HIGH RAF-1 KINASE-ACTIVITY PROTECTS HUMAN TUMOR-CELLS AGAINST PACLITAXEL-INDUCED CYTOTOXICITY

Paclitaxel (Taxol(TM)) is becoming increasingly important in the treat ment of many tumors, although a large proportion of tumors fail to res pond to this drug, The identification of the processes that confer cel lular paclitaxel resistance could provide potential targets for novel therapies that may help to eliminate paclitaxel-resistant tumors. Rece nt reports suggest that the Raf-l protein kinase may have a profound i nfluence on the level of paclitaxel-induced apoptosis, We have critica lly evaluated the relationship between Raf-l kinase activity and de no vo paclitaxel resistance in early-passage human cervical tumors. In th e 12 cell lines studied, Raf-l kinase activity was inversely correlate d (P = 0.0016) with the level of cytotoxicity induced by 60 nM paclita xel, The relationship between these two parameters seems to be more th an an epiphenomenon, because genetic down-regulation of Raf-l kinase a ctivity led to an approximately 4-fold increase in paclitaxel-induced cytotoxicity. The data from both our transfection studies and those on the 12 unperturbed cell lines are consistent with Raf-l kinase being a negative determinant of paclitaxel-induced cytotoxicity, Because the cytotoxicity of paclitaxel is primarily attributable to apoptosis, th ese data suggest that Raf-l kinase acts to suppress paclitaxel-induced apoptosis, These data suggest that the clinical effectiveness of pacl itaxel could be substantially improved by the use of Raf-l kinase inhi bitors, provided that a similar relationship between Raf-l kinase acti vity and paclitaxel cytotoxicity exists in the clinic, especially in t hose tumor sites where paclitaxel is the current treatment of choice e .g., ovarian and breast cancer.