Antagonism by methotrexate on mercaptopurine disposition in lymphoblasts during up-front treatment of acute lymphoblastic leukemia.
BACKGROUND
Methotrexate is postulated to enhance mercaptopurine activation to thioguanine (INN, tioguanine) nucleotides, but the interaction has never been studied in vivo in cancer cells.


METHODS
We investigated the effect of methotrexate on mercaptopurine disposition in plasma and leukemic blasts during up-front treatment of 233 children with newly diagnosed acute lymphoblastic leukemia. Children were randomized to receive intravenous mercaptopurine (1 g/m(2) over a 6-hour period) or to receive methotrexate (low dose, 6 oral doses of 30 mg/m(2), or high dose, 1 g/m(2) intravenously), followed by intravenous mercaptopurine. All combinations have been previously used in frontline trials for acute lymphoblastic leukemia.


RESULTS
Compared with mercaptopurine alone, methotrexate resulted in higher plasma mercaptopurine concentrations (30.3 +/- 14.7 micromol/L versus 23.5 +/- 18.0 micromol/L, P <.001) but, conversely, a 13-fold lower thioguanine nucleotide concentration (0.57 +/- 0.66 pmol/5 x 10(6) cells versus 7.4 +/- 15.2 pmol/5 x 10(6) cells, P <.001) in bone marrow leukemic lymphoblasts. Methotrexate was also associated with higher plasma hypoxanthine concentrations compared with those of patients given mercaptopurine alone (8.7 +/- 13.5 micromol/L versus 3.8 +/- 2.5 micromol/L, P =.029). The percentage change in leukocyte counts measured over a 3-day period showed that mercaptopurine alone had little effect (mean decrease, 20% +/- 33%). In contrast, despite causing lower intracellular thiopurine active metabolite concentrations, methotrexate produced a greater decrease in leukocyte counts (mean, 53% +/- 35%) compared with those in patients receiving mercaptopurine alone (P <.0001).


CONCLUSIONS
These pharmacologic findings in the target tissue are consistent with the recently demonstrated lack of clinical benefit of intravenous mercaptopurine in combination with methotrexate. We conclude that, in the setting of newly diagnosed acute lymphoblastic leukemia, methotrexate antagonizes thiopurine metabolite disposition in leukemic blasts after intravenous mercaptopurine.
Dervieux
Thierry
T
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Hancock
Michael L
ML
Pui
Ching-Hon
CH
Rivera
Gaston K
GK
Sandlund
John T
JT
Ribeiro
Raul C
RC
Boyett
James
J
Evans
William E
WE
Relling
Mary V
MV
D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000378:metabolism* / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism*; D002648:Child; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D019271:Hypoxanthine / Q000378:metabolism; D007275:Injections, Intravenous; D007958:Leukocyte Count; D015122:Mercaptopurine / Q000378:metabolism* / Q000627:therapeutic use; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D009705:Nucleosides / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D013866:Thioguanine / Q000378:metabolism; D014970:Xanthines / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D009705:Nucleosides; D014970:Xanthines; D019271:Hypoxanthine; D015122:Mercaptopurine; D013866:Thioguanine; D008727:Methotrexate