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ABSTRACT dAdo is known to be toxic to both proliferating and resting lymphocytes that lack adenosine deaminase (ADA) activity. We now show that human monocytes are also highly sensitive _in

vitro_ to nM concentrations of dAdo plus the ADA inhibitor deoxycoformycin, and to the ADA-res istant analog CdA. The dose- and time-dependent toxicity of dAdo or CdA to monocytes is blocked

by deoxycytidine, implicating deoxycytidine kinase in the formation of toxic dAdo or CdA nucleotides. Monocytes exposed to dAdo plus deoxycoformycin, or to CdA accumulate massive DNA damage

detectable within 1 hour. The accumulation of DNA strand breaks in lymphocytes stimulates the lethal consumption of NAD and ATP for poly(ADP-ribose) synthesis. However, monocytes lack the

poly(ADP-ribose) polymerase enzyme and therefore show no significant NAD or ATP depletion until cell viability declines (12 hr). The DNA damage in monocytes exposed to CdA is associated with

a decrease in protein synthesis _in vitro_, and with inhibition of IL-6 secretion. The selective toxicity of CdA to monocytes was confirmed by _in vivo_ studies. Thus, the blood monocyte

counts, but not the neutrophil counts, fell to 0 in one week in nearly all patients receiving CdA infusion chemotherapy for cutaneous lymphoma. These results show that dAdo and CdA cause DNA

strand break formation and inhibit protein synthesis in human monocytes _in vitro_, and cause profound monocytopenia _in vivo_. These compounds may have potential use in the therapy of

immune disorders associated with monocyte/macrophage activation. ARTICLE PDF AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Research Inscicuce of Scripps Clinic, La Jolla, CA, USA Carlos J

Carrera, Hisashi Yamanaka, Lawrence D Piro & Dennis A Carson Authors * Carlos J Carrera View author publications You can also search for this author inPubMed Google Scholar * Hisashi

Yamanaka View author publications You can also search for this author inPubMed Google Scholar * Lawrence D Piro View author publications You can also search for this author inPubMed Google

Scholar * Dennis A Carson View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS

ARTICLE Carrera, C., Yamanaka, H., Piro, L. _et al._ 17 PROFOUND TOXICITY OF DEOXYADENOSINE (dAdo) AND 2-CHLORODEOXYADENOSINE (CdA) TOWARD HUMAN MONOCYTES _IN VITRO_ AND _IN VIVO_. _Pediatr

Res_ 24, 114 (1988). https://doi.org/10.1203/00006450-198807000-00041 Download citation * Issue Date: 01 July 1988 * DOI: https://doi.org/10.1203/00006450-198807000-00041 SHARE THIS ARTICLE

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