Evolution of the Arabinosides and the Pharmacology of Fludarabine

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Abstract
An understanding of the pharmacokinetics of a drug is essential to the optimal design of the dose and schedule of chemotherapy protocols. As an extension, knowledge of the mechanism of drug action is necessary to construct the optimal strategy for combination chemotherapy. Nucleoside antimetabolites such as arabinosylcytosine, arabinosyladenine, and fludarabine are prodrugs that must enter cells and be phosphorylated to the respective triphosphates before they can elicit biological activity. DNA synthesis is the major metabolic target for this class of compounds. Common to members of the arabinosyl nucleoside class is the finding in experimental systems of a relationship between incorporation of each drug into DNA and the loss of clonogenicity. Although additional inhibitory mechanisms have been identified, they all require formation of the respective triphosphate. Thus, knowledge of the pharmacokinetics of the triphosphates in target cells and an understanding of the mechanisms by which these active forms of arabinosyl nucleosides kill cells are indispensable to the rational design of treatment protocols. This article considers the clinical development of arabinosyl nucleosides with respect to investigations of their pharmacokinetics and mechanisms of action. An understanding of these elements of arabinosyl nucleoside metabolism should provide a rationale for combinations with other chemotherapeutic agents and anticancer modalities.