Homologous recombinational repair vis-à-vis chlorambucil resistance in chronic lymphocytic leukemia

• Published in: Biochemical pharmacology Vol. 63; no. 9; pp. 1585 - 1588
• Main Authors: Bello, Vanessa E., Aloyz, Raquel S., Christodoulopoulos, Garyfallia, Panasci, Lawrence C.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.05.2002
• Subjects: Antineoplastic Agents, Alkylating - pharmacology; Cell Division - drug effects; Chlorambucil; Chlorambucil - pharmacology; Chronic Disease; Chronic lymphocytic leukemia; DNA repair; DNA Repair - physiology; DNA-Binding Proteins - metabolism; Drug resistance; Drug Resistance, Neoplasm - physiology; Homologous recombinational repair; Humans; Leukemia, B-Cell - metabolism; Leukemia, B-Cell - pathology; Nitrogen mustards; Rad51 Recombinase; ld50; DNA-PK; PCNA; and NHEJ; Nitrogen mustards; Homologous recombinational repair; HRR; Drug resistance; DNA repair; B-CLL; Chlorambucil; Chronic lymphocytic leukemia; ICL; CLB; NER
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(02)00954-1

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 (ld50) 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 ld50. In addition, multiple linear regression analysis showed a significant correlation between Xrcc3 and Rad51 protein levels versus the CLB ld50 (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 ld50 (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.