Research Yields Clues to Drug Resistance in Cancer Therapy
By GINA KOLATA
Published: October 11, 1988
RECENT research advances hold the promise of overcoming one of the most serious problems in cancer treatment: the tendency for tumors in some patients to become resistant to chemotherapy.
A new report pinpoints the way cancer cells become resistant to certain compounds frequently used in chemotherapy. Another preliminary study hints that a drug used to treat heart disease may prevent drug resistance in some cancer patients.
Cancer cells have proven remarkably adaptable, developing various ways to thwart most drugs meant to kill them. If the drug resistance could be overcome, many more cancers could be cured, said Dr. John S. Lazo of the University of Pittsburgh. Responding to Chemotherapy
''Take a woman who comes in with ovarian cancer,'' he said. ''Sixty to sixty-five percent respond to the drugs.'' But the group that does not respond is unlikely to benefit from further chemotherapy, he said. ''I don't care what you treat them with, the response rate drops to less than 10 percent.''
Because they fear that a patient's cancer will become resistant to most drugs, doctors try to destroy it with the initial course of chemotherapy.
The new findings suggest two lines of attack on the problem of drug resistance. One method is to block the ability of cancer cells to resist drugs. The other is to protect normal cells by making them very resistant to drugs, and then to blast tumor cells with huge doses of chemotherapy.
Dr. Lazo and his colleagues, reporting in a recent issue of Science magazine, said they discovered how some cancer cells resist the drug cisplatin, which is widely used in treating ovarian cancer, testicular cancer and some forms of lung cancer.
The drug, a compound containing platinum, works by binding tightly to DNA, the cell's genetic material, and killing the cell. Once cells become resistant to cisplatin, they also resist several other DNA-binding drugs, including chlorambucil and melphalan. Cell Protein Is a Factor
Dr. Lazo and his colleagues found that the tumor cells become resistant by producing large quantities of a normal cell protein, metallothionein. The protein binds to heavy metal compounds, including cisplatin, apparently preventing it from killing the cells. To test their hypothesis, the researchers forced cells that did not normally make the metallothionein to make it. The cells became resistant to the drugs.
Researchers think it should be possible to give cancer patients drugs to overcome the resistance by turning off the metallothionein genes in tumors. Or they may employ the reverse strategy, finding ways to stimulate healthy cells to become even more resistant to chemotherapy by producing more metallothionein.
When patients receive cisplatin, the drug accumulates in their kidneys, where it can kill normal cells. If kidney damage could be averted, patients could take higher doses of cisplatin, Dr. Lazo said.
In Japan, researchers have been experimenting with bismuth, another metallic element. The bismuth concentrates in the kidney and causes cells to make metallothionein. Dr. Lazo said the Japanese have had some preliminary success protecting the kidneys of some animals from cisplatin in their tests. 'Pump' Ejects Drugs
A different form of resistance was recently shown to involve a molecular ''pump,'' which cells develop to eject certain substances. In particular, the pumps seem to work on three classes of anticancer drugs, the group that includes adriamycin and donarubicin, the group that includes vincristine and vinblastine, and the group consisting of actinomycin D. The molecular pumping process probably developed naturally in humans as a form of protection against poisonous plants, researchers said. The toxins from the plants tend to accumulate in the liver, kidney and colon, so these organs normally have large numbers of pumping molecules.
Unfortunately, the three classes of anticancer drugs are derived from plants, and cancers that occur in these organs start out resistant to the drugs, the researchers said. Other cancers can also develop resistance.
''The idea is to use something that will inactivate the pump,'' said Dr. Ira Pastan of the National Cancer Institute in Bethesda, Md. Dr. Pastan and his colleague, Dr. Michael Gottesman, found that verapamil and quinidine, drugs taken by patients with heart disease, inactivate the pumps of cancer cells in the laboratory.
The problem, however, is that these drugs are dangerous in large doses.
Others, including Dr. David Housman of the Massachusetts Institute of Technology, are studying less toxic compounds that also block cancer cells from pumping out therapeutic drugs. But the advantage of verapamil and quinidine, Dr. Pastan said, is that they are already on the market.
Recently, Dr. Sidney Salmon and a team of researchers at the Arizona Cancer Center in Tucson gave verapamil along with the three anticancer drugs adriamycin, vincristine and cyclophosphamide, to seven patients whose lymphoma tumors had become resistant to the drugs. Four patients responded.
But experts, including Dr. Pastan, said the study was too small to be conclusive. In addition, said Dr. James M. Croop of the Dana Farber Cancer Insitute in Boston, other small studies have not shown any beneficial effects at doses of verapamil that patients could tolerate.
But Dr. Croop is optimistic that by understanding cancer drug resistance, researchers can prevent it. ''So much of cancer chemotherapy has lulled over the years,'' he said. ''It has been very empirical, trial and error. I clearly have a positive feeling now.''