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Prepublished online as a Blood First Edition Paper on May 17, 2002; DOI 10.1182/blood-2002-02-0495.
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Blood, 15 August 2002, Vol. 100, No. 4, pp. 1240-1247
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
De novo purine synthesis inhibition and antileukemic effects of
mercaptopurine alone or in combination with methotrexate in
vivo
Thierry Dervieux,
Timothy
L. Brenner,
Yuen Y. Hon,
Yinmei Zhou,
Michael L. Hancock,
John T. Sandlund,
Gaston K. Rivera,
Raul C. Ribeiro,
James M. Boyett,
Ching-Hon Pui,
Mary V. Relling, and
William E. Evans
From the Department of Pharmaceutical Sciences,
Department of Biostatistics, Department of Hematology-Oncology, and
Department of Pathology, St Jude Children's Research Hospital; and
University of Tennessee; both of Memphis, TN.
Methotrexate (MTX) and mercaptopurine (MP) are widely used
antileukemic agents that inhibit de novo purine synthesis (DNPS) as a
mechanism of their antileukemic effects. To elucidate pharmacodynamic differences among children with acute lymphoblastic leukemia (ALL), DNPS was measured in leukemic blasts from newly diagnosed patients before and after therapy with these agents. Patients were randomized to
receive low-dose MTX (LDMTX: 6 oral doses of 30 mg/m2) or
high-dose MTX (HDMTX: intravenous 1 g/m2) followed by
intravenous MP; or intravenous MP alone (1 g/m2), as
initial therapy. At diagnosis, the rate of DNPS in bone marrow leukemia
cells was 3-fold higher in patients with T-lineage ALL compared
with those with B-lineage ALL (769 ± 189 vs 250 ± 38 fmol/nmol/h;
P = .001). DNPS was not consistently inhibited following
MP alone but was markedly inhibited following MTX plus MP (median
decrease 3% vs 94%; P < .001). LDMTX plus MP and HDMTX plus MP produced greater antileukemic effects (percentage decrease in
circulating leukocyte counts) compared with MP alone ( 50% ± 4%,
56% ± 3%, and 20% ± 4%, respectively;
P < .0001). Full DNPS inhibition was associated with
greater antileukemic effects compared with partial or no inhibition
(63% ± 4% vs 37% ± 4%; P < .0001) in
patients with nonhyperdiploid B-lineage and T-lineage ALL. HDMTX plus
MP yielded 2-fold higher MTX polyglutamate concentrations than LDMTX
plus MP (2148 ± 298 vs 1075 ± 114 pmol/109 cells;
P < .01) and a higher percentage of patients with full DNPS inhibition (78% vs 53%; P < .001). Thus, the
extent of DNPS inhibition was related to in vivo antileukemic effects,
and a single dose of intravenous MP produced minimal DNPS inhibition and antileukemic effects, whereas MTX plus MP produced greater antileukemic effects and DNPS inhibition, with full inhibition more
frequent after HDMTX.
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