IMP dehydrogenase basal activity in MOLT-4 human leukaemia cells is altered by mycophenolic acid and 6-thioguanosine.
OBJECTIVE
Depletion of guanine and deoxyguanine nucleotides by inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) or introduction of 6-thioguanine nucleotide antimetabolites are two principles of retarding cell proliferation by interference with the cellular purine nucleotide pool. IMPDH activity may be a promising pharmacodynamic biomarker during immunosuppressive and anticancer pharmacotherapy. The aim of the study was to investigate the impact of mycophenolic acid (MPA) and 6-thioguanosine (tGuO) on IMPDH basal activity.


METHODS
We studied the IMPDH basal activity (i.e. the enzyme activity following inhibitor exposure, but measured in absence of the inhibitor) in response to increasing concentrations of the IMPDH inhibitor MPA and the antimetabolite tGuO in MOLT-4 human leukaemia cells. In parallel, IMPDH gene expression and cellular purine nucleotide concentrations were examined.


RESULTS
A biphasic concentration-dependent influence of MPA on the IMPDH basal activity was observed. At concentrations < or =IC50, MPA increased the IMPDH basal activity. The increase was associated with elevated expression of IMPDH2. Despite increased expression, the basal enzyme activity decreased following exposure to high MPA concentrations. The IMPDH2 expression increased modestly in response to tGuO exposure. However, the IMPDH basal activity decreased when the cells were exposed to a proliferation-blocking tGuO concentration.


CONCLUSIONS
These findings demonstrate that IMPDH basal activity is influenced by MPA and tGuO, and suggest that reduced IMPDH basal activity is related to the proliferation-blocking effects of these agents.
Vethe
N T
NT
Department of Medical Biochemistry, Rikshospitalet Medical Centre, Oslo, Norway.
Bremer
S
S
Bergan
S
S
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007938:Leukemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009173:Mycophenolic Acid / Q000494:pharmacology*; D011687:Purines / Q000378:metabolism; D013872:Thionucleosides / Q000494:pharmacology*
D011687:Purines; D013872:Thionucleosides; D006151:Guanosine; C005783:6-thioguanosine; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid