The role of DNA repair in nitrogen mustard drug resistance.
The nitrogen mustards are an important class of DNA cross-linking agents, which are utilized in the treatment of many types of cancer. Unfortunately, resistance often develops in the treatment of patients and the tumor either never responds to or becomes refractory to these agents. Resistance to the nitrogen mustards in murine and human tumor cells has been reported to be secondary to alterations in (i) the transport of these agents, (ii) their reactivity, (iii) apoptosis and (iv) altered DNA repair activity. In the present review, we will discuss the role of DNA repair in nitrogen mustard resistance in cancer. The nitrogen mustards' lethality is based on the induction of DNA interstrand cross-links (ICLs). Two DNA repair pathways are known to be involved in removal of ICLs: non-homologous DNA end-joining (NHEJ) and Rad51-related homologous recombinational repair (HRR). The reports discussed here lead us to hypothesize that low NHEJ activity defines a hypersensitive state, while high NHEJ activity, along with increased HRR activity, contributes to the resistant state in chronic lymphocytic leukemia. Studies on human epithelial tumor cell lines suggest that HRR rather than NHEJ plays a role in nitrogen mustard sensitivity.
Panasci
Lawrence
L
Lady Davis Institute for Medical Research, Sir Mortimer B Davis Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada. lpanasci@hotmail.com
Xu
Zhi-Yuan
ZY
Bello
Vanessa
V
Aloyz
Raquel
R
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D004260:DNA Repair / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005544:Forecasting; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D011995:Recombination, Genetic
D018906:Antineoplastic Agents, Alkylating; D009363:Neoplasm Proteins; D009588:Nitrogen Mustard Compounds