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Role of Nonhomologous End-Joining and Recombinational DNA Repair in Resistance to Nitrogen Mustard and DNA Crosslinking Agents

  • Lawrence C. Panasci
  • Zhi-Yuan Xu
  • Raquel Aloyz
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

The nitrogen mustards are an important group of alkylating agents with activity against several human tumors (1–4). Many nitrogen mustard analogs are transported by carrier-mediated systems into cells and alkylate DNA, RNA, and proteins (5–7). Alkylation of DNA and, more specifically, the formation of DNA interstrand crosslinks have been considered to be responsible for their cytotoxicity (8–10). Resistance to the nitrogen mustards in murine and human tumor cells has been reported to be secondary to (1) alterations in the transport of these agents (11), (2) alterations in the kinetics of the DNA crosslinks formed by these agents (9,10,12), (3) cytoplasmic metabolism of the chloroethyl alkylating moiety to the inactive hydroxyethyl derivative (13) via glutathione (GSH)/ glutathione-S-transferase (GST) (14–16), (4) overexpression of metallothionein, which confers resistance to cis-platinum and cross-resistance to melphalan (17), (5) changes in resistance to apoptosis (18), and (6) altered DNA repair activity (se e Fig. 1) (19). There have been previous reports of alterations in the kinetics of DNA interstrand crosslink formation and removal associated with resistance to the nitrogen mustards (9,10,12), although others have found no differences in the ability of sensitive or resistant cells to remove nitrogen mustard-induced crosslinks (20, 21). This review will concentrate on the involvement of DNA repair in nitrogen mustard drug resistance and cross-resistance to cisplatin. We will discuss results obtained in clinical samples and human cancer cell lines.

Keywords

Chronic Lymphocytic Leukemia Nucleotide Excision Repair Chronic Lymphocytic Leukemia Patient Nitrogen Mustard Homologous Recombinational Repair 
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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© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Lawrence C. Panasci
  • Zhi-Yuan Xu
  • Raquel Aloyz

There are no affiliations available

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