Growth inhibitory effects of paclitaxel on human epithelioid sarcoma in vitro - Heterogeneity of response and the multidrug resistance phenotype

BACKGROUND. Epithelioid sarcoma is a highly malignant soft tissue tumor tha t is largely resistant to conventional chemotherapy and radiotherapy. Becau se paclitaxel has been proven to be effective in other human malignancies r efractory to conventional chemotherapy, the authors analyzed the in vitro g rowth inhibitory effects of paclitaxel on the human epithelioid-sarcoma cel l line GRU-1 and its clonal subpopulations GRU-1A, GRU-1B, and GRU-1C. METHODS. Paclitaxel-induced morphologic alterations were visualized using L ight microscopy, immunofluorescence microscopy, and transmission electron m icroscopy. The antiproliferative effects of paclitaxel on the cell lines we re determined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium' brom ide (MTT) assay. The extent of paclitaxel-induced apoptosis was determined by light microscopy. The expression and function of P-glycoprotein and the multidrug resistance-associated protein (MRP) were defined by reverse trans criptase-polymerase chain reaction and fluorescence-activated cell sorter a nalysis. RESULTS. Paclitaxel-induced morphologic alterations such as micronucleus fo rmation and microtubule bundles showed no significant differences between t he parental cell line and its clonal subpopulations. A significant (P < 0.0 5) dose-dependent growth inhibition was observed in GRU-1 and its clonal su bpopulation with the IC50 (concentration that inhibits 50%) values ranging from 0.04-0.49 mu M in the different subpopulations. Paclitaxel-induced gro wth inhibition was accompanied by a slight increase in apoptosis. All cell lines showed an expression of and an effective function of P-glycoprotein a nd MRP. CONCLUSIONS. The differential response of GRU-1 and its clonal subpopulatio ns to paclitaxel could not be predicted by the expression and function of P -glycoprotein and MRP, suggesting that other drug resistance mechanisms mig ht be relevant in the heterogenous response observed in the epithelioid sar coma cell lines in the current study. (C) 2000 American Cancer Society.