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[Multidrug resistance induced by surexpression of the mdrl gene]
1Service de médecine A, CHU Brabois, Vandoeuvre-lès-Nancy, France.
Abstract:
Drug resistance of some tumors and hematopoietic diseases is a major problem for clinicians. One of the mechanisms of resistance is called the multidrug resistance. Multidrug resistance is a cross-reactive resistance between molecules different in structure and activities. Multidrug resistance is characterized by an active drug efflux through the cell membrane with a decrease in drug cellular accumulation. This efflux out of the cell is due to a membrane glycoprotein called P-glycoprotein or P-gp 170 encoded by the mdr1 gene. In humans, high levels of mdr1 gene expression are observed in normal tissues as adrenal gland, colon and kidney. Tumors derived from these tissues are usually resistant to chemotherapy. By contrast to this intrinsic drug resistance, acquired drug resistance is defined by the mdr1 gene expression in tumors which relapse and become refractory to chemotherapy as acute lymphoïd and myeloïd leukemia, breast and ovarian cancers, non-Hodgkin lymphomas and multiple myeloma. When the clinical significance of multidrug resistance will be defined, identification of non-responders patients should lead to the use of therapeutic regimens including mdr reversing agents.
Insights
Multidrug resistance, a challenge in cancer therapy, involves P-glycoprotein (P-gp) actively pumping drugs out of cells. Identifying patients with this resistance may allow for targeted therapies using mdr reversing agents.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) poses a significant clinical challenge in treating various tumors and hematopoietic diseases.
- MDR is characterized by cross-resistance to structurally diverse drugs, primarily due to active drug efflux mediated by membrane transporters.
- P-glycoprotein (P-gp), encoded by the mdr1 gene, is a key mediator of this efflux, reducing intracellular drug accumulation.
Purpose of the Study:
- To elucidate the mechanism of multidrug resistance in cancer.
- To highlight the role of P-glycoprotein (P-gp) and the mdr1 gene in drug efflux and reduced drug accumulation.
- To discuss the implications of mdr1 gene expression in both intrinsic and acquired drug resistance.
Main Methods:
- Review of existing literature on multidrug resistance mechanisms.
- Analysis of the role of P-glycoprotein (P-gp) and mdr1 gene expression in various cancers and normal tissues.
- Discussion of clinical observations regarding drug resistance in specific malignancies.
Main Results:
- High mdr1 gene expression is observed in normal tissues (adrenal gland, colon, kidney), correlating with intrinsic drug resistance in tumors derived from these tissues.
- Acquired drug resistance, characterized by mdr1 gene expression, is observed in relapsed and chemotherapy-refractory cancers including leukemias, breast and ovarian cancers, lymphomas, and myeloma.
- P-glycoprotein (P-gp) mediated active drug efflux is the primary mechanism reducing cellular drug accumulation.
Conclusions:
- Multidrug resistance, driven by P-gp efflux, significantly impacts chemotherapy efficacy.
- Understanding mdr1 gene expression can help identify non-responder patients.
- Future therapeutic strategies may involve mdr reversing agents to overcome P-gp mediated drug resistance.