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

293 Citations (Scopus)

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
StatePublished - Jan 1 1993

Fingerprint

Cell death
B-Cell Chronic Lymphocytic Leukemia
Cell Death
Lymphocytes
DNA
DNA Fragmentation
Pharmaceutical Preparations
DNA Cleavage
Apoptosis
Phorbol Esters
Chelation
Refractory materials
Electron microscopy
Optical microscopy
2-fluoroadenine
2'-deoxyadenosine
Assays
Electron Microscopy
Cells
Calcium

ASJC Scopus subject areas

  • Hematology

Cite this

Robertson, L. E., Chubb, S., Meyn, R. E., Story, M., Ford, R., Hittelman, W. N., & Plunkett, W. (1993). Induction of apoptotic cell death in chronic lymphocytic leukemia by 2-chloro-2′-deoxyadenosine and 9-β-D-arabinosyl-2-fluoroadenine. Blood, 81(1), 143-150.

Induction of apoptotic cell death in chronic lymphocytic leukemia by 2-chloro-2′-deoxyadenosine and 9-β-D-arabinosyl-2-fluoroadenine. / Robertson, L. E.; Chubb, Sherri; Meyn, Raymond E.; Story, Michael; Ford, Richard; Hittelman, Walter N.; Plunkett, William.

In: Blood, Vol. 81, No. 1, 01.01.1993, p. 143-150.

Research output: Contribution to journalArticle

Robertson, LE, Chubb, S, Meyn, RE, Story, M, Ford, R, Hittelman, WN & Plunkett, W 1993, 'Induction of apoptotic cell death in chronic lymphocytic leukemia by 2-chloro-2′-deoxyadenosine and 9-β-D-arabinosyl-2-fluoroadenine', Blood, vol. 81, no. 1, pp. 143-150.
Robertson, L. E. ; Chubb, Sherri ; Meyn, Raymond E. ; Story, Michael ; Ford, Richard ; Hittelman, Walter N. ; Plunkett, William. / Induction of apoptotic cell death in chronic lymphocytic leukemia by 2-chloro-2′-deoxyadenosine and 9-β-D-arabinosyl-2-fluoroadenine. In: Blood. 1993 ; Vol. 81, No. 1. pp. 143-150.
@article{7d1e2d5341e043a38d5c6da1fead3cb1,
title = "Induction of apoptotic cell death in chronic lymphocytic leukemia by 2-chloro-2′-deoxyadenosine and 9-β-D-arabinosyl-2-fluoroadenine",
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.",
author = "Robertson, {L. E.} and Sherri Chubb and Meyn, {Raymond E.} and Michael Story and Richard Ford and Hittelman, {Walter N.} and William Plunkett",
year = "1993",
month = "1",
day = "1",
language = "English (US)",
volume = "81",
pages = "143--150",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "1",

}

TY - JOUR

T1 - Induction of apoptotic cell death in chronic lymphocytic leukemia by 2-chloro-2′-deoxyadenosine and 9-β-D-arabinosyl-2-fluoroadenine

AU - Robertson, L. E.

AU - Chubb, Sherri

AU - Meyn, Raymond E.

AU - Story, Michael

AU - Ford, Richard

AU - Hittelman, Walter N.

AU - Plunkett, William

PY - 1993/1/1

Y1 - 1993/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0027505303&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027505303&partnerID=8YFLogxK

M3 - Article

VL - 81

SP - 143

EP - 150

JO - Blood

JF - Blood

SN - 0006-4971

IS - 1

ER -