Regulation of deoxycytidine kinase activity and inhibition by DFDC

Weber, George; Singhal, Radhey L.; Abonyi, Margit; Prajda, Noémi; Hata, Yuki; Szekeres, Thomas; Yeh, Albert C.; Look, Katherine Y.

doi:10.1016/0065-2571(93)90008-2

Cited by 15 publications

(15 citation statements)

References 20 publications

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“…In recent phase II trials, tiazofurin induced complete hematologic remissions in patients with end-stage acute nonlymphocytic leukemia or in myeloblastic crisis of chronic myeloid leukemia (25,26). The efficacy of tiazofurin is associated with its dual antiproliferative and myeloid differentiation-inducing activities (1,(25)(26)(27). Both effects are attributed to a reduction in intracellular guanine nucleotide pools due to inhibition of IMPDH by the dinucleotide analogue TAD (1,26).…”

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confidence: 99%

“…Chemotherapeutic intervention in pathological differentiation and growth (antitumor therapy) or in normal cellular responses to external antigens (immune suppression) is greatly enhanced by the identification of an enzymatic target and the design of agents to interact with this target in a specific manner. Inosine monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) has been identified as a key enzyme in the regulation of cell proliferation and differentiation (1)(2)(3). An extensive literature now addresses the characterization, mechanism, and biological functions of IMPDH, its role as a target for both antileukemic and immunosuppressive therapy, and its inhibition by chemotherapeutic agents (for reviews, see refs.…”

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confidence: 99%

“…An extensive literature now addresses the characterization, mechanism, and biological functions of IMPDH, its role as a target for both antileukemic and immunosuppressive therapy, and its inhibition by chemotherapeutic agents (for reviews, see refs. [1][2][3].…”

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confidence: 99%

“…The effects of IMPDH inhibition have been widely investigated and exploited in antitumor chemotherapy by using the Cnucleoside analogue tiazofurin (1). In vivo, tiazofurin is converted into the NAD analogue thiazole-4-carboxamide adenine dinucleotide (TAD), in which the nicotinamide ring is replaced by the thiazole-4-carboxamide moiety (20).…”

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confidence: 99%

“…The reduction in guanine nucleotides also compromises the ability of G proteins to function as transducers of intracellular signals (12)(13)(14)(15)(16). IMPDH inhibition results in down-regulation of c-myc and͞or Ki-ras oncogenes in a number of human tumor cell lines (1,13,17,18). Signaling effects are accompanied by induction of cell differentiation and apoptosis (1,2,(17)(18)(19).…”

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confidence: 99%

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Crystal structure of human type II inosine monophosphate dehydrogenase: Implications for ligand binding and drug design

Colby

Vanderveen

Strickler

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

138

127

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Inosine monophosphate dehydrogenase (IM-PDH) controls a key metabolic step in the regulation of cell growth and differentiation. This step is the NAD-dependent oxidation of inosine 5 monophosphate (IMP) to xanthosine 5 monophosphate, the rate-limiting step in the synthesis of the guanine nucleotides. Two isoforms of IMPDH have been identified, one of which (type II) is significantly up-regulated in neoplastic and differentiating cells. As such, it has been identified as a major target in antitumor and immunosuppressive drug design. We present here the 2.9-Å structure of a ternary complex of the human type II isoform of IMPDH. The complex contains the substrate analogue 6-chloropurine riboside 5-monophosphate (6-Cl-IMP) and the NAD analogue selenazole-4-carboxamide adenine dinucleotide, the selenium derivative of the active metabolite of the antitumor drug tiazofurin. The enzyme forms a homotetramer, with the dinucleotide binding at the monomer-monomer interface. The 6 chloro-substituted purine base is dehalogenated, forming a covalent adduct at C6 with Cys-331. The dinucleotide selenazole base is stacked against the 6-Cl-IMP purine ring in an orientation consistent with the B-side stereochemistry of hydride transfer seen with NAD. The adenosine end of the ligand interacts with residues not conserved between the type I and type II isoforms, suggesting strategies for the design of isoform-specific agents.

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Crystal structure of human type II inosine monophosphate dehydrogenase: Implications for ligand binding and drug design

Colby

Vanderveen

Strickler

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

138

127

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Intracellular phosphorylation of chloro‐adenosine analogs is a prerequisite for activation of caspase‐3 and induction of apoptosis in human astrocytoma cells

Ceruti

Mazzola

Beltrami

et al. 2003

Drug Development Research

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We previously demonstrated that both Cladribine (2-chloro-deoxyadenosine) and the related compound 2-chloroadenosine induce apoptosis of human astrocytoma cells (Ceruti et al. [2000] J Neurosci Res 60:388-400). In the present study we have characterized the role of the most important ''effector'' caspase (caspase-3) in the same experimental model and the relationship between the intracellular phosphorylation of the two adenosine analogs and activation of this enzyme. Data show that: 1) both adenosine analogs can activate caspase-3 in a time-dependent fashion; 2) significant activation of the enzyme (i.e., 6-7-fold over control level) can be detected before any appearance of nuclear signs of apoptosis; 3) the degree of caspase-3 activation is proportional to the percentage of apoptosis at the end of the incubation period, suggesting a causal relationship between enzyme activation and induction of cell death; and 4) both activation of caspase-3 and induction of cell death can be completely prevented by preexposure of cultures to inhibitors of the intracellular phosphorylation of 2-chloroadenosine and 2-chloro-2 0 -deoxyadenosine (namely, 5-iodotubercidin and 2 0 -deoxycytidine, respectively). Adenosine analogs act, therefore, as prodrugs and the toxic species are represented by the corresponding chloronucleotides. The pathways upstream of caspase-3 activation in human astrocytoma cells still remain to be elucidated. Taken together, these data strongly suggest a possible use of adenosine analogs in the pharmacological treatment of central nervous system tumors and of all tumors characterized by a high activity of nucleoside kinases leading to selective intracellular accumulation of toxic chloro-nucleotides. Drug Dev. Res. 58:396-404, 2003.

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Nucleoside Transport and Metabolism in Lymphocytes, Polymorphonuclear Cells and Cerebral Synaptosomes

Staub

Sasvári-Székely

Solymossy

et al. 1995

Purine and Pyrimidine Metabolism in Man VIII

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Regulation of deoxycytidine kinase activity and inhibition by DFDC

Cited by 15 publications

References 20 publications

Crystal structure of human type II inosine monophosphate dehydrogenase: Implications for ligand binding and drug design

Crystal structure of human type II inosine monophosphate dehydrogenase: Implications for ligand binding and drug design

Intracellular phosphorylation of chloro‐adenosine analogs is a prerequisite for activation of caspase‐3 and induction of apoptosis in human astrocytoma cells

Nucleoside Transport and Metabolism in Lymphocytes, Polymorphonuclear Cells and Cerebral Synaptosomes

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