A study of ovarian cancer patients undergoing chemotherapy determined that individuals with a mutant, nonfunctional version of the tumor-suppressing gene p53 had a survival rate more than twice as high as counterparts with a properly functioning gene. This, despite the fact that the gene in question is, under normal circumstances, essential for preventing cancer in the first place.

In the body, the protein coded for by p53 is recruited to sites where cell damage occurs. This protein first attempts to stop the cell cycle and repair the cell. If that does not work, it initiates a mechanism known as apoptosis, or programmed cell death.

"When you do chemo, we don't want cells to survive," explains John McDonald, chair of the biology department at the Georgia Institute of Technology in Atlanta and the senior investigator on the new report, published this week in PLoS ONE. "If you have functional p53, you may repair some of those cells subjected to chemo—and they are still cancer cells."

McDonald and his colleagues compared the gene activity in malignant and benign tumors excised from ovarian cancer patients, some of whom had been pretreated with chemotherapy before surgery to "'debulk' the tumor." Using a DNA microarray, otherwise known as a gene chip, to see which genes were switched on and which were off, the researchers noticed that tumors from the patients that had undergone presurgery chemo were not the same. These tumors fell into two groups: Some expressed genes similar to what might be activated in a benign tumor. Others looked more like cancerous tumors that had not received chemo at all.

"We found that a lot of the changes in gene expression were involving genes that were in the programmed cell death pathway," says McDonald. The team zeroed in on p53 and found that, in the case of the individuals whose tumors resembled untreated melanomas, the gene had been mutated so that the protein it produced was nonfunctional. "Normally in the literature you will see that if you have a mutation in p53, your prognosis is quite poor," McDonald notes.

Despite their normally poor prognosis, five years after treatment and surgery, 70 percent of those patients with the mutated, nonfunctional p53 gene were still alive, compared with 30 percent of the other group.

"Cells are much more susceptible to DNA damage, such as chemotherapy, when they are in active division cycle," says Yue Xiong, a professor of biochemistry and physics at the University of North Carolina at Chapel Hill, adding that mammals have evolved a mechanisms to stop cell cycling in damaged cells and promote them to apoptosis. "As a result, if a cell with damaged DNA is not in active division cycle—for example, arrested by the function of p53—it would have better chance to survive the chemotherapeutic treatment than those cells that do not have p53 function and continue to their cell cycle progression with damaged DNA." And if those cells continue cycling, cancer can recur.

McDonald and his co-authors suggest that it may be necessary to develop treatments to inhibit the function of p53 during chemotherapy in order to allow for the clearing of cancerous cells. They are currently testing this methodology in cell cultures and in mouse models. "I don't think knocking out p53 in a cancer patient is a good thing," notes McDonald, owing to the protein's tumor suppressor properties. "It's just when you're doing chemotherapy."