Journal of Clinical Oncology, Vol 16, 3607-3615, Copyright © 1998 by American Society of Clinical Oncology
Compound GW506U78 in refractory hematologic malignancies: relationship between cellular pharmacokinetics and clinical response
V Gandhi, W Plunkett, CO Rodriguez Jr, BJ Nowak, M Du, M Ayres, DF Kisor, BS Mitchell, J Kurtzberg and MJ Keating
Department of Clinical Investigation, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. vgandhi@notes.mdacc.tmc.edu
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.
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