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Improving Intermittent Androgen-Deprivation Therapy: OFF Cycle and the Role of Steroid 5α-Reductase Inhibitors

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Androgen Action in Prostate Cancer

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Abstract

Intermittent androgen-deprivation therapy (IADT) consists of cycles of androgen-deprivation (ON cycle) and treatment-free periods (OFF cycle), and is under investigation as a means to improve quality of life and retard progression to castration-recurrent prostate cancer in patients with advanced prostate cancer. IADT appears to be as effective as continuous androgen-deprivation therapy, while improving the side-effect profile. During the OFF cycle of IADT, the androgen-deprived prostate cancer cells are re-exposed to androgens. This milieu of androgen-induced regrowth provides a unique window of opportunity for designing OFF cycle-specific interventions. Testosterone, relative to dihydrotestosterone (DHT), is more potent in the induction of growth suppressive androgen-response genes during regrowth of regressed prostate. These findings suggest that during the OFF cycle of IADT, steroid 5α-reductase (SRD5A) inhibitors can be used to enhance the expression of tumor suppressive androgen-response genes and retard tumor growth by blocking conversion of testosterone to DHT. This chapter discusses how addition of SRD5A inhibitors during the OFF cycle of IADT could improve survival under certain clinical conditions. The molecular changes that accompany treatment suggest that prolongation of the OFF cycle may not be advisable.

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Acknowledgments

We thank Minh Nguyen for critical reading, William H. Blair and Russell Gould for insightful discussion, and support from Department of Defense Prostate Cancer Research Program, DAMD 17-02-1-0113, National Institute of Health, R01 DK51193, and National Institute of Health Prostate Cancer Specialized Program of Research Excellence (SPORE), CA90386.

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    Zhou Wang

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  1. Shubham Gupta
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Gupta, S., Shevrin, D., Wang, Z. (2009). Improving Intermittent Androgen-Deprivation Therapy: OFF Cycle and the Role of Steroid 5α-Reductase Inhibitors. In: Mohler, J., Tindall, D. (eds) Androgen Action in Prostate Cancer. Springer, New York, NY. https://doi.org/10.1007/978-0-387-69179-4_9

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