Since the 1960s, oncologists have known that chemotherapy can cause DNA damage, second cancers, and other serious complications. The increasing popularity of multidrug regimens may increase the possibility of chemoresistance, toxicity, and a myriad of other complications.
At the November 2001 Chemotherapy Foundation meeting in New York, there was much discussion about the efficacy of doublet or triplet therapies for various cancers and the problems that administering these numbers of drugs could present.
Paul A. Vasey, M.D., of the University of Glasgow, Scotland, noted when discussing new ovarian cancer regimens, that "seldom does add a third drug to a chemotherapy regimen adding anything other than toxicity." He also noted that the standard of care for ovarian cancer is still a platinum-taxane doublet that has not substantially improved outcomes in the past decade.
But despite Vaseys concerns about chemotherapy overload, other researchers are taking a molecular approach to solving toxicity and chemoresistance problems. Jonathan S. Berek, M.D., of the University of California at Los Angeles School of Medicine, Los Angeles, helped develop a monoclonal antibody called OvaRexTM (oregovomab) that targets circulating CA125, an antigen that is used as a marker for immune response.
OvaRex has no direct antitumor effects. Instead, it gives "a broad immune response boost," Berek said. He added that OvaRex has no toxicities and that it has no toxicity overlap with chemotherapy agents.
Deborah Armstrong, M.D., of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, believes that looking at the long-term picture is important when trying to figure out strategies to reduce chemoresistance in recurrent disease. She suggested that the order in which drugs are administered may be more important than which drugs are used. She has found that using platinum-based drugs early is important because myelosuppression usually increases once a drug such as topotecan, a topoisomerase I inhibitor, is administered.
All of these considerations about which drug or drugs to use may help lower problems of chemoresistance, but a recent conference at the National Institutes of Health addressed the bigger picture of how to fight chemoresistance at a molecular level for most any type of cancer.
"Organ biology determines the type and responsiveness of which agent to choose, and some therapies work better in one organ than in another," said Isaiah J. Fidler, D.V.M., Ph.D., of the University of Texas M. D. Anderson Cancer Center, Houston.
"There are three basic reasons for drug resistance to chemotherapy: host factors, tumorhost interactions, or cellular resistance, which is a matter of genetics," said Michael Gottesman, M.D., NIH deputy director for intramural research and chief of the Laboratory of Cell Biology at the National Cancer Institute.
|
If a drug is constantly pumped out of a cell, then it never gets a chance to carry out its desired course of action. Gottesman also noted that as more is learned about the genome, more ATP-dependent transporters than previously thought are being discovered, making the problem of chemoresistance more complex.
Gottesmans research focuses on a molecule called P-glycoprotein. P-glycoprotein is ATP dependent and can act as a multi-drug efflux (removal from the cell) pump. "If we can knock out just one of the ATP binding sites on P-glycoprotein, we could knock out its effectiveness," he said.
One measure of where success with P-glycoprotein might be most profound is in solid tumors. "Weve found high levels of P-glycoprotein in solid tumors such as liver, kidney, colon, adrenal and the pancreas," said Gottesman. He also noted that recent research indicates that P-glycoprotein transport could be the reason a drug like Gleevec has not been as effective in the blast phase of a hematological cancer.
One tantalizing question posed to Gottesman was the possibility of reversing the polarity of these efflux pumps so that drugs could be delivered more effectively into cells, making the problem of chemoresistance almost nonexistent. "We dont know how to do this yet," he said, "but hopefully some clever biophysicists will figure it out."
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |