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-leukemic cells. However, poor water solubility of ara-G limits clinical use. 2-Amino-6-methoxypurine arabinoside (506U) is a water-soluble prodrug converted to ara-G by adenosine deaminase. 506U is not a substrate for deoxycytidine kinase, adenosine kinase, or purine nucleoside phosphorylase and is phosphorylated by mitochondrial deoxyguanosine kinase at a rate 4% that of ara-G phosphorylation. Mitochondrial DNA polymerase was the least sensitive to ara-GTP inhibition of the five human DNA polymerases tested. [3H]506U was anabolized to ara-G 5'-phosphates in CEM cells but not to phosphorylated metabolites of 506U. 506U was selective for transformed T over B cells and also inhibited growth in two of three monocytic lines tested. 506U given i.v. to cynomolgus monkeys was rapidly converted to ara-G; the ara-G had a half-life of approximately 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.
Lambe
C U
CU
Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709, USA.
Averett
D R
DR
Paff
M T
MT
Reardon
J E
JE
Wilson
J G
JG
Krenitsky
T A
TA
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000378:metabolism / Q000627:therapeutic use*; D001088:Arabinonucleotides / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D015448:Leukemia, B-Cell / Q000188:drug therapy; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000378:metabolism; D008252:Macaca fascicularis / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D019384:Nucleic Acid Synthesis Inhibitors; D011355:Prodrugs / Q000378:metabolism / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D001088:Arabinonucleotides; D019384:Nucleic Acid Synthesis Inhibitors; D011355:Prodrugs; C028771:9-arabinofuranosylguanine; C022206:9-beta-D-arabinofuranosylguanosine 5'-triphosphate; D006160:Guanosine Triphosphate