Therapy pits useful gene against tumor.

In about half of lung cancer cases, a gene called p53 has mutated and thus fails to encode a protein that oversees programmed cell death. In the absence of this protein, which helps curb the growth of damaged or abnormal cells, cancer can gain a foothold. Replacing such defective p53 genes with fresh ones has shown promise against a variety of cancers in animal experiments and studies of a few patients (SN: 8/31/96, p. 134).

Scientists now report further progress in such localized gene therapy. By enlisting a virus to deliver p53 to tumor sites in 28 people with lung cancer, they temporarily stabilized or reversed the course of the cancer in more than half the patients. The findings appear in the May 5 JOURNAL OF THE NATIONAL CANCER INSTITUTE.

The patients, average age 65, had lung cancer that was either inoperable or was no longer responding to radiation treatment or chemotherapy. The researchers injected the tumors with an adenovirus engineered to contain p53 genes. The virus was also modified to prevent it from replicating and thus causing the upper respiratory infection that it might otherwise bring about.

During the 6-month treatment period, patients received one to six monthly injections of the modified virus. The researchers delivered a range of doses--from 1 million to 100 billion viral units--to gauge any toxicity of the treatment.

Three of the 28 patients died of cancer before doctors could make a 1-month follow-up examination. Among the 25 others, tumors shrank in 2 patients, stabilized in 16, and continued to grow in the other 7.

The dose of virus mattered. Cancer progressed unabated in three of five patients who received injections of 10 million or fewer viral units. In contrast, only 4 of 20 patients getting a larger dose experienced cancer growth.

Biopsies of patients' tumors revealed that the injected p53 was active. The rate of programmed cell death, or apoptosis, had at least doubled in response to the gene therapy, adds study coauthor Jack A. Roth, a surgeon at the University of Texas M.D. Anderson Cancer Center in Houston.

One 72-year-old woman made a striking, although brief, turnaround. After radiation therapy had failed to knock out her cancer in 1994, doctors tried chemotherapy in 1996, also to no avail. She received six large doses of p53, the last in June 1997, which shrank her tumor by more than half. A checkup in March 1998 showed no active cancer, but she has since died.

A 70-year-old woman previously treated with drugs, radiation, and lasers--to clear a tumor that was blocking one bronchial tube--also responded well to the gene therapy. The injections cleared the tube and restored air flow. However, after the p53 treatments ended, her cancer returned and she died.

Only one patient survives from the group, a person in whom the p53 treatment had stabilized the cancer.

Lung cancer patients with inoperable, untreatable tumors typically have less than a 10 percent chance of living a year.

The study shows that p53 is "a viable target" for a genetic approach to cancer treatment, says Nick R. Lemoine, a molecular oncologist at Hammersmith Hospital in London.

The scientists "should be congratulated on their efforts," says Ralph R. Weichselbaum, a radiation oncologist at the University of Chicago. However, he adds, "this gene therapy would probably work better with radiation or chemotherapy. I'm a little skeptical that it's going to work as a strategy by itself."

Roth agrees. "It's been the history of oncology that you see some of the greatest effects with combined-modality treatments," he says.