A biochemical basis for synergism of 6-mercaptopurine and mycophenolic acid in Molt F4, a human malignant T-lymphoblastic cell line.
6-Mercaptopurine (6MP) cytotoxicity was studied in Molt F4 cells, a T-cell acute lymphoblastic leukemia (ALL) cell line. The effects on cytotoxicity were concentration-dependent. Measurements of intracellular thionucleotide intermediates of 6MP demonstrated a rapid rise of thio-IMP (tIMP) levels, and subsequently a rapid decrease. Thio-GMP (tGMP) and methyl-thio-IMP (Me-tIMP) appeared later in time, and persisted longer. Mycophenolic acid (MPA), a specific inhibitor of IMP dehydrogenase (IMPDH), was used to inhibit the conversion of tIMP into tGMP, thereby decreasing the incorporation of 6MP into DNA. A synergistic effect on cell viability and cell growth was observed when cells were treated with a combination of 2 microM 6MP and 0.5 microM MPA. Also, intracellular Me-tIMP increased 5 times with the combination. Based on the increase of Me-tIMP concentration and the observed synergism between 6MP and MPA, we conclude that methylation of tIMP into Me-tIMP is an important alternative route for 6MP cytotoxicity.
Stet
E H
EH
Department of Pediatrics, St. Radboud University Hospital of Nijmegen, Netherlands.
De Abreu
R A
RA
Janssen
Y P
YP
Bökkerink
J P
JP
Trijbels
F J
FJ
D003603:Cytotoxins / Q000633:toxicity*; D004357:Drug Synergism; D006801:Humans; D015122:Mercaptopurine / Q000633:toxicity*; D009173:Mycophenolic Acid / Q000633:toxicity*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D013601:T-Lymphocytes / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D003603:Cytotoxins; D015122:Mercaptopurine; D009173:Mycophenolic Acid