or alkylating agents [6]. These observations led to laboratory and clinical studies combining CdA and F-ara-A with alkylating agents and irradiation. The presence of DNA breaks causes the phosphor-
Biochemical pharmacology of pentostatin and cladribine As the drug doses used in these laboratory studies
ylation and activation of p53, which leads to the release of cytochrome c from the mitochondria. Cyto- chrome c binds to and activates apoptosis-activating factor-1 (Apaf-1) in the cytosol in a process that requires dATP in the formation of the apotosome. The N-terminal of Apaf-1 binds to and causes the autoactivation of procaspase 9 and, subsequently, caspase 3 and apoptosis. The increased levels of dATP and CdATP can enhance the effects of endogenous dATP on the apotosome, thus further increasing apoptosis [7]. In addition to cytochrome c release, apoptosis inducing factor (AIF) is also released from the mitochondria and directly induces DNA breaks. The effect of DNA breaks on the mitochondria requires active p53, and thus patients with mutant p53 are usually resistant to the nucleo- side analogs. CdA differs from dAdo in that it is also phosphorylated by deoxyguanosine kinase in the mitochondria to CdATP, which is directly toxic to the mitochondria [7]. This results in further release of cytochrome c and AIF from the mitochondria, and this explains the 10-fold increased DNA break- formation over dAdo/dCF at later time points and the increased cytotoxicity of CdA. In addition, this effect on mitochondria might explain the greater myelotoxicity seen with CdA as compared with dCF. Cells treated with the analogs die from apoptosis, but the DNA breaks can also activate poly(ADP-ribose) polymerase (PARP), which leads to a depletion of nicotinamide adenine dinucleotide (NAD) and ATP [8]. Cells can thus also die by necrosis, and PARP activation may be an important mechanism of death in the occasional patient with CLL with a p53 mutation who responds to CdA [8].
45
are much higher than the plasma levels seen clinically, it is unclear which of the above biochem- ical mechanisms aremost clinically relevant. As these drugs are so effective in HCL, further studies are warranted to investigate the mechanisms of action of dCF and CdA in this disease.
Potential conflict of interest: A disclosure form provided by the author is available with the full text of this article at
www.informahealthcare.com/lal.
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