2-AMINO-6-METHOXYPURINE ARABINOSIDE - AN AGENT FOR T-CELL MALIGNANCIES

Earlier studies have shown guanine arabinoside (ara-G) is an effective agent against growth of T-cell lines and freshly isolated human T-leu kemic cells. However, poor water solubility of ara-G limits clinical u se. 2-Amino-6-methoxypurine arabinoside (506U) is a water-soluble prod rug converted to ara-G by adenosine deaminase. 506U is not a substrate for deoxycytidine kinase, adenosine kinase, or purine nucleoside phos phorylase and is phosphorylated by mitochondrial deoxyguanosine kinase at a rate 4% that of ara-G phosphorylation. Mitochondrial DNA polymer ase was the least sensitive to ara-GTP inhibition of the five human DN A polymerases tested. [H-3]506U was anabolized to ara-G 5'-phosphates in CEM cells but not to phosphorylated metabolites of 506U. 506U was s elective for transformed T over B cells and also inhibited growth In t wo of three monocytic lines tested. 506U given i.v. to cynomolgus monk eys was rapidly converted to ara-G; the ara-G had a half-life of appro ximately 2 h. 506U had in vivo dose-dependent efficacy against human T -cell tumors in immunodeficient mice. A Phase 1 trial of 506U against refractory hematological malignancies is now in progress at two study sites.