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Biology of multiple drug resistance in acute leukemia
1Department of Haematology, Aarhus University Hospital, Denmark. janmaxgaard@dadlnet.dk
Abstract:
Since the early 1970s, multiple drug resistance (MDR) has been known to exist in cancer cells and is thought to be attributable to a membrane-bound, energy-dependent pump protein (P-glycoprotein [P-gp]) capable of extruding various related and unrelated chemotherapeutic drugs. P-gp is coded for by the MDR1 gene, which in the human genome is located on the long arm of chromosome 7 (7q21-31). At the cellular level, the function of P-gp has been extensively investigated in human cancer. Although innumerable reports have been published in which P-gp has been shown to confer MDR to malignant (including leukemia) cells, so far, large-scale studies in the clinical setting have not convincingly proven that MDR1 plays a major role in clinical drug resistance when the influence of other known prognostic factors in human leukemia are taken into account. At present, results from phase 3 clinical trials evaluating the efficiency of inhibiting (or reversing) the function of P-gp in hematologic malignancies are eagerly awaited. Moreover, the horizon of cellular drug resistance in human cancer has during recent years widened dramatically. Thus, an array of different molecules and mechanisms by which resistant cells can escape the cytotoxic effect of anticancer drugs has now been identified. These molecules and mechanisms include apoptosis-related proteins. In this article, we review the different methods for determining MDR and, in particular, methods for determining P-gp/MDR1, with special reference to their potential importance for therapeutic strategies in human acute leukemia.
Insights
Multiple drug resistance (MDR) in cancer, particularly leukemia, is linked to P-glycoprotein (P-gp) via the MDR1 gene. Clinical evidence for MDR1
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multiple drug resistance (MDR) in cancer cells, known since the 1970s, is often attributed to P-glycoprotein (P-gp).
- P-gp, encoded by the MDR1 gene on chromosome 7, functions as an energy-dependent efflux pump for chemotherapeutic drugs.
- While P-gp's role in cellular drug resistance is well-documented, its significant clinical impact in human leukemia remains debated, especially when other prognostic factors are considered.
Purpose of the Study:
- To review methods for determining MDR, with a focus on P-gp and the MDR1 gene.
- To discuss the potential therapeutic strategies targeting P-gp/MDR1 in human acute leukemia.
- To highlight the expanding landscape of cellular drug resistance mechanisms beyond P-gp, including apoptosis-related proteins.
Main Methods:
- Review of existing literature on P-glycoprotein and MDR1.
- Analysis of studies investigating the role of MDR1 in clinical drug resistance in leukemia.
- Examination of various methods for detecting and quantifying P-gp/MDR1 expression and function.
Main Results:
- P-gp's role in conferring MDR to cancer cells, including leukemia, is established at the cellular level.
- Large-scale clinical studies have not conclusively proven MDR1's major role in leukemia drug resistance when other factors are accounted for.
- Newer mechanisms of drug resistance, such as those involving apoptosis-related proteins, are increasingly identified.
Conclusions:
- Clinical trials investigating P-gp inhibition in hematologic malignancies are anticipated.
- Understanding diverse drug resistance mechanisms is crucial for developing effective therapeutic strategies in acute leukemia.
- Methods for determining P-gp/MDR1 are important for evaluating their therapeutic relevance in leukemia treatment.