Article

Anti-androgens and androgen-depleting therapies in prostate cancer: New agents for an established target

Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
The Lancet Oncology (Impact Factor: 24.73). 10/2009; 10(10):981-91. DOI: 10.1016/S1470-2045(09)70229-3
Source: PubMed

ABSTRACT Activation of the androgen receptor is crucial for prostate cancer growth at all points of the illness. Current therapies targeting the androgen receptor, including androgen-depletion approaches and anti-androgens, do not completely inhibit the receptor activity. Prostate cancer cells develop resistance to castration by acquiring changes that include androgen-receptor overexpression and overexpression of enzymes involved in androgen biosynthesis, which result in reactivation of the receptor. Based on an understanding of these resistance mechanisms and androgen biosynthesis pathways, new anti-androgens and androgen-depleting agents have been developed. Notably, promising activity has been shown in early phase trials by MDV3100, a new anti-androgen designed for activity in prostate cancer model systems with overexpressed androgen receptor, and by abiraterone acetate, a CYP17A inhibitor that blocks steroid biosynthesis in the adrenal gland and possibly within the tumour. Both agents are undergoing phase 3 testing. Here, we review the basic science and clinical development of these and other agents.

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    • "Androgen receptor signaling has been shown to regulate the proliferation of PCa cells even in the advanced phase of the disease. Progression to the castration-resistant state depends on the AR (even after androgen deprivation therapy) because the receptor functions through its mutated form and/or is overexpressed (Chen et al., 2009). Therefore, the AR still remains a key driver of castration-resistant prostate cancer. "
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    • "This necessitates careful monitoring of adverse events and drug interactions. The responses observed after treatment with ketoconazole lead to the investigation of stronger and more selective CYP 17 inhibitors with a more favorable toxicity profile than ketoconazole [25]. "
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    • "These natural or synthesized compounds can express certain influence on different mechanisms of cancercells growth and, in that way, inhibit their proliferation. Steroidal compounds belong to a fundamental class of natural signalling molecules with very high potential for treatment of many types of diseases, including prostate cancer, breast cancer, colorectal cancer , brain tumor, cardiovascular and autoimmune disorders (Chen et al., 2009; Recht et al., 2013; Knutson and Lange, 2014; Vaklavas et al., 2011; Yu et al., 2013; Richmond et al., 2014), etc. Because of very wide spectrum of compounds which have low, moderate or high cytotoxic activity toward certain cancer cells, it is very useful to establish criteria for their selection which will be used for further detailed in vitro and in vivo studies of their desired or side effects. "
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    European Journal of Pharmaceutical Sciences 05/2014; DOI:10.1016/j.ejps.2014.05.031 · 3.01 Impact Factor
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