Imatinib, known commercially as Gleevec, worked best when combined with the chemotherapy paclitaxel to slash the incidence of bone metastases and the size of tumors in mice injected with a multiple-drug resistant form of prostate cancer. Tumors were found in only 4 of 18 mice treated with the combination, median tumor weight was one tenth of a gram, and the cancer spread to the lymph nodes in three cases. Tumors grew in all 19 control mice, their median tumor weight was 1.3 grams, and all metastasized to the lymph nodes.
This extremely drug-resistant form of the cancer, designed by the research team to emulate the grim clinical reality of prostate cancer that has spread into the bone, successfully warded off the combined medications in lab experiments, said Isaiah J. Fidler, D.V.M., Ph.D., chair of the Department of Cancer Biology and director of the Cancer Metastasis Research Center at M. D. Anderson.
"Why, then, did it work so well in the animal? Because we didn't attack the tumor, we attacked the blood vessels. We target and destroy the vasculature that provides oxygen and nutrients to tumor cells," said Fidler, the paper's senior author.
Fidler and colleagues show in the JNCI paper that imatinib killed tumor-related blood vessel (endothelial) cells by inactivating the platelet-derived growth factor receptors (PDGF-R) on the cell surface. This prevents the receptor's activation either by PDGF binding to it externally or by a signal generated internally by the cell.
Activation of PDGF-R stimulates the birth of new blood vessels, promotes cell division and migration, and inhibits a protective form of cell suicide known as apoptosis, all h
Contact: Scott Merville
University of Texas M. D. Anderson Cancer Center