Nucleotide excision repair-deficient human cells in culture exhibit decreased survival after 2-chlorodeoxyadenosine treatment.
2-Chloro-2'-deoxyadenosine (CldAdo, cladribine) is a clinically important nucleoside analog for adult and pediatric leukemias. We previously described an activity in HeLa cell nuclear extracts that specifically recognized CldAMP-substituted oligomers. The factor was present in extracts prepared from repair-deficient xeroderma pigmentosum (XP) complementation group A cells, but not from group E--which are defective in damaged DNA-binding (DDB) protein--suggesting a possible repair process for incorporated analogs. Here we examined XP lymphoblast survival after CldAdo treatment using a cell proliferation assay. Control CEM leukemia cells and immortalized normal human lymphoblasts exhibited similar cytotoxicity profiles at each concentration tested. However, a 2.1-fold increase in sensitivity to CldAdo was detected in XP-E (5) cells lacking a functional DDB subunit. XP-A, XP-D and XP-G cell lines also had increased sensitivity to CldAdo, ranging from 1.61- to 1.91-fold greater compared to normal lymphoblasts. Our findings suggest that the clinical efficacy of CldAdo may be attenuated by repair mechanisms that target and remove such altered nucleic acids from cellular DNA.
Lawrenzi
James
J
Department of Pharmacology, University of Health Sciences, 1750 Independence Avenue, Kansas City, Missouri 64106, USA.
Bunnell
Amy
A
Hentosh
Patricia
P
D000249:Adenosine Monophosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D017338:Cladribine / Q000494:pharmacology*; D004260:DNA Repair / Q000502:physiology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D014407:Tumor Cells, Cultured; D014983:Xeroderma Pigmentosum / Q000473:pathology
D000970:Antineoplastic Agents; D000249:Adenosine Monophosphate; D017338:Cladribine