First-in-human, phase I dose-escalation study of single and multiple doses of a first-in-class enhancer of fluoropyrimidines, a dUTPase inhibitor (TAS-114) in healthy male volunteers

Saito, Kaku; Nagashima, Hirotaka; Noguchi, Kenta; Yoshisue, Kunihiro; Yokogawa, Tatsushi; Matsushima, Eiji; Tahara, Takeshi; Shigeru, Takagi

doi:10.1007/s00280-014-2383-2

Cited by 30 publications

(34 citation statements)

References 17 publications

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“…Moreover, inhibition of these nucleotidohydrolases may constitute a novel approach to improve the efficacy of antitumor therapy with decitabine and circumvent potential drug resistance phenotypes. Indeed, novel molecules have been recently identified with capacity to specifically inhibit the activity of dUTPase and DCTPP1 that enhance the cytotoxic effect of pyrimidine anticancer agents (29,30) thus highlighting the relevance of these nucleotidohydrolases in the mode of action of pyrimidine derivatives currently used in antitumour therapy. …”

Section: Discussionmentioning

confidence: 99%

The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine

Requena

Pérez-Moreno

Horváth

et al. 2016

Biochemical Journal

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Decitabine (5-aza-2′-deoxycytidine, aza-dCyd) is an anti-cancer drug used clinically for the treatment of myelodysplastic syndromes and acute myeloid leukaemia that can act as a DNA-demethylating or genotoxic agent in a dose-dependent manner. On the other hand, DCTPP1 (dCTP pyrophosphatase 1) and dUTPase are two ‘house-cleaning’ nucleotidohydrolases involved in the elimination of non-canonical nucleotides. In the present study, we show that exposure of HeLa cells to decitabine up-regulates the expression of several pyrimidine metabolic enzymes including DCTPP1, dUTPase, dCMP deaminase and thymidylate synthase, thus suggesting their contribution to the cellular response to this anti-cancer nucleoside. We present several lines of evidence supporting that, in addition to the formation of aza-dCTP (5-aza-2′-deoxycytidine-5′-triphosphate), an alternative cytotoxic mechanism for decitabine may involve the formation of aza-dUMP, a potential thymidylate synthase inhibitor. Indeed, dUTPase or DCTPP1 down-regulation enhanced the cytotoxic effect of decitabine producing an accumulation of nucleoside triphosphates containing uracil as well as uracil misincorporation and double-strand breaks in genomic DNA. Moreover, DCTPP1 hydrolyses the triphosphate form of decitabine with similar kinetic efficiency to its natural substrate dCTP and prevents decitabine-induced global DNA demethylation. The data suggest that the nucleotidohydrolases DCTPP1 and dUTPase are factors involved in the mode of action of decitabine with potential value as enzymatic targets to improve decitabine-based chemotherapy.

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Section: Discussionmentioning

confidence: 99%

The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine

Requena

Pérez-Moreno

Horváth

et al. 2016

Biochemical Journal

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“…Three mechanisms have been proposed for its action: Incorporation into RNA (7), incorporation into DNA (8) and the inhibition of thymidine synthase (TS) leading to the inhibition of DNA de novo synthesis by forming a ternary complex composed of TS, 5,10-methylenetetrahydrofolate (CH2THF) and fluoro-deoxyuridine monophosphate (FdUMP) (9). The first step in the activation of 5FU is the phosphorylation of 5FU by orotate phosphoribosyltransferase (OPRT), which metabolizes 5FU to 5-fluorouridine monophosphate (FUMP).…”

Section: Introductionmentioning

confidence: 99%

5FU resistance caused by reduced fluoro-deoxyuridine monophosphate and its reversal using deoxyuridine

et al. 2017

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Abstract. The mechanism of 5-fluorouracil (5FU) resistance was investigated, focusing on the level of thymidylate synthase (TS) ternary complex formed with fluoro-deoxyuridine monophosphate (FdUMP). MKN45 and 5FU-resistant MKN45/F2R cells were treated with 5FU and fluoro-deoxyuridine (FdU) in combination with deoxyuridine (dU) and thymidine (dT). Subsequently, the levels of ternary complex were determined by western blotting and the cell viability was calculated using an MTT assay. MKN45/F2R cells exhibited 5FU resistance (56.2-fold relative to MKN45 cells), and demonstrated decreased orotate phosphoribosyltransferase (OPRT) and increased TS levels, requiring a higher concentration of 5FU to induce ternary complex formation than MKN45 cells. Following transfection of small interfering RNA against OPRT, MKN45 exhibited increased resistance to 5FU and decreased ternary complex formation subsequent to treatment with 5FU, indicating that decreased OPRT led to increased 5FU resistance. However, MKN45/F2R also exhibited resistance to FdU, which can be converted to FdUMP without OPRT, and there was decreased ternary complex formation after treatment with FdU, indicating that the 5FU-resistant cells had the ability to decrease intracellular FdUMP. The addition of dU and thymidine dT to 5FU promoted the formation of ternary complexes and reversed 5FU resistance in MKN45/F2R cells, although dT inhibited the efficacy of raltitrexed (another TS inhibitor). These results suggested that 5FU-resistant cells had the ability to reduce intracellular FdUMP irrespective of decreased OPRT, which led to resistance to 5FU. This resistance was then inhibited by treatment with dT or dU. IntroductionDespite recent advances in the development of diagnostic tools for gastric cancer, many patients with gastric cancer continue to be diagnosed at a late stage, and even following curative surgery, recurrent tumors frequently occur. Therefore, gastric cancer remains a major cause for cancer-associated mortality worldwide (1) and the development of novel drug therapies for gastric cancer is important.5FU is currently a key drug for adjuvant therapy following curative surgery (2-4) and for the treatment of metastatic gastric cancer (5,6). Three mechanisms have been proposed for its action: Incorporation into RNA (7), incorporation into DNA (8) and the inhibition of thymidine synthase (TS) leading to the inhibition of DNA de novo synthesis by forming a ternary complex composed of TS, 5,10-methylenetetrahydrofolate (CH2THF) and fluoro-deoxyuridine monophosphate (FdUMP) (9). The first step in the activation of 5FU is the phosphorylation of 5FU by orotate phosphoribosyltransferase (OPRT), which metabolizes 5FU to 5-fluorouridine monophosphate (FUMP). FUMP is then metabolized into 5-fluorouridine triphosphate (FUTP), which can be incorporated into RNA and into 5-flurodeoxyuridine triphosphate (FdUTP), which can be incorporated into DNA (10). Although the incorporation into RNA and DNA is certainly an important aspect of the mechanism of action of 5FU,...

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“…The enzyme dUTPase, which converts dUTP into dUMP and pyrophosphate, is inhibited by TAS-114, a first-in-class oral fluoropyrimidine that prevents the degradation of another fluoropyrimidine used in combination [62]. TAS-114 also moderately inhibits dihydropyrimidine dehydrogenase, the initial step in pyrimidine catabolism.…”

Section: Pharmacological Tools To Modulate Pyrimidine Nucleotide Biosmentioning

confidence: 99%

Human pyrimidine nucleotide biosynthesis as a target for antiviral chemotherapy

Ökesli

Khosla

Bassik

2017

Current Opinion in Biotechnology

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The development of broad-spectrum, host-acting antiviral therapies remains an important but elusive goal in anti-infective drug discovery. To replicate efficiently, viruses not only depend on their hosts for an adequate supply of pyrimidine nucleotides, but also up-regulate pyrimidine nucleotide biosynthesis in infected cells. In this review, we outline our understanding of mammalian de novo and salvage metabolic pathways for pyrimidine nucleotide biosynthesis. The available spectrum of experimental and FDA-approved drugs that modulate individual steps in these metabolic pathways is also summarized. The logic of a host-acting combination antiviral therapy comprised of inhibitors of dihydroorotate dehydrogenase and uridine/cytidine kinase is discussed.

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First-in-human, phase I dose-escalation study of single and multiple doses of a first-in-class enhancer of fluoropyrimidines, a dUTPase inhibitor (TAS-114) in healthy male volunteers

Cited by 30 publications

References 17 publications

The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine

The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine

5FU resistance caused by reduced fluoro-deoxyuridine monophosphate and its reversal using deoxyuridine

Human pyrimidine nucleotide biosynthesis as a target for antiviral chemotherapy

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