Martin S. Tallrnan, David Hakimian
1995
Citations
4
Influential Citations
97
Citations
Quality indicators
Journal
Blood
Abstract
R ECENTLY, a great deal of interest has been generated in three new purine nucleoside analogs because of their remarkable activity in a variety of incurable malignant lymphoproliferative disorders. 2-Fluoro-ara-AMP (fludarabine), 2-deoxycoformycin (ZDCF, pentostatin), and 2-chlorodeoxyadenosine (2-CdA) are all structurally similar analogs of adenosine, but they differ in their interaction with adenosine deaminase (ADA) (Fig 1). This enzyme normally regulates intracellular adenosine levels through the irreversible deamination of adenosine to inosine and thereby serves to degrade purine and deoxypurine nucleotides. The development of these drugs resulted from the systematic search for compounds that could interfere with ADA activity. This enzyme became a specific target because of the observation that approximately 30% of children with severe combined immunodeficiency syndrome (SCIDS) are congenitally deficient in ADA.',' This deficiency leads to the accumulation of deoxypurine nucleotides, which accounts for the abnormal lymphocyte development present in such patients. Therefore, it was logical to suggest that increasing deoxynucleotide levels in lymphocytes by deliberately interfering with the activity of ADA might prove useful in diseases with abnormal lymphocyte proliferation.3 The development of three novel drugs that are active against common and generally incurable malignancies is a luxury not often afforded the clinical hematologist/oncologist. Furthermore, each has now been approved by the Food and Drug Administration for clinical use. Therefore, it is timely to review the mechanisms of action, pharmacokinetics, and available clinical data and address the issues of potential cross-resistance. Finally, we suggest future directions to exploit these agents in a variety of neoplastic disorders.