title: Mechanism of action of pentostatin and cladribine in hairy cell leukemia.
abstract: Pentostatin (2'-deoxycoformycin; dCF) and cladribine (2-chlorodeoxyadenosine; CdA) are highly effective agents for the treatment of hairy cell leukemia. Although their precise mechanisms of action in this disease are still unknown, a number of mechanisms have been postulated. dCF is a potent inhibitor of adenosine deaminase (ADA), and treatment results in the accumulation of deoxyadenosine (dAdo) and adenosine (Ado) in the plasma. dAdo is phosphorylated by deoxycytidine kinase in lymphocytes to deoxyadenosine monophosphate (dAMP), which is subsequently converted to deoxyadenosine triphosphate (dATP). CdA is the chlorinated derivative of deoxyadenosine, is resistant to degradation by ADA, and accumulates in lymphocytes as CdATP. Both dATP and CdATP cause an initial accumulation of DNA strand breaks in lymphocytes and this results in the activation of p53, the release of cytochrome c from mitochondria, and apoptosis. CdA has several unique mechanisms of action over dAdo and these include the incorportation of CdATP into DNA, the inhibition of DNA polymerase β, and the phosphorylation of CdA to CdATP by deoxyguanosine kinase in mitochondria. These additional modes of action produce further DNA breaks in CdA-treated cells and explain the more potent activity of CdA compared to dCF and the greater myelosuppression with this agent. The cells die by apoptosis, but the DNA strand breaks also cause the activation of poly(ADP-ribose) polymerase (PARP), with resultant cellular depletion of nicotinamide adenine dinucleotide (NAD) and ATP. The induction of necrosis by PARP activation may explain the activity of these analogs in some patients with p53 mutations.
authors.affiliation: Manitoba Institute of Cell Biology, Section of Hematology/Oncology, University of Manitoba, Winnipeg, Manitoba, Canada. james.johnston@cancercare.mb.ca
authors.forename: James B
authors.initials: JB
authors.lastname: Johnston
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D017338:Cladribine / Q000494:pharmacology* / Q000627:therapeutic use; D053960:DNA Breaks / Q000187:drug effects; D006801:Humans; D007943:Leukemia, Hairy Cell / Q000188:drug therapy*; D015649:Pentostatin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D015649:Pentostatin; D017338:Cladribine