Compound GW506U78 in refractory hematologic malignancies: Relationship between cellular pharmacokinetics and clinical response

Varsha Gandhi, William Plunkett, Carlos O. Rodriguez, Billie J. Nowak, Min Du, Mary Ayres, David F. Kisor, Beverly S. Mitchell, Joanne Kurtzberg, Michael J. Keating

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84 Scopus citations

Abstract

Purpose: In vitro investigations with arabinosylguanine (ara-G) demonstrated potent cytatoxicity 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. Patients and Methods: During o 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. Results: 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 [t 1/4 ] = 17 minutes) was faster than the elimination of ara-G (t 1/4 = 3.7 hours). Median peak concentrations of ara-GTP were 23, 42, 85, and 93 μmol/L at 20, 30, 40, and 60 mg/kg, respectively. T-lymphoblasts accumulated significantly (P = .0008) higher peak arabinsyl-guanosine triphosphate (ara-GTP) (median, 140 μmol/L; n = 7) compared with other diagnoses (median, 50 μmol/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 μmol/L) compared with patients who failed to respond (median, 44 μmol/L). Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)3607-3615
Number of pages9
JournalJournal of Clinical Oncology
Volume16
Issue number11
StatePublished - Nov 1998
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Gandhi, V., Plunkett, W., Rodriguez, C. O., Nowak, B. J., Du, M., Ayres, M., Kisor, D. F., Mitchell, B. S., Kurtzberg, J., & Keating, M. J. (1998). Compound GW506U78 in refractory hematologic malignancies: Relationship between cellular pharmacokinetics and clinical response. Journal of Clinical Oncology, 16(11), 3607-3615.