Among the arabinose-derived nucleosides, cytarabine (Ara-C), the 2'-epimer of cytidine, is useful in several leukemias, including acute myelogenous leukemia and non-Hodgkin lymphoma. Cytarabine is employed either as a single agent or in combination with others, specially the anthracyclines, and is the prime example of an antitumor drug specifically acting in the S-phase of the cell cycle because its incorporation into DNA after being activated to the corresponding triphosphate leads to inhibition of strand elongation (Fig. 2.44). Because of this S-phase-speci-ficity, prolonged exposure of cells to cytotoxic concentrations is critical to achieve maximum cytotoxic activity. However, the activity of cytarabine is decreased by its rapid deamination by cytosine deaminase to the biologically inactive metabolite uracil arabinoside.53 For this reason, the search for effective formulations and derivatives of cytarabine that cannot be deaminated and exhibit better pharmaco-kinetic parameters is an active field of research.54
Fazarabine is an aza analog with a very potent activity in animal models, including solid tumors, and has been submitted to several clinical trials.55 Gemcitabine blocks the cell cycle at the S-phase similarly to cytarabine and it is also an inhibitor of RNR in its diphosphate form (see Section 3.3). Gemcitabine can be considered as the leading marketed nucleoside analog and is most commonly used to treat nh,
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