More about mice and men … and doxorubicin … and Viagra


According to a thoroughly confusing media release from the Virginia Commonwealth University last week, “the impotence drug Viagra, in combination with doxorubicin, a powerful anti-cancer drug, enhances its anti-tumor efficacy in prostate cancer while alleviating the damage to the heart at the same time.”

So, just for starters, let us clarify … The media release is actually trying to explain that — in laboratory cell lines and in a mouse model — sildenafil (Viagra) seems to be able to increase the ability of doxorubicin (0ne of the oldest forms of proven chemotherapy) to generate the release of reactive oxygen species that trigger cell death, or apoptosis, in prostate cancer cells. It builds on prior research which has shown that the combination of sildenafil with doxorubicin may be able to reduce the well-known and serious side effects of doxorubicin on cardiac tissue, which has long limited the use of doxorubicin in patients with all sorts of cancers.

Now … before we move further forward … we should also carefully explain that there have never been any good data to demonstrate that either doxorubicin alone or any combination chemotherapy that includes doxorubicin have a significant clinical effect in the management of prostate cancer (see below).

What on Earth is this media release really about?

For several years the senior author of this new study, Rakesh Kukreja, has been investigating the potential effects of sildenafil and other PDE5 inhibitors as cardioprotective agents — agents that may be able to limit or reverse damage done to the heart. To quote from his online bio, “His  research is focused on the mechanisms by which ischemia (heart attack) kills cardiac cells and the development of novel therapeutic strategies which can minimize the damage in the heart muscle.”

Quite why Dr. Kukreja and his colleagues should have decided to explore the activity of doxorubicin and sildenafil in prostate cancer cells and in a mouse model of prostate cancer is unclear. (The full text of the article by Das et al. is available on  line for those who wish to read it.) There is certainly a lack of high quality chemotherapeutic options available for the treatment of men with castration-resistant prostate cancer (CRPC), but it seems highly unlikely to us that a doxorubicin-based form of chemotherapy would have significant impact on prostate cancer in man, even if one could better manage the high risk for cardiovascular complications. In the discussion section of their paper, Das et al. write that their results “suggest that sildenafil may represent a therapeutic approach to improve [doxorubicin] efficacy in prostate cancer while simultaneously reducing the risk of cardiomyopathy.” Indeed, “may represent” is certainly a correct statement. But since doxorubicin has no proven efficacy in the treatment of prostate cancer, it is hard to know exactly what the authors think they are implying.

By contrast, if sildenafil is able to really impact the cardiovascular side effects of doxorubicin, there most certainly are other forms of cancer in which this drug is still widely used. Perhaps it would be wiser for researchers to explore the value of the sildenafil + doxorubicin combination in one of those forms of cancer.

Das et al. also write that, “Clinical studies are warranted to fully define the importance of combined treatment with [doxorubicin] and sildenafil as therapeutic tool in prostate cancer patients.” However, if we were to consider the use of doxorubicin + sildenafil in a clinical trial in patients with CRPC who had ceased to respond to approved forms of chemotherapy, it is not even clear what complete form of combination chemotherapy might be worth trying. The use of doxorubicin + sildenafil alone is highly unlikely to have a significant clinical effect. Doxorubicin is invariably given as just one agent in a chemotherapy “cocktail.”

The last published paper that we are aware of that used doxorubicin in the management of castration-resistant prostate cancer was by Slovin et al. in 2009. According to the abstract of that paper, the combination of cetuximab (Erbitux) + doxorubicin had no clearly demonstrable effect on 36 patients who had received multiple other forms of therapy for treatment of metastatic CPRC. A Cochrane review of chemotherapy for treatment of hormone-refractory prostate cancer conducted in 2006 quite clearly indicates that (at that time) the only known form of chemotherapy that had ever demonstrated a survival benefit was docetaxel + prednisone. (Since that date, as recently reported, cabazitaxel + prednisone has also been able to show a survival benefit in patients with metastatic CRPC.)

What’s the bottom line? Simple. The message you read in the media may well be delusional. Be skeptical. Read with a suspicious mind. We don’t believe that anyone set out to promote the idea that doxorubicin + sildenafil might be appropriate form of treatment for prostate cancer. On the other hand, we also don’t think that this paper (let alone the media release) was reviewed carefully by anyone with an extensive knowledge of the treatment of late stage prostate cancer before it was published in PNAS. And yet again we will repeat that what can be shown in a laboratory mouse or a line of prostate cancer cells in a Petri dish often bears little to no relationship to what can be shown to have clinical impact in humans.

2 Responses

  1. What about another drug called aldoxorubicin? Isn’t this drug a special version of doxorubicin without any heart problems?

  2. As far as I am aware, aldoxorubicin is a drug that is still in development. Whether it is any better or safer than doxorubicin in the management of prostate cancer is completely unknown, and I am not aware of any clinical trials of this drug in the treatment of prostate cancer as yet.

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