Paclitaxel is preferentially cytotoxic to human cervical tumor cells with low Raf-1 kinase activity: implications for paclitaxel-based chemoradiation regimens

Background and purpose: Low Raf-l kinase activity has been reported to be associated with radioresistance in epithelial tumor cell lines and with paclitaxel sensitivity in cervical tumor cells. Paclitaxel might thus be effective in eliminating radioresistant clones from cervical tumors, even in the absence of synergistic interaction between these therapeutic modalities. We thus established the relationship between Raf-l kinase activity and radiosensitivity in human cervical tumor cells and determined if paclitaxel is preferentially cytotoxic to radioresistant tumor clones. Materials and methods: We established and contrasted the radiation and paclitaxel sensitivity of 12 human cervical tumor clones that exhibited a wide range of Raf-l kinase activity. Results: Raf-l kinase activity was inversely correlated (P = 0.001) with SF2 values in the 12 cervical tumor clones studied. Paclitaxel was preferentially cytotoxic to radioresistant tumor clones, with the level of paclitaxel-induced cytotoxicity beings significantly (P = 0.0016) influenced by Raf-l kinase activity levels. Conclusions: Our in vitro data indicate that there are marked, but completely opposite, Raf-l kinase dependencies of radiation and paclitaxel cytotoxicity in cervical tumor cells. The use of combined paclitaxel and radiotherapy treatment may thus lead to higher local control rates for squamous cell carcinoma of the cervix. Circumstantially, our data suggest that the greatest therapeutic gains might accrue if paclitaxel was administered when there is the greatest proportion of tumor clones with low Raf-l kinase activity. It may thus be desirable to use paclitaxel rewards the end of radiotherapy treatment or post-radiotherapy as consolidation therapy. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.