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Drug resistance in hematologic malignancies
1Department of Hematology and Medical Oncology, University Paris 6, Paris, France. jean-pierre.marie@htd.ap-hop-paris.fr
Abstract:
Drug resistance eventually occurs in most hematologic malignancies treated with chemotherapy. The mechanisms responsible for drug resistance include expression of transporters of xenobiotics of the adenosine triphosphate-binding cassette protein superfamily (P-glycoprotein, multidrug resistance associated proteins, breast cancer resistance protein), modifications of enzymes like deoxycytidine kinase, and defects in chemotherapy-induced apoptosis. The efforts to overcome this drug resistance have been focused, thus far, on modulation of P-glycoprotein. Several compounds were manufactured for this purpose, and phase III trials of PSC833, one of the most potent P-glycoprotein inhibitors, are completed. The emergence of modulators with several adenosine triphosphate-binding cassette protein targets, like GG120918 (inhibiting P-glycoprotein and breast cancer resistance protein) and VX710 (inhibiting P-glycoprotein and multidrug resistance associated protein 1), are of clinical interest in malignancies often expressing several efflux pumps simultaneously. Another approach is the use of "furtive" drugs like liposomal or nanoparticular anthracyclines.
Insights
Drug resistance in hematologic malignancies is a major challenge. New strategies target multiple drug efflux pumps and utilize novel drug formulations to overcome chemotherapy resistance.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Drug resistance is a significant clinical problem in hematologic malignancies treated with chemotherapy.
- Mechanisms include overexpression of ATP-binding cassette (ABC) transporters (P-gp, MRPs, BCRP), enzyme modifications, and impaired apoptosis.
- Current strategies primarily focus on P-glycoprotein (P-gp) modulation.
Purpose of the Study:
- To review the mechanisms of chemotherapy drug resistance in hematologic malignancies.
- To discuss emerging strategies for overcoming drug resistance, including multi-target modulators and novel drug delivery systems.
Main Methods:
- Review of existing literature on drug resistance mechanisms in hematologic malignancies.
- Analysis of current and emerging therapeutic strategies targeting ABC transporters.
- Discussion of novel drug formulations like liposomal and nanoparticular anthracyclines.
Main Results:
- P-glycoprotein (P-gp) inhibition has been a primary focus, with compounds like PSC833 completing Phase III trials.
- Development of multi-target modulators (e.g., GG120918, VX710) inhibiting multiple ABC transporters (P-gp, BCRP, MRPs) shows clinical promise.
- Alternative approaches involve "furtive" drug delivery systems, such as liposomal or nanoparticular anthracyclines.
Conclusions:
- Overcoming drug resistance in hematologic malignancies requires addressing multiple resistance mechanisms simultaneously.
- Multi-target ABC transporter inhibitors and innovative drug delivery systems represent promising avenues for improving treatment efficacy.
- Further research into these strategies is crucial for clinical application in treating resistant hematologic cancers.