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


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).


CONCLUSIONS
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.
Gandhi
V
V
Department of Clinical Investigation, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. vgandhi@notes.mdacc.tmc.edu
Plunkett
W
W
Rodriguez
C O
CO
Nowak
B J
BJ
Du
M
M
Ayres
M
M
Kisor
D F
DF
Mitchell
B S
BS
Kurtzberg
J
J
Keating
M J
MJ
D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001088:Arabinonucleotides / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D015448:Leukemia, B-Cell / Q000188:drug therapy; D015458:Leukemia, T-Cell / Q000188:drug therapy; D015337:Multicenter Studies as Topic; D011355:Prodrugs / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D001088:Arabinonucleotides; D011355:Prodrugs; C028771:9-arabinofuranosylguanine; C104457:nelarabine; C022206:9-beta-D-arabinofuranosylguanosine 5'-triphosphate; D006160:Guanosine Triphosphate