Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators

Shirasaka, Tetsuhiko; Shimamato, Yuji; Ohshimo, Hideyuki; Yamaguchi, Masahiro; Kato, Toshiyuki; Yonekura, Kazuya; Fukushima, Masakazu

doi:10.1097/00001813-199607000-00010

Cited by 746 publications

(482 citation statements)

References 0 publications

Supporting

Mentioning

474

Contrasting

Unclassified

Order By: Relevance

“…S-1 (TS-1 ® ) is an oral anticancer drug containing tegafur (FT), a prodrug of Xuorouracil (5-FU) combined with two modulators, 5-chloro-2,4-dihydroxypyridine (gimeracil, CDHP) and oteracil potassium (Oxo), in a molar ratio of 1:0.4:1 [10]. CDHP competitively inhibits dihydropyrimidine dehydrogenase (DPD), a key enzyme of 5-FU degradation, in a reversible manner, to maintain high 5-FU concentrations in plasma and tumors over a long period of time.…”

Section: Introductionmentioning

confidence: 99%

Effect of gastrectomy on the pharmacokinetics of S-1, an oral fluoropyrimidine, in resectable gastric cancer patients

Kochi

Fujii

Kanamori

et al. 2007

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

Purpose The eVect of gastrectomy on pharmacokinetics after S-1 administration was investigated. Patients and methods A dose of 40 mg/m 2 of S-1 was administered orally twice daily for 7 days (80 mg/m 2 / day) preoperatively in ten patients with resectable gastric cancer, and the same dose of S-1 was administered for 28 consecutive days after gastrectomy. Plasma concentrations of tegafur, gimeracil, and oteracil potassium, all the components of S-1, and 5-FU were measured on pre-and postoperative days. Concentrations of 5-FU in tumor and normal tissues were also determined. Results At day 4 from the initial preoperative administration of S-1, the AUC of 5-FU was 1,055 § 304 ng h/ ml. At day 18, day 28, and day 42 after gastrectomy, it was 1,012 § 331, 1,070 § 403, and 946 § 226 ng h/ml, respectively. No signiWcant diVerences for plasma 5-FU were observed between pre-and postoperative days. In the resected tumor tissues, concentrations of 5-FU were 242 § 83 ng/g around 4.5 h and 91.7 § 37.0 ng/g around 20 h after the Wnal administration, respectively. Conclusion Gastrectomy does not aVect on pharmacokinetics of 5-FU derived from S-1 regardless of partial or total gastrectomy, indicating that S-1 can be a useful drug in postoperative adjuvant chemotherapy for gastric cancer.

show abstract

Section: Introductionmentioning

confidence: 99%

Effect of gastrectomy on the pharmacokinetics of S-1, an oral fluoropyrimidine, in resectable gastric cancer patients

Kochi

Fujii

Kanamori

et al. 2007

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

show abstract

“…The recent introduction of a new oral drug, S-1 (Shirasaka et al, 1996), which was developed on the basis of biochemical modulation to inhibit dihydropyrimidine dehydrogenase and orotate phosphoribosyltransferase to therapeutic modality for gastric cancer, has enabled us to increase ORR to 46 -74% and MST to 10.9 -14.8 months by its combination with cisplatin (CDDP), docetaxel or CTP-11, with less toxicity than 5-FU (Koizumi et al, 2003;Ajani et al, 2006;Inokuchi et al, 2006;Yamaguchi et al, 2006).…”

mentioning

confidence: 99%

Phase I study of S-1, docetaxel and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer

et al. 2007

View full text Add to dashboard Cite

The aim of this dose escalation study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs) and preliminary efficacy of docetaxel, S-1 and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer. Seventeen patients received oral S-1 (40 mg m À2 bid) on days 1 -14, intravenous cisplatin (60 mg m À2 ) and docetaxel (60, 70 or 80 mg m À2 depending on DLT) on day 8 every 3 weeks. The MTD of this combination was presumed to be docetaxel 70 mg m À2 . At this dose level, 40% of the patients (two of five) developed grade 4 neutropenia and 20% (one of five) exhibited grade 3 nausea during the first course. Therefore, the recommended dose of docetaxel was defined as 60 mg m À2 . The DLT was neutropenia. The response rate (RR) was 88.2% (15 of 17), consisting of one complete response and 14 partial responses. There were two stable diseases but no progressive disease. Of these 15 responders, four (23.5%) with high VEGF expression showed rapid tumour regression and achieved downstaging, leading to subsequent curative gastrectomy. Three of these have been disease free for about 3 years, suggesting a complete cure. In conclusion, this regimen was tolerable and showed a quite high RR, with an appreciable downstaging rate in metastatic gastric cancer.

show abstract

“…The anticancer drug S-1 (TS-1 s , Taiho Pharmaceutical Co. Ltd., Tokyo, Japan) is an oral formulation containing within each capsule tegafur, a 5-FU prodrug; gimeracil, an inhibitor of dihydropyrimidine dehydrogenase; and oteracil, which inhibits pyrimidine phosphoribosyl transferase specifically in the gastrointestinal tract and thereby decreases the phosphorylation of 5-FU in the intestine (Shirasaka et al, 1996). Phase II studies of S-1 monotherapy in patients with advanced GC showed overall response rates (ORRs) of 26-49% with the most relevant side-effects being diarrhoea in a European study and neutropenia in two Japanese studies Koizumi et al, 2000;Chollet et al, 2003).…”

mentioning

confidence: 99%

Phase I/II study of docetaxel and S-1 in patients with advanced gastric cancer

et al. 2006

View full text Add to dashboard Cite

The aims of this phase I/II study of docetaxel and S-1 were to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and recommended dose (RD) in the phase I part and to explore the tumour response, survival and safety in the phase II part. Patients with histologically-or cytologically confirmed unresectable or recurrent gastric cancer were eligible. Treatment consisted of intravenous docetaxel on day 1 (starting dose 50 mg m À2 ) and oral S-1 at a fixed dose of 40 mg m À2 twice daily on days 1 -14, every 4 weeks up to six cycles. Nine patients took part in the phase I portion of the study. The MTD of docetaxel was determined to be 50 mg m À2 , with the DLTs of grade 3 infection associated with grade 3 neutropenia and grade 4 neutropenia during S-1 administration. The RD of docetaxel was 40 mg m À2 in combination with S-1 40 mg m À2 b.i.d. The efficacy and safety of this regimen was therefore assessed in 46 patients with at least one measurable lesion. The overall response rate and estimated median overall survival were 46% (95% CI, 31 -61%) and 14.0 months (8.3 -17.3 months), respectively. The most common grade 3/4 toxicity was neutropenia (67% of patients), which was predictable and manageable. This regimen showed promising activity with moderate toxicities in advanced gastric cancer.

show abstract

Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators

Cited by 746 publications

References 0 publications

Effect of gastrectomy on the pharmacokinetics of S-1, an oral fluoropyrimidine, in resectable gastric cancer patients

Effect of gastrectomy on the pharmacokinetics of S-1, an oral fluoropyrimidine, in resectable gastric cancer patients

Phase I study of S-1, docetaxel and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer

Phase I/II study of docetaxel and S-1 in patients with advanced gastric cancer

Contact Info

Product

Resources

About