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

Abstract

PURPOSE:

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.

PATIENTS AND METHODS:

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.

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 [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).

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.

• Authors: V Gandhi, W Plunkett, C O Rodriguez Jr, B J Nowak, M Du, M Ayres, D F Kisor, B S Mitchell, J Kurtzberg, M J Keating
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 16 Issue 11 Pg. 3607-15 (Nov 1998) ISSN: 0732-183X [Print] United States
• PMID: 9817282 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Arabinonucleosides
• Arabinonucleotides
• Prodrugs
• 9-arabinofuranosylguanine
• nelarabine
• 9-beta-D-arabinofuranosylguanosine 5'-triphosphate
• Guanosine Triphosphate

Topics

• Adult
• Antineoplastic Agents (therapeutic use)
• Arabinonucleosides (chemistry, pharmacokinetics, therapeutic use)
• Arabinonucleotides (metabolism)
• Child
• Child, Preschool
• Dose-Response Relationship, Drug
• Guanosine Triphosphate (analogs & derivatives, metabolism)
• Hematologic Neoplasms (drug therapy)
• Humans
• Leukemia, B-Cell (drug therapy)
• Leukemia, T-Cell (drug therapy)
• Multicenter Studies as Topic
• Prodrugs (therapeutic use)
• Time Factors
• Treatment Outcome