One of the greatest obstacles to successful cancer treatment is the development of multidrug resistance by tumors -- that is, tumors become better able to withstand the actions of a wide variety of unrelated chemicals. The anti-drug pump is a major tool in multidrug resistance.
The researchers have found a novel way to suppress production of the pump long enough for cancer drugs to work.
Therapies for cancer treatment often use chemicals that impair the genetic machinery of cells. In previous studies, the Dartmouth researchers found that relatively low doses of these DNA-damaging drugs affect genes selectively. Genes active in day-to-day housekeeping -- for example, those involved in cell structure or basic food metabolism -- are less vulnerable to damage than genes induced in response to external signals -- such as hormone fluctuations or an incursion of foreign chemicals. Because the gene for P-glycoprotein is inducible, activated by cues from its environment, investigators were interested in how it would be affected by cancer chemotherapy drugs. They focused initially on one group of drugs called DNA cross-linking agents, which damage genes by fusing strands of their DNA together.
The researchers treated drug-resistant cells with a low dose of the cancer drug mitomycin C, waited 24 hours, then administered a second chemotherapy agent. The low-dose pre-treatment appeared to temporarily turn off the gene that produces P-glycoprotein, producing a "window" of time during which there was an increase in the sensitivity of the cells to the killing effect of the second drug. The researchers achieved similar results by priming cells with three other cross-linking drugs.
"Opening the window takes about 24 hours, and it stays open for another 72 hours -- and that's the period when the second drug is most effective," says Hamilton. The researchers report similar results in drug-resistant cells derived from breast, colon, liver, leukemia and brain tumors. Preliminary results from animal and human studies, using paclitaxel (Taxol), doxorubicin and mitomycin, are consistent with these findings.
The results suggest that a similar pretreatment regimen may increase the efficacy of cancer chemotherapy in patients. Sequential use of chemotherapeutic agents would minimize drug interactions as well as side effects.
The researchers are now doing animal studies to determine the most effective combination of drugs, and human clinical trials to determine the effectiveness of this approach in various natural cancers.
The Dartmouth team includes Michael Ihnat, Jean Lariviere, Amy Warren, Nicole La Ronde, Johanna Blaxall, Karana Pierre and Bruce Turpie. The work was supported by grants from the National Cancer Institute, the International Life Sciences Institute Inc., the American Cancer Society and the Cotton Cancer Center.
Contacts: Nancy Serrell
Associate Professor of Pharmacology & Toxicology
Dartmouth Medical School