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Drug resistance and DNA repair in leukaemia

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Multiple Drug Resistance in Cancer 2

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Abstract

Most cytotoxic agents exert their action via damage of DNA. Therefore, the repair of such lesions is of major importance for the sensitivity of malignant cells to chemotherapeutic agents. The underlying mechanisms of various DNA repair pathways have extensively been studied in yeast, bacteria and mammalian cells. Sensitive and drug resistant cancer cell lines have provided models for analysis of the contribution of DNA repair to chemosensitivity. However, the validity of results obtained by laboratory experiments with regard to the clinical situation is limited. In both acute and chronic leukaemias, the emergence of drug resistant cells is a major cause for treatment failure. Recently, assays have become available to measure cellular DNA repair capacity in clinical specimens at the single-cell level. Application of these assays to isolated lymphocytes from patients with chronic lymphatic leukaemia (CLL) revealed large interindividual differences in DNA repair rates. Accelerated O6-ethylguanine elimination from DNA and faster processing of repair-induced single-strand breaks were found in CLL lymphocytes from patients nonresponsive to chemotherapy with alkylating agents compared to untreated or treated sensitive patients. Moreover, modulators of DNA repair with different target mechanisms were identified which also influence the sensitivity of cancer cells to alkylating agents. In this article, we review the current knowledge about the contribution of DNA repair to drug resistance in human leukaemia.

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Abbreviations

AGT:

O6-alkylguanine-DNA alkyltransferase

AML:

acute myeloid leukaemia

ALL:

acute lymphatic leukaemia

AP:

apurinic site

BER:

base excision repair

CLL:

chronic lymphatic leukaemia

CML:

chronic myeloid leukaemia

EtNU:

N-ethyl-N-nitrosourea

ICA:

immunocytological analysis

LRP:

lung resistance related protein

MDR:

multiple drug resistance

MMR:

mismatch repair

MRP:

multiple drug resistance-related protein

NER:

nucleotide excision repair

O6-ethylguanine:

O6-EtGua

PARP:

poly(ADP-ribose)polymerase

SCGE:

single-cell gel electrophoresis

TCR:

transcription-coupled repair

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Authors and Affiliations

  1. Department of Internal Medicine (Cancer Research), University of Essen Medical School, West German Cancer Centre Essen, Hufelandstraße 55, D-45122, Essen, Germany

    Mark R. Müller & Siegfried Seeber

  2. Institute of Cell Biology (Cancer Research), University of Essen Medical School, West German Cancer Centre Essen, Hufelandstraße 55, D-45122, Essen, Germany

    Jürgen Thomale & Manfred F. Rajewsky

Authors
  1. Mark R. Müller
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  2. Jürgen Thomale
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  3. Manfred F. Rajewsky
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  4. Siegfried Seeber
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Correspondence to Mark R. Müller .

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Editors and Affiliations

  1. National Cell & Tissue Center, Bioresearch Ireland, Dublin City University, Glasnevin, Dublin, Ireland

    Martin Clynes

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Müller, M.R., Thomale, J., Rajewsky, M.F., Seeber, S. (1998). Drug resistance and DNA repair in leukaemia. In: Clynes, M. (eds) Multiple Drug Resistance in Cancer 2. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-2374-9_11

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  • DOI: https://doi.org/10.1007/978-94-017-2374-9_11

  • Publisher Name: Springer, Dordrecht

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