Fludarabine increases oxaliplatin cytotoxicity in normal and chronic lymphocytic leukemia lymphocytes by suppressing interstrand DNA crosslink removal.
Oxaliplatin and fludarabine have different but potentially complementary mechanisms of action. Previous studies have shown that DNA repair is a major target for fludarabine. We postulate that potentiation of oxaliplatin toxicity by fludarabine may be due to the inhibition by fludarabine of the activity of the DNA excision repair pathways activated by oxaliplatin adducts. To test this, we investigated the cytotoxic interactions between the 2 drugs in normal and chronic lymphocytic leukemia (CLL) lymphocytes. In each population, the combination resulted in greater than additive killing. Analysis of oxaliplatin damage revealed that fludarabine enhanced accumulation of interstrand crosslinks (ICLs) in specific regions of the genome in both populations, but to a lesser extent in normal lymphocytes. The action of fludarabine on the removal of oxaliplatin ICLs was explored to investigate the mechanism by which oxaliplatin toxicity was increased by fludarabine. Lymphocytes from patients with CLL have a greater capacity for ICL unhooking compared with normal lymphocytes. In the presence of fludarabine the extent of repair was significantly reduced in both populations, more so in CLL. Our findings support a role of fludarabine-mediated DNA repair inhibition as a mechanism critical for the cytotoxic synergy of the 2 drugs.
Moufarij
Mazin A
MA
Department of Experimental Therapeutics Unit 71, The University of Texas M D Anderson Cancer Center, Houston, TX 77030-4009, USA.
Sampath
Deepa
D
Keating
Michael J
MJ
Plunkett
William
W
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use; D018736:DNA Adducts / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D009944:Organoplatinum Compounds / Q000819:agonists / Q000494:pharmacology*; D000077150:Oxaliplatin; D014740:Vidarabine / Q000819:agonists / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D014740:Vidarabine; C024352:fludarabine