Reduction of 5-fluorouracil (5-FU) gastrointestinal (GI) toxicity resulting from the protection of thymidylate synthase (TS) in GI tissue by repeated simultaneous administration of potassium oxonate (Oxo) in rats

Synthetic procedures are described that allow access to the new complexes cis-[Mo 2 O 5 (apc) 2 ], cis-[WO 2 (apc) 2 ], trans-[UO 2 (apc) 2 ], [Ru(apc) 2 (H 2 O) 2 ], [Ru(PPh 3 ) 2 (apc) 2 ], [Rh(apc) 3 ], [Rh(PPh 3 ) 2 (apc) 2 ]ClO 4 , [M(apc) 2 ], [M(PPh 3 ) 2 (apc)]Cl, [M(bpy)(apc)]Cl (M(II) = Pd, Pt), [Pd(bpy)(apc)Cl], [Ag(apc)(H 2 O) 2 ] and [Ir(bpy)-(Hapc) 2 ]Cl 3 , where Hapc, is 3-aminopyrazine-2-carboxylic acid. These complexes were characterized by physicochemical and spectroscopic techniques. Both Hapc and several of its complexes display significant anticancer activity against Ehrlich ascites tumour cells (EAC) in albino mice.

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“…Group (1) tumour-bearing mice were treated with 5-fu (standard [35]). Group (2) tumour-bearing mice were treated with the compounds of interest.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, characterization and anticancer activity of 3-aminopyrazine-2-carboxylic acid transition metal complexes

Gabr

El-Asmy

Emmam

et al. 2009

Transition Met Chem

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“…28 Oxo is a reversible competitive inhibitor of orotate phosphoribosyltransferase and is reported to concentrate selectively in gastrointestinal tissues after oral administration and suppresses gastrointestinal toxicity induced by phosphoribosylation of 5-FU in the gastrointestinal tract without reducing antitumor activity. 29,30 These features provide S-1 with high efficacy and low toxicity. 30 Moreover, S-1 is an oral anticancer agent, thus having a great advantage for administration without the need for hospitalization.…”

Section: Discussionmentioning

confidence: 99%

“…29,30 These features provide S-1 with high efficacy and low toxicity. 30 Moreover, S-1 is an oral anticancer agent, thus having a great advantage for administration without the need for hospitalization. In Japan, S-1 is widely used for the treatment of gastric cancer, colorectal cancer, pancreatic cancer, neck cancer, cervical cancer, nonsmall cell lung cancer, and breast cancer, and excellent antitumor activity has been reported.…”

Section: Discussionmentioning

confidence: 99%

Pilot study of combination chemotherapy of S‐1, a novel oral DPD inhibitor, and interferon‐α for advanced hepatocellular carcinoma with extrahepatic metastasis

Nakamura

Nagano

Marubashi

et al. 2008

Cancer

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BACKGROUND.To the authors' knowledge, there is no effective therapy for extrahepatic metastasis of hepatocellular carcinoma (HCC). In a pilot study, the results of combination therapy of S‐1, a novel oral dehydropyrimidine dehydrogenase (DPD) inhibitor, and interferon‐alpha (IFN‐α) are reported for HCC patients with extrahepatic metastasis.METHODS.Twelve patients with extrahepatic metastasis of HCC were enrolled in the pilot study. S‐1 was administered orally at a dose based on body surface area, twice daily after a meal, for 4 weeks. IFN‐α was injected subcutaneously on Days 1, 3, and 5 of each week. One course consisted of consecutive administration for 28 days followed by 14 days rest.RESULTS.An objective response was observed in 3 (25%) of 12 patients. The overall 1‐year survival rate was 61.7%. Grade 3 leukocytopenia was observed in 1 patient (8.3%). No severe toxicity or treatment‐related deaths were observed.CONCLUSIONS.The combination therapy of S‐1 and IFN‐α appears to be highly efficacious, with low toxicity in patients with extrahepatic metastases of HCC. The combination chemotherapy of oral S‐1 and subcutaneous IFN‐α is a potentially promising treatment strategy for advanced HCC with extrahepatic metastasis. Cancer 2008. ©2008 American Cancer Society.

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“…7) or 5-chloro-2,4-dihydroxypyridine (CDHP) in the formulation S-1 (8). The latter formulation also contains oxonic acid, which specifically accumulates in the gut inhibiting phosphoribosylation to the active metabolite fluorouridine monophosphate (9). All formulations have shown a comparable antitumor effect compared with i.v.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Food on the Pharmacokinetics of S-1 after Single Oral Administration to Patients with Solid Tumors

Peters¹,

Noordhuis²,

Groeningen³

et al. 2004

Clinical Cancer Research

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Purpose:The purpose is to determine the effect of food on the bioavailability of S-1, an oral formulation of the 5-fluorouracil (5FU) prodrug Ftorafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), a dihydropyrimidine dehydrogenase inhibitor, and oxonic acid (an inhibitor of 5FU phosphoribosylation in normal gut mucosa) in a molar ratio of 1:0.4:1.Experimental Design: Eighteen patients received a single dose of S-1 of 35 mg/m 2 with (535-885 kcal) or without food in a crossover study design: in arm A without breakfast on day ؊7 and with breakfast on day 0 and in arm B the reversed sequence. Blood samples were taken before and after S-1 administration. This food effect was evaluated according to the Food and Drug Administration guidelines using log-transformed data.Results: Pharmacokinetic parameters for 5FU without breakfast were as follows: Tmax, 107 min; Cmax, 1.60 M; area under the plasma concentration-time curve (AUC) 441 M ؋ min; and T 1/2 , 104 min. Fasting decreased Tmax of FT, 5FU, CDHP, and oxonic acid significantly (P < 0.006) and increased the Cmax (P < 0.013). The food/fast ratio for the AUC of FT was not different, which for 5FU was 0.84 (P ‫؍‬ 0.041), for CDHP was 0.89 (P ‫؍‬ 0.191), for oxonic acid was 0.48 (P < 0.0005), and for cyanuric acid, the breakdown product of oxonic acid, was 5.1 (P ‫؍‬ 0.019). Accumulation of uracil, indicative for dihydropyrimidine dehydrogenase inhibition, was not affected, as well as the T 1/2 of FT, 5FU, CDHP, and oxonic acid. Evaluation of the log-transformed data demonstrated that the 90% confidence interval for the food/fast ratio for the Cmax and AUC of FT, 5FU, CDHP, and uracil were within 70 -143% and 80 -125%, respectively, indicating no food effect. Only for oxonic acid and cyanuric acid were these values outside this interval.Conclusions: Food intake affected only the pharmacokinetics of the S-1 constituent oxonic acid but not of FT, CDHP, and 5FU. Because oxonic acid is included to protect against gastrointestinal toxicity, this observation might affect the gastrointestinal toxicity and thus the efficacy of S-1.

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Reduction of 5-fluorouracil (5-FU) gastrointestinal (GI) toxicity resulting from the protection of thymidylate synthase (TS) in GI tissue by repeated simultaneous administration of potassium oxonate (Oxo) in rats

Abstract: Our results suggest that repeated simultaneous administration of Oxo and FT can effectively protect the activity of TS by decreasing FdUMP via FUMP from 5-FU in GI tissue, and may lead to a reduction in GI toxicity.

Cited by 22 publications

References 14 publications

Synthesis, characterization and anticancer activity of 3-aminopyrazine-2-carboxylic acid transition metal complexes

Synthesis, characterization and anticancer activity of 3-aminopyrazine-2-carboxylic acid transition metal complexes

Pilot study of combination chemotherapy of S‐1, a novel oral DPD inhibitor, and interferon‐α for advanced hepatocellular carcinoma with extrahepatic metastasis

The Effect of Food on the Pharmacokinetics of S-1 after Single Oral Administration to Patients with Solid Tumors

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