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Diagnosis and Treatment |

2-Chlorodeoxyadenosine: A Newer Purine Analog Active in the Treatment of Indolent Lymphoid Malignancies

Alan Saven, MD; and Lawrence D. Piro, MD
[+] Article and Author Information

From the Ida M. and Cecil H. Green Cancer Center, Scripps Clinic and Research Foundation, La Jolla, California. Requests for Reprints: Alan Saven, MD, Scripps Clinic and Research Foundation, 10666 North Torrey Pines Road, La Jolla, CA 92037.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1994;120(9):784-791. doi:10.7326/0003-4819-120-9-199405010-00010
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Objective: To review the structure, mechanism of action, pharmacologic features, and clinical trial results of the newer purine analog, 2-chlorodeoxyadenosine (2-CdA).

Data Sources and Study Selection: English-language medical literature review of more than 70 articles.

Data Synthesis: 2-Chlorodeoxyadenosine is unique compared with traditional antimetabolite drugs in that it is equally active against dividing and resting lymphocytes, which may be especially important in indolent lymphoid malignancies, such as chronic lymphocytic leukemia, because most cells in these disorders are in the resting phase. In patients with alkylator-refractory chronic lymphocytic leukemia who were treated with 2-CdA, 44% achieved a response (4% complete responses, 40% partial responses), and 54%, scored as nonresponders, had a sustained reduction in their peripheral lymphocytosis. Patients with untreated chronic lymphocytic leukemia had an 85% response rate (25% complete responses, 60% partial responses). Patients with previously treated low-grade lymphoma achieved an overall response rate of 43%. The most striking clinical effects of this drug have been seen in hairy cell leukemia, in which a single course of therapy induces complete remissions in 85% of partial remissions in 12%. Activity has also been shown in cutaneous T-cell lymphoma and the myeloid leukemias.

Conclusions: 2-Chlorodeoxyadenosine is a newer purine analog with potent activity in the treatment of indolent lymphoproliferative diseases and illustrates the model for rational drug development.

Figures

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Figure 1.
Molecular structures of deoxyadenosine and 2-chlorodeoxyadenosine.
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Figure 2.
Deoxyadenosine metabolism.d. adenosineDCKNTd. AMPd. ADPd. ATPADAd. adenosined. inosinePNPXO

Deoxyadenosine ( ) enters the cell through an efficient transport system. The favorable ratio of deoxycytidine kinase ( ) to 5′-nucleotidase (5′- ) results in the formation of deoxyadenosine monophosphate ( ), -diphosphate ( ), and -triphosphate ( ). Adenosine deaminase ( ) irreversibly deaminates deoxyadenosine ( ) to deoxyinosine ( ). Purine nucleoside phosphorylase ( ) catalyzes the reversible phosphorolysis of deoxyinosine to hypoxanthine, which is oxidized by xanthine oxidase ( ) to uric acid to be excreted.

Grahic Jump Location
Grahic Jump Location
Figure 3.
2-Chlorodeoxyadenosine mechanism of action.2-CdAADADCK5′-NT2-CdAMP2-CdADP2-CdATPRNRNADATP++/Mg++

2-Chlorodeoxyadenosine ( ) enters the cell through an efficient transport system where it resists (‡) deamination by adenosine deaminase ( ). The high ratio of deoxycytidine kinase ( ) to 5′-nucleotidase ( ) favors the formation of 2-chlorodeoxyadenosine monophosphate ( ), -diphosphate ( ), and -triphosphate ( ). In dividing cells, excess 2-CdATP inhibits ribonucleotide reductase ( ) with resultant inhibition of DNA synthesis. In resting cells, DNA strand breaks occur, activating a poly(adenosine-diphosphate-ribose) polymerase, which results in the in-tracellular depletion of nicotinamide adenine dinucleotide ( ) and adenosine triphosphate ( ). A Ca -dependent endonuclease then cleaves DNA into fragments, apoptosis.

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