ATP-dependent transport of vinblastine in vesicles from human multidrug-resistant cells.
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- M Horio
- Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD 20892.
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- M M Gottesman
- Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD 20892.
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- I Pastan
- Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD 20892.
抄録
<jats:p>Resistance of human cancer cells to multiple cytotoxic hydrophobic agents (multidrug resistance) is due to overexpression of the "MDR1" gene, whose product is the plasma membrane P-glycoprotein. Plasma membrane vesicles partially purified from multidrug-resistant human KB carcinoma cells, but not from drug-sensitive cells, accumulate [3H]vinblastine in an ATP-dependent manner. This transport is osmotically sensitive, with an apparent Km of 38 microM for ATP and of approximately equal to 2 microM for vinblastine. The nonhydrolyzable analog adenosine 5'-[beta, gamma-imido]triphosphate does not substitute for ATP but is a competitive inhibitor of ATP for the transport process. Vanadate, an ATPase inhibitor, is a potent noncompetitive inhibitor of transport. These results indicate that hydrolysis of ATP is probably required for active transport of vinblastine. Several other drugs to which multidrug-resistant cell lines are resistant inhibit transport, with relative potencies as follows: vincristine greater than actinomycin D greater than daunomycin greater than colchicine = puromycin. Verapamil and quinidine, which reverse the multidrug-resistance phenotype, are good inhibitors of the transport process. These results confirm that multidrug-resistant cells express an energy-dependent plasma membrane transporter for hydrophobic drugs, and establish a system for the detailed biochemical analysis of this transport process.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 85 (10), 3580-3584, 1988-05
Proceedings of the National Academy of Sciences
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詳細情報 詳細情報について
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- CRID
- 1362825894757004160
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- NII論文ID
- 30016282742
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- ISSN
- 10916490
- 00278424
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- データソース種別
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