Combining flavopiridol with various signal transduction inhibitors

Treatment of human tumors with a combination of chemotherapeutic agents results in improved response as well as the ability to use less toxic concentrations of the drugs. Recent phase I clinical trials with the cyclin-dependent kinase inhibitor, flavopiridol, have shown some promise in the treatment of a variety of human tumors. Because of the severe toxicity, however, the use of less toxic doses in combination with other antiproliferative agents would be desirable. The purpose of this study was to examine the effects of combining flavopiridol with several signal transduction inhibitors: the SC236 COX-2 inhibitor, a PKC kinase inhibitor and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor in a control vector transfected MCF-7 human breast cancer cell line (MCF/neo) and a HER-2/neu transfected MCF-7 cell line (MCF/18). Enhanced (better than that seen with either agent alone but not additive) growth inhibition was observed in both cell lines with the combination of flavopiridol and the PKC kinase inhibitor. The combination of flavopiridol and the SC236 COX-2 inhibitor resulted in an enhanced effect in the MCF/18 cell line and a synergistic effect in the MCF/neo cells. The combination of flavopiridol and LY294002 resulted in a synergistic effect in the MCF/18 cell line and an additive effect in the MCF/neo cells. These data suggest that combinations of flavopiridol and signal transduction inhibitors warrant further studies as treatments for breast tumors, and that HER-2/neu expression may influence the choice of inhibitor to combine with flavopiridol.