Homologous recombinational repair vis-à-vis chlorambucil resistance in chronic lymphocytic leukemia.
The objective of this study was to further define the role of homologous recombinational repair (HRR) in resistance to the nitrogen mustards in B-cell chronic lymphocytic leukemia (B-CLL). We have demonstrated previously that increased chlorambucil (CLB)-induced HsRad51 nuclear foci formation correlated with a CLB-resistant phenotype in B-CLL lymphocytes. In this report, we measured the protein levels of HsRad51 and Xrcc3 (an HsRad51 paralog) and correlated them with the in vitro CLB cytotoxicity (LD(50)) in lymphocytes from seventeen B-CLL patients. Both HsRad51 (r=0.75, P=0.0005) and Xrcc3 (r=0.52, P=0.03) protein levels correlated with the in vitro CLB LD(50). In addition, multiple linear regression analysis showed a significant correlation between Xrcc3 and Rad51 protein levels versus the CLB LD(50) (r=0.78, P=0.0014), suggesting that both proteins influence CLB cytotoxicity. Moreover, since HsRad51 expression varies in cell lines during the cell cycle, we determined proliferating cell nuclear antigen (PCNA) protein levels to assess possible differences in cell cycle progression. There was no correlation between PCNA protein levels and the CLB LD(50) (r=0.042, P=0.87) or with HsRad51/Xrcc3 protein levels. Our data suggest that HsRad51 and Xrcc3 protein expression may be predictive of the response in B-CLL patients to treatment with nitrogen mustards.
Bello
Vanessa E
VE
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Côte Ste. Catherine, Québec, Montreal, Canada.
Aloyz
Raquel S
RS
Christodoulopoulos
Garyfallia
G
Panasci
Lawrence C
LC
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002699:Chlorambucil / Q000494:pharmacology*; D002908:Chronic Disease; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D015448:Leukemia, B-Cell / Q000378:metabolism* / Q000473:pathology; D051135:Rad51 Recombinase
D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; C110901:X-ray repair cross complementing protein 3; D002699:Chlorambucil; C495153:RAD51 protein, human; D051135:Rad51 Recombinase