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 that is largely resistant to conventional chemotherapy and radiotherapy. Because paclitaxel has been proven to be effective in other human malignancies refractory to conventional chemotherapy, the authors analyzed the in vitro growth inhibitory effects of paclitaxel on the human epithelioid-sarcoma cell line GRU-1 and its clonal subpopulations GRU-1A, GRU-1B, and GRU-1C.


METHODS
Paclitaxel-induced morphologic alterations were visualized using light microscopy, immunofluorescence microscopy, and transmission electron microscopy. The antiproliferative effects of paclitaxel on the cell lines were determined by 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium' bromide (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 transcriptase-polymerase chain reaction and fluorescence-activated cell sorter analysis.


RESULTS
Paclitaxel-induced morphologic alterations such as micronucleus formation and microtubule bundles showed no significant differences between the parental cell line and its clonal subpopulations. A significant (P < 0.05) dose-dependent growth inhibition was observed in GRU-1 and its clonal subpopulations, with the IC(50) (concentration that inhibits 50%) values ranging from 0.04-0.49 microM in the different subpopulations. Paclitaxel-induced growth inhibition was accompanied by a slight increase in apoptosis. All cell lines showed an expression of and an effective function of P-glycoprotein and MRP.


CONCLUSIONS
The differential response of GRU-1 and its clonal subpopulations to paclitaxel could not be predicted by the expression and function of P-glycoprotein and MRP, suggesting that other drug resistance mechanisms might be relevant in the heterogenous response observed in the epithelioid sarcoma cell lines in the current study.
Reinecke
P
P
Institute of Pathology, University Hospital of Düsseldorf, Germany.
Knopf
C
C
Schmitz
M
M
Schneider
E M
EM
Gabbert
H E
HE
Gerharz
C D
CD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D018432:Drug Resistance, Multiple; D005434:Flow Cytometry; D006801:Humans; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D008854:Microscopy, Electron; D008870:Microtubules / Q000187:drug effects; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel / Q000494:pharmacology*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel