17 PROFOUND TOXICITY OF DEOXYADENOSINE (dAdo) AND 2-CHLORODEOXYADENOSINE (CdA) TOWARD HUMAN MONOCYTES IN VITRO AND IN VIVO

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.