Helping cancers mature so they might die - retinoic acids as cancer treatment

Science News, June 1, 1991 by Carol Ezzell

Promising results from a pair of new U.S. studies bolster the credibility of retinoic acids, compounds derived from vitamin A, as drug treatments--and even potential cures -- for certain cancers. Retinoic acids differ from other cancer treatments because they help malignant cells grow normally instead of simply killing the cells off.

Researchers reported conducting successful trials with one of the drugs nearly three years ago in China and last year in France. The National Cancer Institute (NCI) in Bethesda, Md., has recently approved more than 50 U.S. requests to conduct human trials with retinoic acids against various cancers, says David R. Parkinson of NCI's Cancer Therapy Evaluation Program.

The rare but difficult-to-treat acute promyelocytic leukemia (APL) proved the first cancer to succumb to a retinoic acid. This disease, striking roughly 1,500 people in the United States each year, is characterized by the uncontrolled growth of a subclass of immature white blood cells bearing a specific chromosomal abnormality. Oncologists cannot effectively treat APL patients with chemotherapy because this disease leaves its victims vulnerable to excessive bleeding, which the drugs only exacerbate.

In the previous Chinese and French APL studies, a retinoic acid named tretinoin cured all of 24 patients, and 14 of 22 patients, respectively. Now a team of U.S. researchers led by Raymond P. Warrell Jr. of the Memorial Sloan-Kettering Cancer Center in New York City reports administering tretinoin (all-trans-retinoic acid) to 11 patients with APL. In the May 16 NEW ENGLAND JOURNAL OF MEDICINE, the group reports that while tretinoin failed to benefit two patients, it caused complete remission in the other nine by prompting their immature -- and otherwise immortal -- leukemic white cells to finish developing and die off after a normal white-cell life span.

The leukemic cells made defective receptors for retinoic acid, and Warrell's group says this could explain their failure to develop normally. The researchers believe the tretinoin treatment entered the cells by other means.

Rohini C. Vyas from M.D. Anderson Cancer Center in Houston, a member of Warrell's group, gave a more detailed account of tretinoin's curative effects two weeks agao. At the annual meeting of the American Association for Cancer Research, in Houston, she reported that two chromosomes in all of the APL patients' white cells had swapped large pieces, leaving the cells arrested in early development. Vyas found that once tretinoin treatment began, however, the cells began aging normally despite their chromosomal abnormalities. In the patients who sustained a cure, Vyas notes, all abnormal white cells had died and had been replaced by young cells capable of normal development.

Last week, at the annual meeting of the American Society of Clinical Oncology, in Houston, Scott M. Lippman from M.D. Anderson reported on another retinoic acid success--this time against advanced squamous cell carcinoma of the skin. Treatment that combined isotretinoin (13-cis retinoic acid) with alpha interferon reduced tumors in 16 of 26 patients with squamous cell carcinoma of the head and neck. The drug combo caused complete remission in six of the 16.

Advanced squamous cell carcinomas of the head and neck have been difficult to treat, Lippman notes, because surgery and radiotherapy are often disfiguring, and chemotherapy has proved largely ineffective. But in this study, he says, relatively low doses of the two compounds produced nearly double the benefits of either one alone.

Retinoic acids are "the most interesting story in molecular biology applied to cancer," concludes M.D. Anderson oncologist Razelle Kurzrock. "It makes you think that we'll be able to solve cancer."