Borrowing Therapies

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Two Anti-Cancer Drugs Are Tapped in the Fight Against HIV
by Chael Needle

New types of drugs are needed in the fight against HIV but some of them are not being developed from scratch. In a lateral-thinking move, drugs that are already approved by the FDA for conditions other than HIV/AIDS are being screened for potential action against the virus. “Drug repositioning” may produce much-needed additions to the armamentarium.

Researchers are looking into repositioning two approved anti-cancer drugs. Led by Louis M. Mansky, PhD, professor of microbiology and diagnostic and biological sciences and director of the Institute for Molecular Virology at the University of Minnesota, studies conducted so far on decitabine and gemcitabine have shown enough promise for future investigation.

The processes for identifying possible candidates from a pool of already approved drugs are myriad, says Dr. Mansky. “In our case, we identified already approved drugs that we thought might have the potential to possess anti-HIV activity. We were also interested in ones that might have this ability to cause HIV to elevate its mutation rate.”

Researchers looked at the drugs separately at first and once they identified that these two possessed anti-HIV activity they “wanted to test to see if their individual effects would work together in synergy if we put the two together,” says Dr. Mansky. Their experiments proved successful.

The combination of the two anti-cancer drugs reduced HIV infectivity by seventy-three percent. This decreased infectivity was accompanied by an elevation in the rate of mutation, a state that can lead to lethal mutagenesis. Though HIV uses beneficial mutations in its replication process, the virus is not inured to “lethal” mutations—ones that cause the virus to collapse and die.

Lethal mutagenesis can occur naturally, as a function of the body. “From a lot of the basic research that’s been done on HIV over the last seven years, I think that there’s pretty good agreement in the AIDS research community that there are certain innate immune mechanisms that appear to have evolved a particular strategy of fending off viruses like HIV: They basically force the virus to mutate itself to death,” he explains. And though scientists do not know how to manage this type of lethal mutagenesis, “certainly there’s interest in trying to engineer that, exploit that, for the benefit of therapy,” says Dr. Mansky.

One of the “keen interests” of Dr. Mansky and his research team is figuring out the details of how lethal mutagenesis works. “From a practical standpoint, it’s probably not as important initially [to know how it happens] as long as it seems like the drugs do work and they have the right balance between efficacy for preventing HIV replication and minimal toxicity in terms of causing other effects that are detrimental to the individual.”

Mansky and his colleagues were attracted to decitabine and gemcitabine because they were both anti-metabolytes. “None of the currently approved anti-HIV drugs are anti-metabolytes, and we thought that these ones, if they did possess anti-HIV activity, might actually have a distinct target to block the HIV from replicating…,” he notes. Aside from anti-HIV activity, they thought the anti-cancer drugs might have a different effect than the known drugs, an important concern in the context of drug resistance.

Next, researchers are developing a pill form of the anti-cancer drugs, normally administered through an IV. Anti-HIV drugs are commonly given in pill form as the oral route confers increased bioavailability, the degree of absorption of a drug into the bloodstream. IV-based drugs can be converted into pill form but first need to be chemically modified into a prodrug. Dr. Mansky and his research team are making these modified versions and testing them in animals to make sure that the anti-HIV activity is retained in the process of making them more bioavailable.

“We consider this a fairly important step because in order for individuals affected by HIV to be able to use the therapy—in order for it to have any long-term viability—we’d really need to be able to deliver these kinds of medicines in a pill form. It’s just not practical for infected individuals to be taking medication through an IV on a daily basis.”

Dr. Mansky believes the drug combination could be used in many different treatment contexts—a new therapy option for treatment-experienced patients; in combination with already used anti-HIV drugs, if studies prove this effective; and in treatment-naive patients, as well. “Probably the most pressing need would be for those who are treatment-experienced and have developed resistance to all the available HIV drugs,” he notes. “Obviously those individuals would probably be in the greatest need for new treatment options.”

Chael Needle wrote about viral decay acceleration in the November issue.

December 2010