Staying one step ahead
The battle to outwit drug-resistant cancers
By Richard Saltus
Illustrations by David Cutler
Treating cancer with a single drug may fail because a small number of cells develop resistance (depicted here as yellow shields) to the drug.
ABVD, CHOP, and POMP: Alphabet-soup acronyms like these are the rule in modern chemotherapy, harnessing the power of several drugs in combination to fight cancer more effectively than one or two antitumor agents at a time. CHOP, for example, is a standard four-drug regimen—cyclophosphamide, hydroxydoxorubicin, Oncovin (vincristine), and prednisone—used in treating non-Hodgkin's lymphoma as well as other cancers.
Patients who receive these potent combinations today are benefiting from a daring and controversial strategy first tried a half-century ago by Dana-Farber Physician-in-Chief Emeritus Emil "Tom" Frei III, MD, and two of his colleagues (see story, Different eras, continuing goals). At the time, the successes of chemotherapy were often shortlived; patients initially responded to single drugs for leukemia and other blood cancers, but then relapsed after repeated treatments. The reason: A tiny minority of the tumor cells were inherently resistant to each drug when given alone—or underwent random genetic changes that made them resistant—and survived the chemical onslaught. Because the chemotherapy killed off their competitors, the hardy cells flourished and took over, and the cancer was now virtually untreatable with the original drug.
Taking a page from infectious disease specialists who were using several drugs simultaneously to treat tuberculosis that had outwitted single-agent antibiotics, Frei and his coworkers surmised that hitting a cancer like acute lymphoblastic leukemia (all) with several drugs, each working in a different way, might work as a preemptive strike against resistance.
"This is an elegant example of how rational drug design—developing drugs based on a molecular understanding of cell structures and processes—can be used to attack human diseases."
—James Griffin, MD
"Tom Frei began doing this some 45 years ago when he was at the National Cancer Institute," says Dana-Farber investigator Joseph Paul Eder, MD, who conducts clinical trials of experimental drug therapies. "Treating the leukemia with all the active drugs available killed the maximum amount of cancer and prevented drug-resistant forms from emerging." This approach, embodied in a chemotherapy combination known as POMP, led to the first complete cures for childhood leukemia in some patients during the 1960s and quickly gained widespread acceptance among cancer clinicians. In fact, the revolutionary insights of Frei and his colleagues, Drs. Emil Freireich and James Holland, and their persistence in the face of skepticism and dire predictions, ranks as one of the most important advances in cancer treatment.
But this disease usually doesn't yield to one-time solutions, and today, half a century later, resistance remains the greatest obstacle to successful cancer treatment. "For most solid organ tumors that have become metastatic—like breast, lung, and colorectal cancer—chemotherapy tries to slow down the growth of the tumor," says Dana-Farber physician-scientist Jeffrey Meyerhardt, MD, who treats patients with gastrointestinal tumors. "But no matter what drug regimen you use, resistance will eventually develop, and the disease will probably progress."
- Next: Many roads to resistance
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