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Pharmacologic circumvention of multidrug resistance

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Abstract

The ability of malignant cells to develop resistance to chemotherapeutic drugs is a major obstacle to the successful treatment of clinical tumors. The phenomenon multidrug resistance (MDR) in cancer cells results in cross-resistance to a broad range of structurally diverse antineoplastic agents, due to outward efflux of cytotoxic substrates by themdr1 gene product, P-glycoprotein (P-gp). Numerous pharmacologic agents have been identified which inhibit the efflux pump and modulate MDR. The biochemical, cellular and clinical pharmacology of agents used to circumvent MDR is analyzed in terms of their mechanism of action and potential clinical utility. MDR antagonists, termed chemosensitizers, may be grouped into several classes, and include calcium channel blockers, calmodulin antagonists, anthracycline andVinca alkaloid analogs, cyclosporines, dipyridamole, and other hydrophobic, cationic compounds. Structural features important for chemosensitizer activity have been identified, and a model for the interaction of these drugs with P-gp is proposed. Other possible cellular targets for the reversal of MDR are also discussed, such as protein kinase C. Strategies for the clinical modulation of MDR and trials combining chemosensitizers with chemotherapeutic drugs in humans are reviewed. Several novel approaches for the modulation of MDR are examined.

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Abbreviations

ALL:

acute lymphocytic leukemia

AML:

acute myelogenous leukemia

CaM:

calmodulin

CsA:

cyclosporin A

MDR:

multidrug resistance

P-gp:

P-glycoprotein

PMA:

phorbol 12-myristate 13-acetate

PKC:

protein kinase C

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  1. Division of Oncology, M-211, Stanford University Medical Center, 94305, Stanford, CA, USA

    James M. Ford

  2. Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 679 Hoes Lane, 08854, Piscataway, NJ, USA

    William N. Hait

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Ford, J.M., Hait, W.N. Pharmacologic circumvention of multidrug resistance. Cytotechnology 12, 171–212 (1993). https://doi.org/10.1007/BF00744664

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