Journal
CLINICAL CANCER RESEARCH
Volume 17, Issue 14, Pages 4731-4741Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-10-2561
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Funding
- National Cancer Institute [CA81534, CA16672]
- Department of Health Human Service
- CLL Global Research Foundation
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Purpose: Chronic lymphocytic leukemia (CLL) resistant to fludarabine-containing treatments responds to oxaliplatin-based therapy that contains fludarabine. We postulated that a mechanism for this activity is the incorporation of fludarabine into DNA during nucleotide excision repair (NER) stimulated by oxaliplatin adducts. Experimental Design: We analyzed CLL cell viability, DNA damage, and signaling pathways in response to treatment by fludarabine, oxaliplatin, or the combination. The dependency of the combination on oxaliplatin-induced DNA repair was investigated using siRNA in CLL cells or cell line models of NER deficiency. Results: Synergistic apoptotic killing was observed in CLL cells after exposure to the combination in vitro. Oxaliplatin induced DNA synthesis in CLL cells, which was inhibited by fludarabine and was eliminated by knockdown of XPF, the NER 5'-endonuclease. Wild-type Chinese hamster ovarian cells showed synergistic killing after combination treatment, whereas only additive killing was observed in cells lacking XPF. Inhibition of repair by fludarabine in CLL cells was accompanied by DNA single-strand break formation. CLL cells initiated both intrinsic and extrinsic apoptotic pathways as evidenced by the loss of mitochondrial outer membrane potential and partial inhibition of cell death upon incubation with FasL antibody. Conclusions: The synergistic cell killing is caused by a mechanistic interaction that requires the initiation of XPF-dependent excision repair in response to oxaliplatin adducts, and the inhibition of that process by fludarabine incorporation into the repair patch. This combination strategy may be useful against other malignancies. Clin Cancer Res; 17(14); 4731-41. (C)2011 AACR.
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