Profound toxicity of deoxyadenosine and 2-chlorodeoxyadenosine toward human monocytes in vitro and in vivo.
Deoxyadenosine 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 nanomolar concentrations of deoxyadenosine plus the ADA inhibitor deoxycoformycin, and to the ADA-resistant analogue 2-chlorodeoxyadenosine (CdA). Monocytes exposed to deoxyadenosine or to CdA in vitro accumulate massive DNA damage detectable within 1 hour. The DNA damage in monocytes exposed to CdA is associated with a decrease in protein synthesis and with inhibitions of phagocytosis and IL-6 secretion. However, unlike lymphocytes with similar DNA damage, the monocytes show no significant NAD or ATP depletion until cell viability declines. The selective toxicity of CdA to monocytes was confirmed by in vivo studies. In almost all patients receiving CdA infusion chemotherapy for cutaneous lymphoma, the blood monocytes counts fell to near 0 during one week of therapy. Our results suggest that CdA and related compounds may have potential clinical use in the therapy of immune disorders associated with monocyte/macrophage activation.
Carrera
C J
CJ
Department of Basic and Clinical Research, Scripps Clinic & Research Foundation, La Jolla, California.
Yamanaka
H
H
Piro
L D
LD
Lotz
M
M
Carson
D A
DA
D015762:2-Chloroadenosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017338:Cladribine; D004249:DNA Damage; D003839:Deoxyadenosines / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D008223:Lymphoma / Q000097:blood / Q000188:drug therapy; D009000:Monocytes / Q000187:drug effects*; D015649:Pentostatin / Q000494:pharmacology; D013601:T-Lymphocytes
D003839:Deoxyadenosines; D015762:2-Chloroadenosine; D015649:Pentostatin; D017338:Cladribine