Differential impact of Raf-1 kinase activity on tumor cell resistance to paclitaxel and docetaxel.
Docetaxel (Taxotere) is becoming increasingly important in the treatment of many tumor sites and is unusually active in tumors that are resistant to the structurally similar taxane, paclitaxel. These data suggest that the processes that confer cellular paclitaxel resistance may have a substantially lower impact upon the cytotoxicity induced by docetaxel. We have recently reported that there is a marked Raf-1 kinase dependency of paclitaxel resistance in human cervical and ovarian tumor cell lines. We therefore characterized the impact that inherent and genetically induced variations in Raf-1 kinase activity have on the docetaxel cytotoxicity in human ovarian and cervical cancer cell lines. Our data suggest that docetaxel cytotoxicity is independent of Raf-1 kinase activity in the cell lines studied and that the lack of cross-resistance between these two taxane compounds may be due to the differential impact that Raf-1 kinase activity has on their cytotoxicity. Should these relationships pertain to the clinical situation, these findings could form the basis for a molecular-based triage of patients to receive docetaxel when response to paclitaxel may be unlikely due to high Raf-1 kinase activity.
Britten
R A
RA
Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Canada. richardb@cancerboard.ab.ca
Klein
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K
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D043823:Taxoids; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000201:enzymology
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D019908:Proto-Oncogene Proteins c-raf; D017239:Paclitaxel