Chemotherapeutic potential of plant alkaloids and multidrug resistance mechanisms in malignant fibrous histiocytoma of the heart.
Primary malignant fibrous histiocytoma (MFH) of the heart is a rare and highly malignant soft tissue tumor, which is largely resistant to conventional chemotherapy and radiotherapy. Therefore, we analyzed growth inhibitory effects of different chemotherapeutic agents and mechanisms of drug resistance in the recently established cell line MFH-H derived from a human primary cardiac MFH. The growth inhibitory effects of etoposide, vincristine, and paclitaxel were tested using the MTT assay. The expression and function of multidrug resistance-related proteins, i.e. the P-glycoprotein, the multidrug resistance-associated protein (MRP) and the lung resistance-related protein (LRP) were determined by FACScan and functional assays of cellular drug efflux. The concentration required for a 50% inhibition of growth (IC50) was 0.001 microM for etoposide and 0.035 microM for vincristine. Paclitaxel dissolved in Cremophor EL/ethanol inhibited the cell growth of MFH-H cells more intensively (IC50: 0.27 microM) than paclitaxel dissolved in DMSO (IC50: 11.09 microM) suggesting that Cremophor EL is contributing to the inhibitory effects of paclitaxel. The response of MFH-H to etoposide, vincristine and paclitaxel/Taxol could not be predicted by the expression and function of P-glycoprotein, MRP and LRP. This study demonstrates that etoposide and to a lesser extent vincristine can effectively inhibit the growth of MFH-H cells, irrespective of the multidrug resistance phenotype. MFH-H cells are relatively insensitive to paclitaxel dissolved in DMSO, in contrast to paclitaxel dissolved in Cremophor EL/ethanol indicating that the diluent Cremophor contributes to the antiproliferative effects of the taxane paclitaxel.
Reinecke
P
P
Institute of Pathology, Heinrich-Heine-University, D-40225 Düsseldorf, Germany. reinecke@med.uni-duesseldorf.de
Steckstor
M
M
Schmitz
M
M
Gabbert
H E
HE
Gerharz
C D
CD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000470:Alkaloids / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D045744:Cell Line, Tumor; D002469:Cell Separation; D002470:Cell Survival; D002478:Cells, Cultured; D004396:Coloring Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D006338:Heart Neoplasms / Q000188:drug therapy*; D018219:Histiocytoma, Benign Fibrous / Q000188:drug therapy*; D006801:Humans; D020128:Inhibitory Concentration 50; D017239:Paclitaxel / Q000494:pharmacology; D010641:Phenotype; D010936:Plant Extracts / Q000627:therapeutic use*; D012983:Soft Tissue Neoplasms / Q000188:drug therapy*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D020394:Vault Ribonucleoprotein Particles / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology; D000099187:Major Vault Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D005047:Etoposide; D017239:Paclitaxel; D010936:Plant Extracts; D013778:Tetrazolium Salts; D013844:Thiazoles; D020394:Vault Ribonucleoprotein Particles; D014750:Vincristine; D000099187:Major Vault Protein; C022616:thiazolyl blue