6-thioguanosine and Leukemia

Thiopurines are in widespread clinical use for the treatment of immunological disorders and certain cancers. However, treatment failure due to resistance or adverse drug reactions are common, asking for new therapeutic strategies. We investigated the potential of 6-thioguanosine monophosphate (6sGMP) prodrugs to overcome resistance to 6-thioguanine. We successfully developed synthetic routes toward diverse 6sGMP prodrugs, tested their proliferation inhibitory potential in different cell lines, and examined their mode of action. Our results show that 4-acetyloxybenzyl- and

Topics: Breast Neoplasms; Female; Humans; Leukemia; Prodrugs; Purine Nucleosides; Thioguanine

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.. 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.. 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.. 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.

Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Gene Expression Regulation, Leukemic; Guanosine; Humans; IMP Dehydrogenase; Intracellular Space; Leukemia; Mycophenolic Acid; Purines; Thionucleosides

Topics: Animals; Cattle; Cytarabine; Daunorubicin; DNA Polymerase I; DNA Polymerase II; Doxorubicin; Guanosine; Leukemia; Nucleic Acid Synthesis Inhibitors; Thionucleosides