SAN FRANCISCOUse of tyrosine kinase inhibitors, including PKI166 (investigational, Novartis) and imatinib(Drug information on imatinib) mesylate (STI571, Gleevec) can significantly reduce the size of metastatic bone tumors, decrease angiogenesis, and preserve bone structures, according to animal studies presented at the 93rd Annual Meeting of the American Association for Cancer Research.
In the studies, the tyrosine kinase inhibitors PKI166 and imatinib mesylate were tested against human prostate and kidney cell lines implanted in mice. Both agents reduced bone lesions significantly and significantly reduced angiogenesis by specifically targeting endothelial cells associated with bone metastasis.
"We hope this treatment modality can increase the specificity of cancer treatment and reduce side effects by blocking the growth factors EGFR [epithelial growth factor receptor] and PDGFR [platelet derived growth factor receptor]," said Sun Jin Kim, MD, PhD, instructor, Cancer Biology Department at The University of Texas M. D. Anderson Cancer Center.
In the study (abstract 4234), conducted in the laboratory of Dr. Isaiah J. Fidler, the tibias of male mice were injected with tumor cells from a patient with end-stage prostate cancer. Groups of 10 mice received one of seven treatments or saline. The treatments consisted of paclitaxel(Drug information on paclitaxel) (Taxol), PKI166, or imatinib mesylate alone; paclitaxel plus PKI166 or imatinib mesylate; PKI166 plus imatinib mesylate; or a combination of all three drugs.
Results showed that mice treated with saline or paclitaxel alone retained significantly large tumors in the tibia with bone lysis. In mice treated with paclitaxel plus PKI166 or paclitaxel plus imatinib mesylate, the bone tumors were smaller and the bone structure was preserved. The incidence of lymph node metastasis was also significantly lower in mice treated with PKI166 or imatinib mesylate.
Combination therapy with PKI166, imatinib mesylate, and paclitaxel produced the most significant therapeutic effects, with decreased tumorigenicity, tumor size, lymph node metastasis, and preservation of bone structure.
Analysis showed that the drugs blocked the phosphorylation of EGFR and PDGFR. Treatment also induced apoptosis of endothelial cells in tumor-related blood vessels, but not in endothelial cells of normal leg vessels.