K252A, KT5720, KT5926, AND U98017 SUPPORT PACLITAXEL (TAXOL)-DEPENDENT CELLS AND SYNERGIZE WITH PACLITAXEL

We have used paclitaxel-dependent Tax 2-4 cells to screen for compound s that have paclitaxel-like functional activity. The indolocarbazole s erine/threonine kinase inhibitor K252a and analogues such as KT5926, K T5720, and K252b partially support the growth of the paclitaxel-depend ent cells in the absence of paclitaxel. A novel kinase inhibitor of si milar structure, U98017, supports the growth of the dependent cells to 48% of that seen with paclitaxel. Used in combination with paclitaxel , these compounds reduce the amount of paclitaxel required for maximum growth of the dependent cells. Isobologram analysis demonstrates that these compounds also act synergistically with paclitaxel to promote t oxicity in wild-type Chinese hamster ovary cells. These selected indol ocarbazoles may act at sites distinct from that of paclitaxel and may specifically inhibit kinases that contribute to the destabilization of microtubules. Other indolocarbazoles such as staurosporine and rebecc amycin do not support paclitaxel-dependent cell growth. Structurally u nrelated serine/threonine kinase inhibitors such as H-9 and H-7 or tyr osine kinase inhibitors such as lavendustin do not support the growth of these cells. These results define a screen for functional paclitaxe l analogues and suggest that it may be useful to investigate the possi ble synergy of selected indolocarbazoles and paclitaxel in vivo.