Pentostatin is combined with adenosine-derived antitumor drugs in order to increase their half-life. On its own, pentostatin is also an antitumor agent that is useful in the treatment of some types of leukemias, like hairy cell leukemia. The mechanism of its antitumor activity is unclear and complex, and includes the following events (Fig. 2.42):

a. Pentostatin is triphosphorylated and misincorporated into DNA.

b. Inhibition of adenosine deaminase leads to accumulation of adenosine, and hence to retroinhibition of the enzyme S-adenosylhomocysteine hydrolase. The subsequently accumulated S-adenosylhomocysteine acts as a competitive inhibitor of most of the methyltransferases that use S-adenosylmethionine as a cofactor, and therefore perturbs the processes related to the methylation of nucleic acids (see Section 3.1 of Chapter 10).

c. Accumulation of deoxyadenosine also leads to high levels of deoxyadenosine triphosphate, which is an inhibitor of RNR, the enzyme that removes the 20 -hydroxy group of the ribose ring during the biosynthesis of DNA.

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