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Testosterone and prostate cancer – new insights to help guide therapy

Christian Kratzik
Published in : HAMDAN MEDICAL JOURNAL ; Vol 6, No 2 (2013)
DOI : 10.7707/hmj.v6i2.276

Abstract


The role of androgen deprivation in slowing the effects of metastatic prostate cancer (PCa) has been recognized and established for more than 60 years. Nevertheless, the effect is only temporary, and virtually all cancers progress to a castration-resistant state. The discovery that late-stage PCa was driven by androgen receptor (AR) signalling led to it being described as ‘castration resistant’ rather than ‘hormone refractory’. During the castration-resistant stage, the PCa cell develops multiple cellular pathways to overcome androgen deprivation, including AR gene amplification, AR gene mutation, ligand-independent activation of the AR, involvement of coregulators and tumour stem cells as well as androgen production via a ‘backdoor pathway’. New therapeutic options have been created to work against these survival abilities of the PCa cell. Abiraterone [Zytige® (Jannsen-Cilag, Neuss, Germany)] inhibits the cytochrome P450 17 (CYP17) enzyme, which is essential for synthesis of testosterone from cholesterol, therefore affecting the traditional, as well as backdoor, pathways. Another promising drug, enzalutamide [Xtandi® (Astellas, Tokyo, Japan)] (formerly known as MDV3100), is an AR signalling inhibitor that may be able to overcome the increased transcription of ARs. It has been well known for several years that, in a certain number of PCa patients, the application of testosterone results in a decrease in prostate-specific antigen (PSA). To maintain cellular genetic stability and viability, chromosomal DNA must be precisely replicated once and only once during each cell cycle. This is carried out through a process known as DNA replication licensing, in which a licensing factor is bound at the origin of replication. In PCa cells, the AR has a ‘gain of function’ and acts as a licensing factor, which implies that the AR is degraded during mitosis because, without such degradation, the androgen-sensitive PCa cell will come to a subsequent S-phase arrest. This may be an explanation for the long-standing experimental paradox that testosterone can have a deleterious effect on PCa cells.


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