Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein
| Autor: | Paul Krimpenfort, Raymond Evers, Guido J.R. Zaman, M. R. Van Leusden, U. Mayer, M. A. Van Der Valk, Piet Borst, Jan Wijnholds, J. H. Beijnen, C. A. A. M. Mol |
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| Rok vydání: | 1997 |
| Předmět: |
Adult
Antineoplastic Agents Bone Marrow Cells Drug resistance Pharmacology Biology General Biochemistry Genetics and Molecular Biology chemistry.chemical_compound Mice stomatognathic system medicine Tumor Cells Cultured Animals Humans Secretion Etoposide Inflammation Mice Knockout Leukotriene C4 Membrane Transport Proteins General Medicine Glutathione Neoplasms Experimental Antineoplastic Agents Phytogenic Drug Resistance Multiple Neoplasm Proteins Multiple drug resistance chemistry Drug Resistance Neoplasm ATP-Binding Cassette Transporters Multidrug Resistance-Associated Protein 1 Multidrug Resistance-Associated Proteins Carrier Proteins medicine.drug |
| Zdroj: | Nature medicine. 3(11) |
| ISSN: | 1078-8956 |
| Popis: | The multidrug resistance-associated protein (MRP) mediates the cellular excretion of many drugs, glutathione S-conjugates (GS-X) of lipophilic xenobiotics and endogenous cysteinyl leukotrienes. Increased MRP levels in tumor cells can cause multidrug resistance (MDR) by decreasing the intracellular drug concentration. The physiological role or roles of MRP remain ill-defined, however. We have generated MRP-deficient mice by using embryonic stem cell technology. Mice homozygous for the mrp mutant allele, mrp-/-, are viable and fertile, but their response to an inflammatory stimulus is impaired. We attribute this defect to a decreased secretion of leukotriene C4 (LTC4) from leukotriene-synthesizing cells. Moreover, the mrp-/- mice are hypersensitive to the anticancer drug etoposide. The phenotype of mrp-/- mice is consistent with a role for MRP as the main LTC4-exporter in leukotriene-synthesizing cells, and as an important drug exporter in drug-sensitive cells. Our results suggest that this ubiquitous GS-X pump is dispensable in mice, making treatment of MDR with MRP-specific reversal agents potentially feasible. |
| Databáze: | OpenAIRE |
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