The importance of methylthio-IMP for methylmercaptopurine ribonucleoside (Me-MPR) cytotoxicity in Molt F4 human malignant T-lymphoblasts.
The importance of methyl-thioIMP (Me-tIMP) formation for methylmercaptopurine ribonucleoside (Me-MPR) cytotoxicity was studied in Molt F4 cells. Cytotoxicity of Me-MPR is caused by Me-tIMP formation with concomitant inhibition of purine de novo synthesis. Inhibition of purine de novo synthesis resulted in decreased purine nucleotide levels and enhanced 5-phosphoribosyl-1-pyrophosphate (PRPP) levels, with concurrent increased pyrimidine nucleotide levels. The Me-tIMP concentration increased proportionally with the concentration of Me-MPR. High Me-tIMP concentration also caused inhibition of PRPP synthesis. Maximal accumulation of PRPP thus occurred at low Me-MPR concentrations. As little as 0.2 microM Me-MPR resulted already after 2 h in maximal inhibition of formation of adenine and guanine nucleotides, caused by inhibition of purine de novo synthesis by Me-tIMP. Under these circumstances increased intracellular PRPP concentrations could be demonstrated, resulting in increased levels of pyrimidine nucleotides. So, in Molt F4 cells, formation of Me-tIMP from Me-MPR results in cytotoxicity by inhibition of purine de novo synthesis.
Vogt
M H
MH
Department of Pediatrics, St. Radboud University Hospital, Nijmegen, The Netherlands.
Stet
E H
EH
De Abreu
R A
RA
Bökkerink
J P
JP
Lambooy
L H
LH
Trijbels
F J
FJ
D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007291:Inosine Monophosphate / Q000031:analogs & derivatives*; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D008778:Methylthioinosine / Q000031:analogs & derivatives* / Q000378:metabolism; D010754:Phosphoribosyl Pyrophosphate / Q000096:biosynthesis; D011685:Purine Nucleotides / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects*; D013868:Thioinosine / Q000031:analogs & derivatives*; D013872:Thionucleosides / Q000378:metabolism / Q000494:pharmacology*; D013873:Thionucleotides / Q000378:metabolism* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D011685:Purine Nucleotides; D013872:Thionucleosides; D013873:Thionucleotides; D007291:Inosine Monophosphate; D008778:Methylthioinosine; D013868:Thioinosine; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; D010754:Phosphoribosyl Pyrophosphate; D015122:Mercaptopurine