Reversal of methylmercaptopurine ribonucleoside cytotoxicity by purine ribonucleosides and adenine.
6-Methylmercaptopurine ribonucleoside-5'-phosphate (MeSPuRMP), the sole metabolite of 6-methylmercaptopurine ribonucleoside (MeSPuRib), is a strong inhibitor of purine de novo synthesis, inducing depletion of intracellular purine nucleotides and subsequent cell death in several tumor cell lines. In this study prevention of MeSPuRib cytotoxicity by compounds of the purine salvage pathway was studied in Molt F4 human malignant T-lymphoblasts. Adenosine, adenine and inosine were able to prevent depletion of the adenine nucleotide pool when used in combination with 0.5 microM MeSPuRib, but had virtually no effect on depletion of guanine nucleotides. Nevertheless, these three purine compounds were able to reduce the cytotoxic effects induced by MeSPuRib. Addition of guanosine to cells treated with 0.5 microM MeSPuRib normalized the guanine nucleotide pool, but adenine nucleotides remained depleted. Under these conditions, inhibition of cell growth was significantly decreased. With the combination of guanosine and 10 microM MeSPuRib, cytotoxicity was increased compared to 10 microM MeSPuRib alone, associated with a depletion of adenine nucleotides to 9% of untreated cells. Since cell growth and cell viability of Molt F4 cells are less inhibited by MeSPuRib under conditions where adenine nucleotide depletion is prevented by purine compounds (and where the other nucleotides are depleted) we conclude that depletion of adenine nucleotides is an important factor in MeSPuRib cytotoxicity.
Department of Pediatrics, St Radboud University Hospital of Nijmegen, The Netherlands.
E H
EH
Stet
R A
RA
De Abreu
J P
JP
Bökkerink
L H
LH
Lambooy
T M
TM
Vogels-Mentink
J J
JJ
Keizer-Garritsen
F J
FJ
Trijbels
D000225:Adenine / Q000494:pharmacology*; D000241:Adenosine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006151:Guanosine / Q000494:pharmacology; D006801:Humans; D007288:Inosine / Q000494:pharmacology; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D008778:Methylthioinosine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D009705:Nucleosides / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism; D011684:Purine Nucleosides / Q000494:pharmacology*; D012263:Ribonucleosides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D013868:Thioinosine / Q000031:analogs & derivatives / Q000633:toxicity; D013873:Thionucleotides / Q000633:toxicity
D000970:Antineoplastic Agents; D009705:Nucleosides; D009711:Nucleotides; D011684:Purine Nucleosides; D012263:Ribonucleosides; D013873:Thionucleotides; D006151:Guanosine; D008778:Methylthioinosine; D013868:Thioinosine; D007288:Inosine; C010240:6-methylthiopurine; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; D015122:Mercaptopurine; D000225:Adenine; D000241:Adenosine