AIDS Drugs May Help Against Cancer, Too

A drug widely used to treat H.I.V. infection may also be effective in fighting cancer, a new study suggests, and a human trial of the medicine is already under way.

In laboratory and animal tests of six protease inhibitors, three were found to slow growth in a variety of cancer cell types, in dosages that have been tolerated in patients with H.I.V. Of the six, nelfinavir, sold under the brand name Viracept, had the most powerful effect. It is now being used in a Phase 1 trial, the first step in testing the drug in humans for use against cancer.

In a paper published Sept. 1, researchers reported that the six drugs were tested using 60 cell lines that had been derived from nine types of tumors. In all the lines, the higher the dose of medicine, the more cell growth was reduced.

Nelfinavir was also found to be effective against breast cancer cells that are resistant to currently used cancer drugs like Nolvadex (tamoxifen) and Herceptin (trastuzumab). The protease inhibitors used in the study were donated by Pfizer.

The scientists also tested nelfinavir in mice that had been experimentally injected with cancer cells. In smaller doses, it worked well to reduce the size of tumors, but larger doses produced unacceptable side effects.

Exactly how nelfinavir acts against cancer cells is not clear. Protease inhibitors are known to interfere with a protein pathway that helps cancer cells survive, but in the study only nelfinavir, ritonavir and saquinavir worked against them. There are different proteases - enzymes that break down proteins - in H.I.V. and cancer. It is possible that protease inhibitors target a protease in cancer that does not exist in H.I.V.

The study, which appears in Clinical Cancer Research, says the cost of developing a cancer drug is about billion, and the process takes about 15 years from conception to approval by the Food and Drug Administration, should it be granted.

One way to shorten this time and reduce the cost is to consider drugs for which there are already data on safety and a clear understanding of the way the drugs are absorbed, how long they work, what organs they affect and how they are excreted. Protease inhibitors have been in use since 1993, and their safety, toxicity and various effects in humans are well known.

Now, only a year and a half after doing the experiments in cultured cancer cells, the researchers are using nelfinavir in a Phase 1 trial. Their main goal is to find out how large a dose can be safely administered. When nelfinavir was tested for use in H.I.V. patients, researchers increased the dosage only until a patient's viral load decreased, so the maximum dose was never determined. For this test, the scientists are recruiting 45 people who have tumors, any type except leukemias, that have not responded to treatment.

Volunteers are being started with 1,250 milligrams orally twice a day, a standard dose in people with H.I.V. infection. The amount will gradually be increased. The maximum tolerated dose will be the level at which one out of three patients experiences toxic effects like gastrointestinal problems or elevated blood levels of lipids or glucose.

The trial is not designed to determine the drug's efficacy, but patients whose tumors respond to it will continue to receive it.

"The endpoint of the trial is safety and tolerability," said Dr. Phillip A. Dennis, the senior author of the study and the principal investigator on the clinical trial. "But for an effective drug, we look for hints of activity. Preliminary efficacy will be further investigated in trials with specific types of cancer."

Dr. Dennis, a medical oncologist at the National Cancer Institute, said his laboratory was also designing trials for drugs to be used with nelfinavir to treat cancer. "We'll use the information from the Phase 1 trial," he said, "to determine where we start the nelfinavir dose in any combination trial."