What’s “bipolar” androgen therapy? How does it work?

Traditional forms of hormone therapy for prostate cancer are based on the idea that you reduce testosterone levels as low as you can so as to stop the ability of testosterone and its metabolites (e.g., dihydrotestosterone) to stimulate growth of prostatic tissues — including prostate cancer cells.

These traditional forms of hormone therapy — also known as androgen deprivation therapy or ADT, using drugs like LHRH agonists, LHRH antagonists, and antiandrogens — are highly effective in the palliation of symptoms of metastatic prostate cancer (e.g., bone pain) but eventually all men will relapse.

What we have been learning about during the development of some of the currently investigational types of “second-line” hormone therapies (e.g., abiraterone acetate and MDV 3100) is the paradoxical idea that the growth of some “androgen-sensitive” prostate cancer cells can also be inhibited by “supraphysiologic” levels of androgens. In other words, the presence of testosterone and other androgens in levels far higher than normal may also help to inhibit growth of some prostate cancer cells.

Why does this happen?

According to a new article by Denmeade and Isaacs, the effect may be a consequence of the way that high levels of androgens affect the DNA of cells that express high levels of specific androgne receptors. One such recently described effect might be the way in which androgens can induce breaks into the double strands of DNA.

The authors have now initiated a small clinical trial in men with castration-resistant prostate cancer (CRPC). The trial is designed to test the effect of monthly treatments with an intramuscular depot injection of testosterone. This injection raises levels of testosterone far beyond what can be achieved with standard, gel-based testosterone applications (found in testosterone patches). The induction of a supraphysiologic level of testosterone is immediately followed by the use of etopside to augment any effect on breaks in the patient’s DNA and then by standard ADT to induce a rapid drop of testosterone levels down in to the castrate range with each cycle of therapy.

The authors have termed this “bipolar androgen therapy.” According to their theory, bipolar androgen therapy eliminates the time needed for prostate cancer cells to adapt their androgen receptor expression to the environmental conditions in the body. Denmeade and Isaacs state that, “The goal is to determine if a clinical response can be achieved through this non-adaptive rapid cycling approach in men with CRPC.”

One Response

  1. What a cool and interesting study!

    I’m sure a lot of us will be looking for the results.

    Dr. Robert Leibowitz has been saying for years that he believed achieving a high testosterone after blockade (during the off-therapy phase of intermittent blockade) was probably beneficial. The Johns Hopkins work refines the tactic.

    Here’s hoping this works!

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