Dihydropyrimidine Dehydrogenase Activity during Long-Term Adjuvant Treatment with Oral Uracil and Tegafur for Colorectal Cancer

Sadahiro, Sotaro; Suzuki, Toshiyuki; Maeda, Yuji; Ishikawa, Kenji; Tanaka, Yoïchi; Yasuda, Seiei; Kamijo, Akemi; Makuuchi, Hiroyasu; Murayama, Chieko

doi:10.1159/000110016

Cited by 2 publications

(2 citation statements)

References 22 publications

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“…One advantage of oral treatment is patient convenience. Patients can take the medication themselves; there is no need for expensive hospitalization or the discomfort of injection, which is associated with a risk of extravasation or phlebitis [1][2][3] . However, cytotoxic drugs have a narrow therapeutic window; they must often be used at the highest tolerated dose due to their variable bioavailability, which may result in unanticipated toxicities or decreased efficacy when patients' plasma drug concentrations fail to achieve therapeutic levels.…”

Section: Introductionmentioning

confidence: 99%

Gefitinib Increases Serum Concentrations of Oral Irinotecan and SN-38 without Increasing the Biliary Concentration of SN-38 in Rats

et al. 2008

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Background: Gefitinib competes with topoisomerase I inhibitors at drug efflux pumps in vitro. We evaluated the effects of oral gefitinib on pharmacokinetic parameters of orally coadministered irinotecan. Methods: We measured the serum pharmacokinetic parameters and biliary excretion of irinotecan, SN-38 and its glucuronide after irinotecan (50 or 100 mg/kg) was orally administered with or without gefitinib 100 mg/kg to rats. We measured the concentrations of irinotecan and SN-38 in the small intestine, liver, lungs and kidneys in each rat. Results: The plasma area under the curve (0–24 h) of irinotecan and SN-38 was increased significantly, while the apparent elimination constant of irinotecan was decreased significantly. Gefitinib significantly increased the biliary cumulative amounts of irinotecan, but not of SN-38, and also influenced the enterohepatic circulation of irinotecan, but not of SN-38. Conclusions: Gefitinib increased the serum concentrations of irinotecan and SN-38 following oral administration of irinotecan without increasing the biliary excretion of SN-38 in vivo.

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Section: Introductionmentioning

confidence: 99%

Gefitinib Increases Serum Concentrations of Oral Irinotecan and SN-38 without Increasing the Biliary Concentration of SN-38 in Rats

et al. 2008

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“…Several cytotoxic compounds having purine or pyrimidine bases in the molecule, such as azathiopurine 1, 5,6) 5-fluorouracil 2 (5-FU) 7-10) and tegafur 3, 11,12) have been synthesized and used in clinical chemotherapy. In this study, syntheses of anthraquinone derivatives having nucleic acid bases (adenine, thymine, uracil or 5-FU) on the side chain of the anthraquinone skeleton were performed (Fig.…”

Section: Chemical Results and Dicscussionmentioning

confidence: 99%

Preparations of Anthraquinone and Naphthoquinone Derivatives and Their Cytotoxic Effects

Cui

Saito

Kubo

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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Previously, we reported 1) a comparison of the cytotoxic effects of naturally occurring hydroxyanthraquinone derivatives, isolated from the root of Rhubarb (Rheum palmatum (Polygonaceae)) and hydroxynaphthoquinone derivatives, isolated from the roots of Lithosperumum erythrorhizon SIEB. et ZUCC. and Macrotomia euchroma (ROYLE) PAULS. (Boraginaceae), using human colorectal (HCT 116) 2) and human hepatoma (Hep G2) 3) cell lines. In addition, we prepared 1,8-di-O-alkylaloe-emodins and 15-amino-, 15-thiocyano-and 15-selenochrysophanol derivatives from aloe-emodin, which is one of hydroxyanthraquinone compounds isolated from the root of Rhubarb. A comparison of cytotoxic acivities of the derivatives using the same cancer cell lines were also reported. 4)The present study deals with preparations of chrysophanol and 18-di-O-hexylchrysophanol derivatives having various nucleic acid bases at position of 15 from aloe-emodin and 18-di-O-hexylaloe-emodin, respectively. We also synthesize napthoquinone derivatives having various nucleic acid bases, amines, and thiocyanato (-SCN), selenocyanato (-SeCN) and thioacetyl (-SAc) groups on the side chains of the naphthoquinone skeletons derived from menadione (Vitamin K 3 , 2-methylnaphthoquinone). Furthermore, we evaluate the cytotoxic effects of the synthetic derivatives using HCT 116 and Hep G2 cancer cell lines, and compare the effects with those of 5-fluorouracil (5-FU). Chemical Results and DicscussionSeveral cytotoxic compounds having purine or pyrimidine bases in the molecule, such as azathiopurine 1, 5,6) 5-fluorouracil 2 (5-FU) 7-10) and tegafur 3, 11,12) have been synthesized and used in clinical chemotherapy. In this study, syntheses of anthraquinone derivatives having nucleic acid bases (adenine, thymine, uracil or 5-FU) on the side chain of the anthraquinone skeleton were performed (Fig. 1).Firstly, anthraquinone derivatives having the nucleic acid bases at position 15 were synthesized. 1,8-Di-O-hexylaloeemodin 4, which displayed the highest cytotoxic activity of the synthesized 1,8-O-alkylaloe-emodins, 4) was selected as the starting material. The synthesis of tosylate 5 from 4 was previously reported. 13) Compound 5 was reacted with adenine 6, thymine 7, uracil 8 or 5-FU 2 in the presence of NaH in N,N-dimethylformamide (DMF) to give 9, 10, 11 and 12 in 19.5%, 27.9%, 39.7% and 55.9% yield, respectively (Fig. 2). The substituted positions of the nucleic acid bases of compounds 9-12 were confirmed from the heteronuclear multiple bond connectivity (HMBC) spectra shown in Fig. 3. In the spectrum of compound 9, correlations between the proton signals due to the methylene group (CH 2 ) on the anthraquinone residue at d 5.43 and the carbon signal at d 117.2 due to C-4 on the quinone residue and those at d 153. -2-21 Miyama, Funabashi, Chiba 274-8510, Japan. Received July 20, 2010; accepted December 14, 2010 Chrysophanol and 1,8-di-O-hexylchrysophanol derivatives having nucleic acid bases at position 5 were synthesized. Furthermore, derivatives of menadione substitu...

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Dihydropyrimidine Dehydrogenase Activity during Long-Term Adjuvant Treatment with Oral Uracil and Tegafur for Colorectal Cancer

Cited by 2 publications

References 22 publications

Gefitinib Increases Serum Concentrations of Oral Irinotecan and SN-38 without Increasing the Biliary Concentration of SN-38 in Rats

Gefitinib Increases Serum Concentrations of Oral Irinotecan and SN-38 without Increasing the Biliary Concentration of SN-38 in Rats

Preparations of Anthraquinone and Naphthoquinone Derivatives and Their Cytotoxic Effects

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