AZT, the only drug approved for widespread use against the AIDS virus, can cause cancer in animals at very high doses, according to the results of a study mailed out to physicians Tuesday by the drug's manufacturer.
The study, conducted by Burroughs Wellcome Co. and required for all drugs on the market, found that some mice and rats given the highest doses of AZT for many months developed vaginal tumors toward the end of their life span.
The company, as well as many experts in treating AIDS, said the findings warrant no change in medical practice. They said the drug, also known as zidovudine, is a weak carcinogen in animals, and it remains unknown whether it can cause cancer in humans.
"Patients with the disease appear to be at far greater risk from not receiving zidovudine treatment than from any potential risk of cancer associated with the drug's use," said Dr. James O. Mason, assistant secretary of the U.S. Department of Health and Human Services.
Several physicians said that principle applies even to men and women infected with the human immunodeficiency virus (HIV) who have yet to develop full-blown AIDS--a group in which AZT is increasingly used to postpone the onset of symptoms.
However, federal researchers said Tuesday that they are suspending a study of AZT in infected pregnant women in light of the new findings. And some researchers said the study reaffirms the need for caution in using the drug, and the need for research into alternatives.
"It's a good reason not to use this drug indiscriminately, and it's a good reason to continue looking for drugs with other modes of action," said Dr. Robert T. Schooley, an AIDS researcher at Massachusetts General Hospital, who took part in trials of AZT.
According to Burroughs Wellcome, seven vaginal tumors were found in 60 female animals given the highest dose of AZT for 22 months. The earliest tumor was seen after 19 months of continuous dosing; most occurred after 21 months.
Risk Considered Low
Two of the tumors were benign. The other five were cancerous but were not spreading. In all cases, the lesions were discovered only upon examining tissue. The animals died or were killed for reasons not related to the treatment.
A company spokeswoman said it was not possible to compare the animal doses to human doses.
"These results are very, very mild," said Mathilde Krim, a biologist and co-founder of the nonprofit American Foundation for AIDS Research. "Considering the important role that AZT plays in controlling infection, these results should not change the medical use of AZT."
Dr. Neil Schram, a Los Angeles internist who treats many patients infected with HIV, said cancer risk from AZT appears to be so low that he would be unlikely even to bring it up with patients in discussing the top three or four risks associated with the drug.
"With any medication, we're talking about benefit versus potential risk," said Schram. "Almost any medication that causes cancer does so many years after it's been given.
"So at this stage in our use of the drug, considering that there are no viable options, in my opinion its benefit tremendously outweighs the minimal extra risk, or even extra potential risk, that we've read about today," he said.
The test used by Burroughs, called a rodent bioassay, is carried out on new drugs and takes about three years to conduct. It is a critical, although controversial, litmus test on which regulators rely in determining whether drugs, food additives and pesticides might cause cancer in humans.
The test involves treating animals with various doses--low, medium and the highest tolerable. By studying the effects of relatively high doses in animals over two years, regulators try to gauge the effects of lower doses in humans over many years.
"While the studies with zidovudine can be viewed as a general indicator of some potential carcinogenic risk to humans, current scientific knowledge does not permit accurate prediction," Burroughs Wellcome wrote in its mailing to physicians.
"It is important to stress that animals do handle AZT differently than humans," said Dr. Samuel Broder, director of the National Cancer Institute. "They remove it from the body in a different way, and, inside the cells, they handle it in a different way."
Numerous AIDS experts also urged caution in interpreting the results.
Dr. Daniel Hoth, director of the division of AIDS for the National Institute of Allergy and Infectious Diseases, emphasized that the rodents' treatment was in no way parallel to human treatment. He also noted that numerous other marketed drugs cause tumors in animals.
However, Hoth said that a trial being conducted by his institute using AZT to treat pregnant women infected with the human immunodeficiency virus has been "put on hold" in light of the new findings "until we have thought this through thoroughly."
"The only area that we have put up the caution light is for the use of AZT among people who may not have HIV infection, such as health care workers who are exposed to infected blood, or the administration of AZT to pregnant women," he said. In August, federal officials advocated wider use of the drug after studies showed it postponed the onset of AIDS symptoms in infected people.
One source at the U.S. Food and Drug Administration who requested anonymity said the new data would be unlikely to alter treatment of patients with fully developed AIDS. But he said the agency would have to review the data "before we can determine how these animal studies will impact AZT's use in earlier stages of infection."
Several AIDS researchers, too, said it was not surprising that the category of drugs into which AZT falls might be found to cause cancer. Any drug that affects the machinery of living organisms--the way AZT blocks the replication of the AIDS virus--might end up damaging cells along with the virus, one explained.
"The fact remains, though, that in the patient population taking AZT, the disease being treated is of such a severity that the risk-benefit ratio still favors treatment with AZT," said Schooley of Massachusetts General Hospital.
There had been earlier indications that AZT might be carcinogenic: In high doses, it had damaged chromosomes in mammalian cells in laboratory tests. Those results are included in the printed labeling information distributed to all physicians who prescribe the drug.
In its letter, Burroughs Wellcome said there are several ways of distinguishing between weak and potent carcinogens: Drugs that induce late-onset tumors only after high doses in a single sex and at a single site would be viewed as relatively less carcinogenic.
"A further perspective is provided by the fact that a number of commonly prescribed drugs have been associated with tumors in animal studies," the company wrote. Those drugs are still used when physician and patient agree that "the benefits of the drug outweigh the potential risk."
Burroughs Wellcome has established a hot line for health professionals seeking additional information, said Mason of the Department of Health and Human Services. The number is 1-800-443-6763.
1964: AZT synthesized by Dr. Jerome P. Horwitz, a chemist in Michigan looking for anti-cancer drugs. The drug proves ineffective and is largely forgotten.
1984-1985: Scientists at the Burroughs Wellcome Co. and the National Cancer Institute perform lab tests that identify AZT as potentially useful against the human immunodeficiency virus, or HIV.
July, 1985: Trials of AZT begin in AIDS patients in the United States.
October, 1986: Based on preliminary evidence of effectiveness, the Food and Drug Administration allows widespread distribution of AZT to AIDS patients prior to final marketing approval.
March, 1987: The FDA approves AZT, which is also known as zidovudine, as a treatment for AIDS and severe AIDS-related conditions.
August, 1989: Evidence accumulates that AZT may be effective in preventing the progression of disease in some asymptomatic individuals and those with early HIV-related symptoms. As a result, U.S. clinical trials of AZT in such individuals are stopped early and federal health officials recommend wide use of the drug.
September, 1989: Responding to widespread public criticism, Burroughs Wellcome reduces the wholesale price of AZT by 20% to $1.20 a capsule. At the maximum recommended dose of 12 capsules a day, a year's supply of AZT would cost more than $5,000.