The multidrug resistance in human leukemias. Minireview

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Clinically refractory leukemia and lymphoma often overexpress P-glycoprotein (P-gp).
• P-gp is encoded by the multidrug resistance (MDR) gene, mdr1.
• MDR confers resistance to various lipophilic chemotherapy drugs.

Purpose of the Study:

• To investigate the role of P-gp in multidrug resistance.
• To explore methods for circumventing P-gp mediated drug efflux.

Main Methods:

• Utilized cell lines expressing the mdr1 gene.
• Assessed drug resistance to anthracyclines, vinca alkaloids, and epopodophyllotoxins.
• Employed mdr1 cDNA transfer to confer resistance.
• Measured P-gp activity using the rhodamine 123 fluorescence probe.
• Evaluated the effect of verapamil and cyclosporin A on drug resistance.

Main Results:

• mdr1-expressing cells demonstrated resistance to multiple structurally unrelated drugs.
• MDR phenotype was transferable via mdr1 cDNA.
• Resistant cells showed increased P-gp overexpression and enhanced efflux of rhodamine 123.
• Verapamil and cyclosporin A effectively circumvented P-gp mediated drug efflux.

Conclusions:

• P-glycoprotein (P-gp) is a key mediator of multidrug resistance (MDR) in leukemia and lymphoma.
• The mdr1 gene product, P-gp, drives drug efflux and therapeutic refractoriness.
• Non-cytotoxic drugs like verapamil and cyclosporin A show potential for overcoming MDR.