Magazine article Science News

Resisting Cancer Chemotherapy; Researchers Are Struggling to Learn How Cancer Cells Survive in the Presences of Lethal Drugs. the Aim Is to Prevent Resistance

Magazine article Science News

Resisting Cancer Chemotherapy; Researchers Are Struggling to Learn How Cancer Cells Survive in the Presences of Lethal Drugs. the Aim Is to Prevent Resistance

Article excerpt

RESISTING CANCER CHEMOTHERAPY Researchers are struggling to learn how cancer cells survive in the presence of lethal drugs. The aim is to prevent resistance.

The ideal anticancer drug would bean agent that could kill cancer cells without harming normal cells, and one that cancer cells couldn't neutralize. A detailed understanding of the second component -- how cancer cells resist chemotherapy or acquire an immunity to it after exposure -- is crucial if cancer researchers are to develop successful countermeasures.

When some of the leaders in the fieldgathered in Washington, D.C., recently for a symposium on cancer drug resistance, what emerged was a picture of a problem that can arise in any cancer, with at least part of the blame placed on some fancy genetic changes and a specific cell membrane protein.

Clinically, all cancers are, or have thepotential to become, resistant to chemotherapy, says oncologist Paul V. Woolley III of Georgetown University in Washington, D.C. With potentially curable cancers, the chances of survival go down dramatically with each recurrence -- the second, third or fourth time around, the cancer is much less responsive to chemotherapy, says Woolley. "from a clinical point of view, the emergence of resistance, if it's not there to begin with, is a universal problem."

Resistance, he says, is either inherentin the cancer cell, or acquired when the cell is exposed to chemotherapy. these cells initially started out as normal cells. In the inherent form of resistance, this origin can be the source of the problem; some cancer cells retain whatever it is that allows the normal cell to persist in the presence of a toxic drug.

Colon cells, for example, are regularlyexposed to toxins in digested food passing through the intestine, and are more resistant than other normal cells to conventional chemotherapeutic agents. The cancers that arise from colon cells tend to maintain that property. "despite a quarter century of drug testing, we have made only at best modest gains in the [chemical] treatment of colon cancer," Woolley said at the symposium, which was organized by Georgetown and sponsored by Bristol-Myers Co.

The other type of resistance, the acquiredform, has its roots in the cancer cell's ability to change, which it has already demonstrated in its metamorphosis from a normal cell. The development of drug resistance is just one more change; the key to the puzzle is figuring out how that change occurs.

Robert T. Schimke of Stanford Universitysays that at least part of the answer is the overproduction of a gene or genes whose protein products enable the cell to withstand a chemotherapeutic onslaught. Such gene amplification, he says, is "one of the most common types" of cancer drug resistance.

Schimke has seen an example of this inhis studies of resistance to the cancer drug methotrexate. The drug works by inhibiting the activity of an enzyme, dihydrofolate reductase (DHFR), that is instrumental in the synthesis of a DNA precursor necessary for cell reproduction.

Multiple copies of the DHFR gene havebeen found in tumor cells of some methotrexate-resistant patients, enabling the production of above-normal amounts of DHFR. "You have more enzyme than you have methotrexate within the cell," he says. "So even though you've inhibited most of the enzyme [with methotrexate], there's always going to be some free enzyme that can carry out the reaction." It's too early to say whether such amplification accounts for all methotrexate resistance, Schimke says.

The gene amplification process doesnot work by killing sensitive cells, thereby promoting the growth of preexisting cells that are inherently resistant to the drug. Such selection was once the standard explanation for how cancers dodge chemotherapy. Instead, methotrexate itself "is in fact generating resistance" by causing a change in genetic material, he says. …

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