value for the results of human clinical trials. The objective of this article is to describe the induction protocol of this model, demonstrate its robustness and reproducibility over time and across rat strains, provide diagnostic criteria for the identification of prostate lesions, and present the current tumor induction protocol so that others can use this model in a reliable manner. The majority of accessory sex gland tumors in this model are adenocarcinomas originating in the anterior and dorsolateral prostate that metastasize to lungs and abdominal structures. The rat strain used is of critical importance, with the commercially available Wistar WU and Fischer F344 strains yielding the highest tumor incidences. Low dose, long-term testosterone treatment is essential for a high tumor incidence, but in advanced stage, large adenocarcinomas do not appear to be androgen dependent. This rat model is a robust and reproducible prostate cancer animal model of human prostate cancer.

Appraising Animal Models of Prostate Cancer for Translational Research: Future Directions

“…The animals of the second sacrifice were exposed to the implants for 44 weeks whereas the animals sacrificed first were only exposed for 18 weeks. This is in agreement with other studies and demonstrated that the longer the exposure to testosterone by slow-release implants, the greater the number of lesions (24,26). It is worth noting that control rats sacrificed at 61 weeks-old also developed lesions, although at a much lower frequency than those observed in treated rats.…”

“…This protocol induced adenocarcinomas and atypical hyperplastic lesions in the ventral, dorsolateral, and anterior prostate. Later, Marteen C. Bosland developed a chemical carcinogen plus testosterone rat model of prostate carcinogenesis that resembles human PCa in several aspects and became the most widely used animal model (7,24). First, rats are treated daily with an antiandrogen, such as flutamide or cyproterone acetate, to inhibit prostate epithelial cell proliferation, followed by the administration of testosterone propionate to induce a synchronous cell proliferation peak.…”

“…Finally, the rats receive lowdose testosterone via slow-release silastic implants until the end of experiment to sustain tumor development. This long multistep protocol was reported to induce a high incidence of adenocarcinomas in the rat dorsolateral prostate, 12-13 months after MNU administration (24)(25)(26). Considering the wide use of the Bosland rat model for PCa chemoprevention studies, the present work aimed to critically evaluate this animal model of cancer, appraising tumor incidence, location, and histological characteristics.…”

Validation of the Rat Model of Prostate Cancer: Correlating Seminal Vesicle Lesions With Dorsolateral Prostate Lesions

“…This multistep protocol induces lesions in the dorsolateral prostate lobe of the rat, which is considered homologous to the peripheral zone of the prostate in humans, where most carcinomas develop (15). Associated with this protocol, the seminal vesicles also develop preneoplastic and neoplastic lesions, such as atypical hyperplasia and adenocarcinoma (11,12). The present article is innovative by presenting specific results of seminal vesicle lessons, correlating them with prostate lesions, and characterizing their proliferation index.…”

“…Adenocarcinomas of the seminal vesicles are rare spontaneous tumors in most strains of rats and mice (9,10). However, seminal vesicle lesions, mainly adenocarcinomas, are frequently found in animal models of chemically and hormonally induced prostate cancer (PCa) (11,12). Despite this, the development of PCa lesions have rarely been correlated with seminal vesicle lesions.…”