Cladribine mechanism of action. 2-CdA enters the cell through an efficient transport system. Cladribine is resistant to deamination by ADA. The high DCK to 5′-NT ratio favors the formation of 2-chlorodeoxyadenosine monophosphate (2-CdAMP), 2-chlorodeoxyadenosine diphosphate (2-CdADP), and 2-chlorodeoxyadenosine triphosphate (2-CdATP). In dividing cells, the accumulation of 2-CdATP inhibits RNR and the DNA polymerases (DNAP), abrogating DNA synthesis and causing cell death. In resting cells, 2 unique pathways result in apoptosis. First, cladribine increases DNA strand breaks, activating poly(ADP-ribose)polymerase, PARP, which depletes NAD and ATP, resulting in apoptosis. Second, cladribine alters the mitochondrial membrane resulting in cytoplasmic translocation of cytochrome c and nuclear translocation of apoptosis-inducing factor (AIF), which leads to caspase-dependent and -independent apoptosis, respectively. Hypomethylation may occur through cladribine's inhibition of S-adenosylhomocysteine hydrolase (SAH), thereby diminishing the methyl donor pool.9 (Illustration by Katya Kadyshevskaya.)
