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J. B. Johnston
Figure 1. The rate limiting step for the production of dATP from dAdo and CdATP from CdA is the initial phosphorylation to dAMP and CdAMP by deoxycytidine kinase, a cytoplasmic enzyme. CdA differs from dAdo in that it can also be phosphorylated to CdAMP by deoxyguanosine kinase, which is present in the mitochondria.
inhibitors of ADA for use in lymphoid malignancies and as immunosuppressive agents. Pentostatin (20- deoxycoformycin; dCF) was the most potent of these agents, having a Ki of 2.5610712 M, and has been evaluated in a variety of lymphoid malig- nancies. Good responses are seen in chronic lymphocytic leukemia (CLL), while hairy cell leukemia (HCL) is exquisitely sensitive to this drug. Both diseases have low levels of ADA, which can be inhibited with relatively low and non-toxic doses of drug [2,3]. Treatment of both CLL and HCL with dCF is associated with an increase in plasma dAdo and Ado, and CLL cells can accumu- late dATP when incubated in vitro with dAdo and dCF [3]. Although atypical forms of HCL may also accumulate dATP following incubation with dAdo and dCF in vitro, it is not known whether this occurs in typical HCL as it has not been possible to obtain sufficient numbers of these leukemia cells to study [3]. Following the development of dCF, cladribine (2-chlorodeoxyadenosine; CdA) and F-ara-A were similarly evaluated. Being halogenated, these deox- yadenosine derivatives are resistant to degradation by ADA and, like dAdo, CdA and F-ara-A are taken up into lymphocytes by a nucleoside transport system and accumulate in lymphocytes as their phosphorylated derivatives (Figure 1) [4]. For clinical use, F-ara-A is administered as the more water-soluble monophosphate, F-ara-adenosine monophosphate (fludarabine); fludarabine is rapidly
dephosphorylated in the plasma to F-ara-A. Although fludarabine has been shown in case reports to have activity in HCL, it is primarily used in CLL, while dCF and CdA are the standard treatments for HCL. Further discussion will thus be related to these two latter agents.
Mechanism of action of pentostatin and cladribine
Although dCF and CdA may produce cell death in proliferating cells through the inhibition of ribonu- cleotide reductase, this is an unlikely mechanism in CLL and HCL, where the majority of cells are not dividing [5]. As it is difficult to obtain sufficient numbers of hairy cells to perform pharmacological studies, most mechanistic studies have used CLL cells. When CLL cells are exposed to dAdo/dCF or CdA, there is an accumulation of DNA single strand breaks which accompany the accumulation of dATP or CdATP [2,5]. These breaks appear to occur as a result of the inhibition of repair of spontaneously formed DNA breaks, and this is at least partly related to the imbalance in deoxynucleotide triphosphate pools. CdA has additional effects on DNA repair as it can be incorporated as a fraudulent base into DNA and inhibits DNA polymerase b. Early studies showed that dAdo and dCF can inhibit the repair of irradiation-induced DNA breaks, and synergy is observed on combining dAdo/dCF with irradiation
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