Pharmacological, molecular, and cytogenetic analysis of 'atypical' multidrug-resistant human leukemic cells
| Autor: | W T, Beck, M C, Cirtain, M K, Danks, R L, Felsted, A R, Safa, J S, Wolverton, D P, Suttle, J M, Trent |
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| Rok vydání: | 1987 |
| Předmět: |
Leukemia
Membrane Glycoproteins Chromosomes Human Pair 13 Drug Resistance Chloroquine Vinblastine Chromosome Banding Molecular Weight Verapamil Dactinomycin Tumor Cells Cultured Humans ATP Binding Cassette Transporter Subfamily B Member 1 Drug Screening Assays Antitumor Colchicine Vinca Alkaloids Podophyllotoxin Teniposide |
| Zdroj: | Cancer research. 47(20) |
| ISSN: | 0008-5472 |
| Popis: | We previously described the cross-resistance patterns and cellular pharmacology of a human leukemic cell line, CEM/VM-1, selected for resistance to the epipodophyllotoxin teniposide (M. K. Danks et al., Cancer Res., 47: 1297-1301, 1987). Compared to CEM/VLB100, which is a well characterized "classic" multidrug-resistant (MDR) cell line, the CEM/VM-1 cells display "atypical" multidrug resistance (at-MDR) in that they are cross-resistant to a wide variety of natural product antitumor drugs, except the Vinca alkaloids, and they are not impaired in their ability to accumulate radiolabeled epipodophyllotoxin. We have extended our characterization of this at-MDR cell line in the present study. In comparison to CEM/VLB100 cells, we found that CEM/VM-1 cells are not cross-resistant to either actinomycin D or colchicine. Verapamil and chloroquine, which enhance the cytotoxicity of vinblastine in CEM/VLB100 cells, had little or no ability to do so in the CEM/VM-1 cells. Membrane vesicles of the two resistant sublines were examined for overexpression of the MDR-associated plasma membrane protein (P-glycoprotein, Mr 170,000 protein, or 180,000 glycoprotein) by photoaffinity labeling with the vinblastine analogue N-(p-azido[3-125I]salicyl)-N'-beta-aminoethylvindesine. We were unable to visualize the MDR-associated protein in the CEM/VM-1 membranes with this photoaffinity probe under conditions in which the P-glycoprotein was readily seen in the membranes of CEM/VLB100 cells. Furthermore, no hybridization of the pMDR1 complementary DNA was seen in slot-blot analyses of the RNA from at-MDR cells, indicating that the mdr gene coding for P-glycoprotein is not overexpressed as is the case in the classic MDR cells. However, cytogenetic analysis indicated that the CEM/VM-1 cells contained an abnormally banded region on chromosome 13q, suggesting that a gene other than mdr may be amplified in these cells. Thus, despite the two cell lines having approximately equal degrees of resistance to epipodophyllotoxins, our data indicate that the mechanism(s) responsible for at-MDR is different from that for classic, P-glycoprotein-associated MDR. |
| Databáze: | OpenAIRE |
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