Targeting castration-induced tumour hypoxia enhances the acute effects of castration therapy in a rat prostate cancer model

UNLABELLED: What's known on the subject? and What does the study add? Castration therapy has rather modest effects on cell death in tumours but can be enhanced by other treatments targeting tumour stroma and vasculature. This study shows that the prostate becomes hypoxic following castration and that targeting hypoxic cells during castration therapy potently enhances the effects of castration.

OBJECTIVE: To explore the effects of castration therapy, the standard treatment for advanced prostate cancer, in relation to tumour hypoxia and to elicit its importance for the short- and long-term therapeutic response.

MATERIAL AND METHODS: We used the androgen-sensitive rat Dunning H prostate tumour model that transiently responds to castration treatment followed by a subsequent relapse, much like the scenario in human patients. Tumour tissues were analysed using stereological methods in intact, 1 and 7 days after castration therapy.

RESULTS: Hypoxia was transiently up-regulated after castration therapy and correlated with the induction of tumour cell apoptosis. When castration therapy was combined with tirapazamine (TPZ), a drug that targets hypoxic cells and the vasculature, the effects on tumour cell apoptosis and tumour volume were enhanced in comparison to either castration or TPZ alone.

CONCLUSION: The present study suggests that castration-induced tumour hypoxia is a novel target for therapy.