Reversal of multidrug resistance of tumor cells

D. Szabó, H. Keyzer, H. E. Kaiser, J. Molnár

Research output: Contribution to journalReview article

63 Citations (Scopus)

Abstract

Drug resistance to chemotherapy is rapidly emerging. Resistance to one drug carries over resistance to unrelated anticancer drugs leading to multidrug resistance (MDR). A major factor of MDR is P-glycoprotein (P-gp) mediated ABC transport found in many eukaryotic cells. P-gp acts as a drug eMux pump. The mdr1 gene involved in P-gp 170 protein production is localized in the human chromosome 7 band p2 1.0 - 21.1. Point mutations alter cross-resistance patterns. A variety of stimuli increase the expression of the mdr1 gene: lowered extracellular pH, heat shock, arsenite, cytotoxic agents, anticancer drugs, transfection with oncogenes, HIV-I, and UV-irradiation. An alternative hypothesis to the efflux pump claims that P-gp modifies the intracellular environment to reduce accumulation of anticancer drugs in cancer cells by creating ionic or proton gradients. Chemosensitizers that block P-gp drug extrusion are generally lipid-soluble at physiological pH, possess a basic nitrogen atom and at least two co-planar rings. P-gp blocking does not depend on drug chirality. This opens the way of treating P-gp related MDR with chiral versions of drugs relatively harmless in terms of side-effects. We believe that resistance modifiers combined with cytostatics will chemotherapeutically be more effective for cancer patients.

Original languageEnglish
Pages (from-to)4261-4274
Number of pages14
JournalAnticancer research
Volume20
Issue number6 B
Publication statusPublished - Dec 1 2000

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Keywords

  • Human mdr1-gene
  • Mouse lymphoma
  • Multidrug resistance reversal
  • Specificity and stereselectivity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Szabó, D., Keyzer, H., Kaiser, H. E., & Molnár, J. (2000). Reversal of multidrug resistance of tumor cells. Anticancer research, 20(6 B), 4261-4274.