TY - JOUR
T1 - The impact of high-dose methotrexate on intracellular 6-mercaptopurine disposition during interval therapy of childhood acute lymphoblastic leukemia
AU - De Beaumais, T. Adam
AU - Dervieux, T.
AU - Fakhoury, M.
AU - Medard, Y.
AU - Azougagh, S.
AU - Zhang, D.
AU - Yakouben, K.
AU - Jacqz-Aigrain, E.
PY - 2010/9/1
Y1 - 2010/9/1
N2 - Purpose: Low-dose methotrexate (MTX) therapy is the cornerstone treatment of acute lymphoblastic leukemia (ALL) and may enhance the activation of 6-mercaptopurine (6-MP) to 6-thioguanine nucleotides (6-TGN). Yet, data have established that high-dose MTX (HDMTX) hampers the accumulation of 6-TGN in red blood cells (RBC) and lymphoblasts. Methods: To clarify the pharmacokinetic interactions between these two antimetabolites, we serially measured RBC 6-TGN and MTX polyglutamates (MTXPG) levels following repeated courses of HDMTX (5 g/m2 over 24 h) with daily oral 6-MP (25 mg/m2) during interval therapy in 20 children with ALL. Results: HDMTX produced a rapid reduction in RBC 6-TGN 24 h after the start of MTX, and this effect was sustained at least by the third day (median decrease-21%; P < 0.001). However, a return to pre-infusion of 6-TGN levels was observed by the time of the following HDMTX course 14 days later (P < 0.001). RBC MTX polyglutamates accumulation followed Michaelis-Menten kinetics but was not associated with the change in pre-infusion 6-TGN levels which remained stable during the interval period. Conclusion: HDMTX does not appear to enhance 6-MP activation to 6-TGN. Moreover, given that the deleterious effect of HDMTX on intracellular 6-MP disposition has been shown to be several folds greater in lymphoblasts than in RBC. Our data warrant additional studies elucidating the optimal MTX dose synergizing with 6-MP.
AB - Purpose: Low-dose methotrexate (MTX) therapy is the cornerstone treatment of acute lymphoblastic leukemia (ALL) and may enhance the activation of 6-mercaptopurine (6-MP) to 6-thioguanine nucleotides (6-TGN). Yet, data have established that high-dose MTX (HDMTX) hampers the accumulation of 6-TGN in red blood cells (RBC) and lymphoblasts. Methods: To clarify the pharmacokinetic interactions between these two antimetabolites, we serially measured RBC 6-TGN and MTX polyglutamates (MTXPG) levels following repeated courses of HDMTX (5 g/m2 over 24 h) with daily oral 6-MP (25 mg/m2) during interval therapy in 20 children with ALL. Results: HDMTX produced a rapid reduction in RBC 6-TGN 24 h after the start of MTX, and this effect was sustained at least by the third day (median decrease-21%; P < 0.001). However, a return to pre-infusion of 6-TGN levels was observed by the time of the following HDMTX course 14 days later (P < 0.001). RBC MTX polyglutamates accumulation followed Michaelis-Menten kinetics but was not associated with the change in pre-infusion 6-TGN levels which remained stable during the interval period. Conclusion: HDMTX does not appear to enhance 6-MP activation to 6-TGN. Moreover, given that the deleterious effect of HDMTX on intracellular 6-MP disposition has been shown to be several folds greater in lymphoblasts than in RBC. Our data warrant additional studies elucidating the optimal MTX dose synergizing with 6-MP.
KW - Leukemia
KW - Mercaptopurine
KW - Methotrexate
KW - Methotrexate polyglutamates
KW - Thioguanine nucleotides
UR - http://www.scopus.com/inward/record.url?scp=77955916827&partnerID=8YFLogxK
U2 - 10.1007/s00280-009-1205-4
DO - 10.1007/s00280-009-1205-4
M3 - Article
C2 - 20033410
AN - SCOPUS:77955916827
SN - 0344-5704
VL - 66
SP - 653
EP - 658
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 4
ER -