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Prepublished online as a Blood First Edition Paper on May 17, 2002; DOI 10.1182/blood-2002-02-0495.
Submitted February 14, 2002
Accepted April 9, 2002
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, C-H Pui, Mary V Relling, and William E Evans*
Pharmaceutical Division, St. Jude Children's Research Hospital, Memphis, TN, USA; University of Tennessee, Memphis, TN, USA
Pharmaceutical Division, St. Jude Children's Research Hospital, Memphis, TN, USA
* Corresponding author; email: william.evans{at}stjude.org.
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 (LD: 6 oral doses of 30 mg/m2) or high-dose MTX (HD: IV 1 g/m2) followed by IV MP; or IV 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 to those with B-lineage ALL (769±189 versus 250±38 fmol/nmol/h; p=0.001). DNPS was not consistently inhibited following MP alone, but was markedly inhibited following MTX+MP (median decrease= 3% versus 94%; p<0.001). LDMTX+MP and HDMTX+MP produced greater antileukemic effects (percentage decrease in circulating leukocyte counts) compared to MP alone (-50±4%, -56±3%, and
-20±4%, respectively; p<0.0001). Full DNPS inhibition was associated with greater antileukemic effects compared to partial or no inhibition (-63±4% versus -37±4%; p<0.0001) in patients with non-hyperdiploid B-lineage and T-lineage ALL. HDMTX+MP yielded 2.0-fold higher MTX polyglutamate concentrations than LDMTX+MP (2148±298 versus 1075±114 pmol/109 cells; p<0.01), and a higher percentage of patients with full DNPS inhibition (78% versus 53%; p<0.001). Thus, the extent of DNPS inhibition was related to in vivo antileukemic effects, and a single dose of IV MP produced minimal DNPS inhibition and antileukemic effects, whereas MTX+MP produced greater antileukemic effects and and DNPS inhibition, with full inhibition more frequent after HDMTX.
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