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Drug Resistance: New Approaches to Treatment

  • J. R. Bertino
  • S. Srimatkandada
  • M. D. Carman
  • M. Jastreboff
  • L. Mehlman
  • W. D. Medina
  • E. Mini
  • B. A. Moroson
  • A. R. Cashmore
  • S. K. Dube
Part of the NATO ASI Series book series (NSSA, volume 120)

Abstract

Mechanisms by which malignant cells may become resistant to chemotherapeutic agents are reviewed, with emphasis on methotrexate resistance. At least four mechanisms of resistance have been described in experimental systems, including human tumor cells propagated in vitro: impaired uptake of methotrexate, an altered target enzyme (dihydrofolate reductase), and an elevated level of dihydrofolate reductase, or decreased methotrexate polyglutamylation. Combinations of these changes have been noted to occur in cells acquiring resistance to methotrexate. In the clinic, examples of resistance due to alteration of dihydrofolate reductase or elevated levels of this enzyme due to gene amplification have been reported. A strategy for selectively eradicating these resistant cells with second generation antifolates that are cytotoxic to resistant cells is discussed.

Keywords

Acute Lymphocytic Leukemia Dihydrofolate Reductase Thymidylate Synthetase DHFR Gene Impaired Transport 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • J. R. Bertino
    • 1
  • S. Srimatkandada
    • 1
  • M. D. Carman
    • 1
  • M. Jastreboff
    • 1
  • L. Mehlman
    • 1
  • W. D. Medina
    • 1
  • E. Mini
    • 1
  • B. A. Moroson
    • 1
  • A. R. Cashmore
    • 1
  • S. K. Dube
    • 1
  1. 1.Departments of Medicine and PharmacologyYale University School of MedicineNew HavenUSA

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