Cancer's genes and chemotherapy.

Cancer's genes and chemotherapy

Some cancer cells protect themselves from the chemotherapydrug methotrexate with high levels of a protein that detoxifies the drug; the cell makes these high protein levels with extra copies of the responsible gene (SN: 1/3/87, p.12). Researchers studying another type of resistance, in which a different protein disarms several other drugs, have now found that such "multidrug-resistant" cells also make extra protein, but not by producing extra genes.

Instead, the protein's gene becomes more productive, reportIra Pastan and Michael M. Gottesman of the National Cancer Institute (NCI) and their colleagues at NCI and at the University of California at Los Angeles. They have also discovered that the gene is active in certain normal cells. The findings, they say, may enable predetermination of tumor resistance.

Multidrug resistance is dependent on p-glycoprotein, a cellsurface molecule that pumps a variety of chemotherapeutic drugs out of the cells. The researchers, who previously reported that such resistance can occur in the absence of gene amplification (production of extra copies), thought the extra p-glycoprotein could be coming from an overactive gene.

In a series of experiments described in the January PROCEEDINGSOF THE NATIONAL ACADEMY OF SCIENCES (Vol. 84, No. 1), the researchers measured the levels of p-glycoprotein messenger RNA (mRNA). Messenger RNA is the "workisng copy" of DNA and its levels indicate actual protein production.

They found high mRNA levels in cells from human tumors oftypes that are often resistant to chemotherapy. They also observed a six-fold increase in before-and-after samples from a tumor that weas initially sensitive to drugs but then became resistant.

In addition, some normal digestive system cells also hadhigh levels of p-glycoprotein gene expression, presumably to help the cells deal with toxic chemicals in food. "Tumors derived from these tissues are intrisically drug resistant," says Gottesman. "I'd hypothesize that might be because the tissue is already able to handle [toxins]."

In the future, physicians might be able to use increases inp-glycoprotein mRNA to predict inherent resistance or as an early signal of the development of resistance.