Hairy-cell leukaemia as a model for drug development.
Hairy-cell leukaemia cells have a low rate of growth but an even lower rate of apoptosis. Accordingly, this malignancy is an excellent model for studying the effects of drugs on the pathways of apoptosis independently of cell proliferation. The remarkable effectiveness of 2-chlorodeoxyadenosine in hairy-cell leukaemia affirms the feasibility of developing drugs that can destroy even non-proliferating malignant cells. The major nucleotide metabolite of 2-chlorodeoxyadenosine accumulates selectively in lymphocytes and co-activates two key apoptosis-regulating enzymes: poly(ADP-ribose) polymerase and Apaf-1/caspase-9. The ability of 2-chlorodeoxyadenosine to induce durable remissions in hairy-cell leukaemia may also be attributable to its effects on lymphocytes and monocytes in the microenvironment, although this latter effect remains to be proven experimentally.
Carson
Dennis A
DA
Department of Medicine, The Sam and Rose Stein Institute for Research on Aging, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0663, USA. dcarson@ucsd.edu
Leoni
Lorenzo M
LM
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D053477:Apoptotic Protease-Activating Factor 1; D053453:Caspase 9; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D017338:Cladribine / Q000627:therapeutic use*; D004341:Drug Evaluation / Q000379:methods*; D006801:Humans; D007943:Leukemia, Hairy Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000187:drug effects / Q000378:metabolism
C506592:APAF1 protein, human; D000970:Antineoplastic Agents; D053477:Apoptotic Protease-Activating Factor 1; D011506:Proteins; D017338:Cladribine; D011065:Poly(ADP-ribose) Polymerases; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases