Induction of multiple-drug resistance during anti-neoplastic chemotherapy in vitro.
Induction of P-glycoprotein-related multi-drug-resistance (MDR) has been shown in normal and malignant tissues to result from environmental stresses such as heat shock, exposure to carcinogens or X-ray irradiation. To identify conditions under which MDR is enhanced during anti-neoplastic chemotherapy, a cell line showing low-level intrinsic MDR was investigated. In the pleural mesothelioma cell line, PXF1118, less than 1% of cells expressed P-glycoprotein (P-gp), as shown by immunocytochemical staining with monoclonal antibody (MAb) MRK16. Exposure of PXF1118 to vincristine, vindesine, vinblastine or doxorubicin for 2-3 weeks led to an increase in the MDR cell fraction of up to 15-28% during 2 to 3 weeks. For doxorubicin and vindesine, dose-dependence was observed: drug concentrations not capable of eliciting cytotoxicity failed to induce significant P-gp expression. Nutrient starvation in aging medium, exposure to activated cyclophosphamide (even at high concentrations) or cisplatin caused only negligible MDR induction. After exposure to vindesine for 6 weeks, tumor colonies exhibited highly enhanced resistance to Vinca alkaloids, doxorubicin, etoposide and dacarbacine, whereas their sensitivity to mitomycin, activated cyclophosphamide or cisplatin remained unchanged. As determined by [3H]-thymidine uptake and proliferation antigen expression, induction of MDR phenotype was observed at minimal proliferative activity with no change in cell count during exposure to anti-cancer drugs, thus suggesting that the drug treatments changed the phenotype of the cells rather than selecting for a resistant sub-population. In addition, changes in cell differentiation were observed during MDR induction. Induction of P-gp during exposure to anti-cancer drugs thus provides a model for MDR development during initially successful chemotherapy. of P-gp during exposure to anti-cancer drugs thus provides
University of Freiburg, Department of Internal Medicine (Hematology/Oncology), Germany.
T
T
Licht
H H
HH
Fiebig
K J
KJ
Bross
F
F
Herrmann
D P
DP
Berger
R
R
Shoemaker
R
R
Mertelsmann
D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics; D009368:Neoplasm Transplantation; D013936:Thymidine / Q000378:metabolism; D014183:Transplantation, Heterologous; D014410:Tumor Stem Cell Assay; D014700:Verapamil / Q000494:pharmacology
D000970:Antineoplastic Agents; D006023:Glycoproteins; D009363:Neoplasm Proteins; D014700:Verapamil; D013936:Thymidine