Induction of apoptotic cell death in chronic lymphocytic leukemia by 2- chloro-2'-deoxyadenosine and 9-β-D-arabinosyl-2-fluoroadenine

L. E. Robertson, Sherri Chubb, Raymond E. Meyn, Michael Story, Richard Ford, Walter N. Hittelman, William Plunkett

Research output: Contribution to journalArticle

298 Scopus citations

Abstract

2-Chloro-2'-deoxyadenosine (CldAdo) and 9-β-D-arabinosyl-2-fluoroadenine (F-ara-A) have shown marked activity in the treatment of indolent lymphoid malignancies. Based on the susceptibility of various lymphocyte populations to apoptosis, we investigated whether CldAdo or F-ara-A would induce this process in lymphocytes from patients with chronic lymphocytic leukemia (CLL). In vitro exposure of leukemic lymphocytes to CldAdo or F-ara-A for 24 to 72 hours elicited features of apoptosis visible by light and electron microscopy. Analysis of DNA integrity showed DNA cleavage into nucleosomal- sized multimers. Using a quantitative assay, drug-induced DNA fragmentation was both time and dose dependent. Inhibition of active macromolecular synthesis did not prevent drug-induced fragmentation; however, both drug- induced and spontaneous DNA fragmentation were prevented by intracellular calcium chelation. In vitro culture with phorbol ester generally decreased drug-induced DNA cleavage. After prolonged incubation, CLL cells exhibited spontaneous cleavage; albeit, at significantly lower rates than drug-treated cells. Heterogeneity was observed for spontaneous and drug-induced DNA fragmentation and was significantly lower in B-leukemic cells obtained from patients with high-risk and refractory disease. We conclude that CldAdo and F-ara-A are potent inducers of apoptotic death in CLL and that this feature correlates with the disease status.

Original languageEnglish (US)
Pages (from-to)143-150
Number of pages8
JournalBlood
Volume81
Issue number1
DOIs
StatePublished - 1993

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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