Leukemia & Lymphoma, June 2011; 52(S2): 43–45
Mechanism of Action of Pentostatin and Cladribine in Hairy Cell Leukemia
JAMES B. JOHNSTON Manitoba Institute of Cell Biology, Section of Hematology/Oncology, University of Manitoba, Winnipeg, Canada
Abstract Pentostatin (20-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)andadenosine (Ado) in the plasma.dAdois 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 ofDNAstrand 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 ofCdATPintoDNA,the inhibition ofDNApolymerase b, and the phosphorylation of CdA to CdATP by deoxyguanosine kinase in mitochondria. These additional modes of action produce furtherDNAbreaks in CdA-treated cells and explain the more potent activity ofCdAcompared todCFand the greater myelosuppression with this agent. The cells die by apoptosis, but theDNAstrand 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.
Keywords: Pentostatin, cladribine, hairy cell leukemia, chronic lymphocytic leukemia Introduction
Dr. Eloise Giblett first noted 40 years ago that children with adenosine deaminase (ADA) deficiency have severe combined immunodeficiency disease (SCID) [1]. These children have reduced numbers of T and B lymphocytes, in addition to having abnormalities in other organs such as bone and brain. Adenosine deaminase is responsible for the deamination of deoxyadenosine (dAdo) and adenosine (Ado) to deoxyinosine and inosine, respectively, and children with ADA deficiency have increased plasma levels of dAdo and Ado. The Ado is derived from degraded RNA and dAdo from the small amount of ineffective erythropoiesis that occurs normally in
themarrow.The decrease in lymphocytes and changes in other organs are due to the cellular effects of dAdo and Ado, and
multiplemechanismshavebeenproposed[1].Probably the most important mechanism is the intracellular accumulation of deoxyadenosine triphosphate (dATP) whenADAdeficient cells are exposed to dAdo (Figure 1). This occurs preferentially in lymphocytes, as these cells have high deoxycytidine kinase activity (converts dAdo to deoxyadenosine monophosphate [dAMP]) and low 50nucleotidase activity (degrades dAMP to dAdo), thus allowing the rapidaccumulation ofdAMP, and subsequently deoxyadenosine diphosphate (dADP) and dATP. Why high intracellular levels of dATP are cytotoxic is discussed later.
Development of pentostatin and cladribine
Following the observation that ADA deficiency causes lymphopenia, efforts were made to develop
Correspondence: James B. Johnston, MB, BCh, FRCPC, CancerCare Manitoba, 675 McDermot Ave., Rm. ON5042, Winnipeg, MB R3E 0V9, Canada. Tel/Fax: (204)787-2051/787-2190. E-mail:
james.johnston@
cancercare.mb.ca
ISSN 1042-8194 print/ISSN 1029-2403 online 2011 Informa UK, Ltd. DOI: 10.3109/10428194.2011.570394
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