Reversal of 6-mercaptopurine and 6-methylmercaptopurine ribonucleoside cytotoxicity by amidoimidazole carboxamide ribonucleoside in Molt F4 human malignant T-lymphoblasts.
Cytotoxicity of 6-mercaptopurine (6MP) and 6-methylmercaptopurine ribonucleoside (Me-MPR) was studied in Molt F4 human malignant lymphoblasts. Both drugs are converted into methylthioIMP (Me-tIMP), which inhibits purine de novo synthesis. Addition of amidoimidazole carboxamide ribonucleoside (AICAR) circumvented inhibition of purine de novo synthesis, and thus partly prevented 6MP and Me-MPR cytotoxicity. Purine nucleotides, and especially adenine nucleotides, were recovered by addition of AICAR. Under these conditions, Me-tIMP formation decreased. The results of this study indicate that formation of Me-tIMP may be important for 6MP cytotoxicity in Molt F4 cells. These data suggest that depletion of adenine nucleotides is the main cause for Me-tIMP cytotoxicity.
Stet
E H
EH
Department of Pediatrics, St. Radboud University Hospital of Nijmegen, The Netherlands.
De Abreu
R A
RA
Bökkerink
J P
JP
Vogels-Mentink
T M
TM
Lambooy
L H
LH
Trijbels
F J
FJ
Trueworthy
R C
RC
D000227:Adenine Nucleotides / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D004347:Drug Interactions; D006150:Guanine Nucleotides / Q000378:metabolism; D006801:Humans; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*; D008778:Methylthioinosine / Q000031:analogs & derivatives / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology*; D013868:Thioinosine / Q000031:analogs & derivatives*; D013872:Thionucleosides / Q000037:antagonists & inhibitors*; D013873:Thionucleotides / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000227:Adenine Nucleotides; D006150:Guanine Nucleotides; D012263:Ribonucleosides; D013872:Thionucleosides; D013873:Thionucleotides; D008778:Methylthioinosine; D000620:Aminoimidazole Carboxamide; D013868:Thioinosine; C011651:acadesine; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; D015122:Mercaptopurine