Potent toxicity of 2-chlorodeoxyadenosine toward human monocytes in vitro and in vivo. A novel approach to immunosuppressive therapy.
Lymphoid cells were thought to be uniquely susceptible to excess 2'-deoxyadenosine (dAdo), when exposed to inhibitors of adenosine deaminase (ADA). However, we now find that human monocytes are as sensitive as lymphocytes to dAdo or to the ADA-resistant congener 2-chloro-2'-deoxyadenosine (CldAdo). Monocytes exposed in vitro to CldAdo, or to dAdo plus deoxycoformycin rapidly developed DNA strand breaks. Both the DNA damage and the toxicity of CldAdo or dAdo toward monocytes were blocked by deoxycytidine, but not by inhibitors of poly(ADP-ribose) polymerase. A partial decrease in RNA synthesis and a gradual decline of cellular NAD were early biochemical events associated with monocyte DNA damage. Low CldAdo concentrations (5-20 nM) inhibited monocyte phagocytosis and reduced the release of interleukin 6. Higher CldAdo concentrations led to a dose- and time-dependent loss of monocyte viability. Circulating monocytes disappeared within 1 wk in patients with cutaneous T cell lymphoma or with rheumatoid arthritis during continuous CldAdo infusion. The marked sensitivity of human monocyte function and survival to CldAdo in vitro, together with the monocyte depletion in patients receiving CldAdo chemotherapy, suggests that CldAdo or other dAdo analogues offer a novel therapeutic strategy for chronic inflammatory and autoimmune diseases characterized by inappropriate monocyte deployment or function.
Carrera
C J
CJ
Department of Molecular and Experimental Medicine, Research Institute of Scripps Clinic, La Jolla, California 92037.
Terai
C
C
Lotz
M
M
Curd
J G
JG
Piro
L D
LD
Beutler
E
E
Carson
D A
DA
D015762:2-Chloroadenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D000255:Adenosine Triphosphate / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017338:Cladribine; D004249:DNA Damage; D003839:Deoxyadenosines / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000097:blood / Q000188:drug therapy; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009153:Mutagens; D009243:NAD / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D014176:Protein Biosynthesis; D012313:RNA / Q000096:biosynthesis; D013997:Time Factors
D003839:Deoxyadenosines; D015850:Interleukin-6; D009153:Mutagens; D009243:NAD; D015762:2-Chloroadenosine; D017338:Cladribine; D012313:RNA; D000255:Adenosine Triphosphate; C058118:2'-deoxyadenosine