[Biochemical and clinico-pharmacological aspects of antimetabolites in the treatment of leukemia].
Methotrexate (MTX) and 6-mercaptopurine (6MP) have been used since 30 years in the maintenance treatment of acute lymphoblastic leukemia (ALL) of childhood. A synergistic effect of this combination was demonstrated in mouse and childhood leukemia. In this article an overview is given of our investigations, concerning the biochemical basis of this synergism. This synergism is caused by a selective inhibition of the purine de novo synthesis in malignant lymphoblasts by MTX, associated with an enhanced intracellular uptake of 6MP. Pharmacokinetic studies of MTX in various schemes of prophylactic central nervous system treatment in ALL are discussed. Treatment with 24-hr infusions of MTX in a dosage of 5 g/m2, as recommended in the new BFM-86/SNWLK ALL VII protocol, seems to be optimal. Pharmacokinetic studies of intravenous 6MP infusions demonstrated a good cerebral fluid penetration. Exploiting the synergistic action of the combination of MTX and 6MP may offer an improvement of the prophylactic central nervous systems treatment in ALL in the future, using intravenous administration of both MTX and 6MP.
Bökkerink
J P
JP
Kinderoncologisch Centrum Zuid-Oost Nederland. Afd. Kindergeneeskunde, Sint Radboudziekenhuis, Nijmegen.
de Abreu
R A
RA
Lippens
R J
RJ
Schouten
T J
TJ
de Vaan
G A
GA
D002648:Child; D004357:Drug Synergism; D006801:Humans; D007945:Leukemia, Lymphoid / Q000188:drug therapy*; D015122:Mercaptopurine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008727:Methotrexate / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
D015122:Mercaptopurine; D008727:Methotrexate
Biochemisch- en klinisch-farmacologische aspecten van antimetabolieten bij de behandeling van leukemie.