9-arabinofuranosylguanine and Leukemia--T-Cell

In vitro investigations with arabinosylguanine (ara-G) demonstrated potent cytotoxicity to T-lymphoblastoid cell lines. The goals of the present study were to evaluate GW506U78, a prodrug of ara-G, against human hematologic malignancies and to determine its pharmacokinetics in plasma and cells.. During a phase I multicenter trial of GW506U78, 26 patients were treated at M.D. Anderson Cancer Center (MDACC). Daily doses between 20 and 60 mg/kg were administered for 5 days. Parallel plasma and cellular pharmacokinetic studies were conducted.. Complete (n=5) or partial remission (n=5) was achieved in T-cell acute lymphoblastic leukemia (T-ALL), T-lymphoid blast crisis, T-lymphoma, and B-cell chronic lymphocytic leukemia (B-CLL) (n=13). In contrast, patients with B-ALL, B-lymphoma, acute myelogenous leukemia (AMI), or T-CLL did not respond. Peak plasma concentrations of GW506U78 and ara-G were dose-dependent. The elimination of GW506U78 (half-life [t1/2]=17 minutes) was faster than the elimination of ara-G (t1/2=3.7 hours). Median peak concentrations of ara-GTP were 23, 42, 85, and 93 micromol/L at 20, 30, 40, and 60 mg/kg, respectively. T-lymphoblasts accumulated significantly (P=.0008) higher peak arabinsylguanosine triphosphate (ara-GTP) (median, 140 micromol/L; n=7) compared with other diagnoses (median, 50 micromol/L; n=9) and normal mononuclear cells (n=3). The ara-GTP elimination was slow in all diagnoses (median, > 24 hours). Responders accumulated significantly (P=.0005) higher levels of ara-GTP (median, 157 micromol/L) compared with patients who failed to respond (median, 44 micromol/L).. GW506U78 is an effective prodrug and a potent agent for hematologic malignancies with major efficacy in T-cell diseases. The pharmacokinetics of ara-GTP in leukemia cells are strongly correlated with clinical responses to GW506U78.

Topics: Adult; Antineoplastic Agents; Arabinonucleosides; Arabinonucleotides; Child; Child, Preschool; Dose-Response Relationship, Drug; Guanosine Triphosphate; Hematologic Neoplasms; Humans; Leukemia, B-Cell; Leukemia, T-Cell; Multicenter Studies as Topic; Prodrugs; Time Factors; Treatment Outcome

The nucleoside analog 9-beta-D-arabinofuranosylguanine (araG) is presently evaluated in clinical trials for therapy of T-cell lymphoid malignancies. AraG is a substrate for the mitochondrial deoxyguanosine kinase and we have recently shown that araG is predominantly incorporated into mitochondrial DNA (mtDNA). In this study we have investigated the effects of araG on mtDNA content and function. Although araG was incorporated into mtDNA, no decrease in mtDNA levels or effect on the expression of the mtDNA encoded cytochrome c oxidase was detected. Cells depleted of mtDNA were resistant to araG, but the mechanism of resistance was not specific for nucleoside analogs incorporated into mtDNA. Furthermore, the results suggest that the cells need to pass the S-phase in order for araG to induce caspase-dependent apoptosis. In summary, our findings suggest that the incorporation of araG into mtDNA does not cause the acute cytotoxicity of araG.

Topics: Antineoplastic Agents; Arabinonucleosides; Caspases; DNA, Mitochondrial; Electron Transport Complex IV; Humans; Leukemia, T-Cell; Tumor Cells, Cultured

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.

Topics: Animals; Antineoplastic Agents; Arabinonucleosides; Arabinonucleotides; Drug Screening Assays, Antitumor; Female; Guanosine Triphosphate; Humans; Leukemia, B-Cell; Leukemia, T-Cell; Macaca fascicularis; Mice; Mice, Nude; Nucleic Acid Synthesis Inhibitors; Prodrugs; Tumor Cells, Cultured