Persistent induction of apoptosis and suppression of mitosis as the basis for curative therapy with S-1, an oral 5-fluorouracil prodrug in a colorectal tumor model.
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In an effort to improve the therapeutic selectivity of 5-fluorouracil (FUra) against colorectal cancer, S-1, a combination agent including a prodrug of FUra with two modulators, was recently developed by Taiho Pharmaceuticals Co. S-1 is a combination of tegafur (FT), 5-chloro-2,4-hydroxypyridine, and potassium oxonate in the molar ratio of 1.0:0.4:1.0, with the latter two components as inhibitors of dihydropyrimidine dehydrogenase and phosphoribosylpyrophosphate transferase, respectively. In this study, the therapeutic selectivity and efficacy of S-1 (oral) was compared with FT (oral) and FUra (i.v. infusion) in rats bearing advanced colorectal cancer by using clinically relevant schedules. The maximum tolerated doses (MTDs) of S-1, FT, and FUra were 31.5, 200, and 25 mg/kg/d for 7 days and 22.5, 150, and 12.5 mg/kg/d for 28 days, respectively. The therapeutic index of S-1 was 4- to 5-fold higher than that of either FT or FUra. S-1 achieved 100% complete tumor regression (CR) at its MTD in both 7-day and 28-day schedules. Furthermore, the high incidences of stomatitis, alopecia, and diarrhea observed with FUra and FT, were not observed with S-1. In an attempt to understand the basis for the observed superior therapeutic selectivity with S-1, we studied pharmacokinetic analysis of FUra, drug-induced apoptosis, suppression of mitosis, and inhibition of thymidylate synthase (TS) after S-1, FUra, or FT administration. The peak plasma FUra concentrations derived from FUra or S-1 (FT) at comparable MTDs were similar, but the plasma level of FUra was higher with S-1 than with FUra. Induction of high and sustained apoptosis was achieved with S-1. Although the initial level of apoptosis induced by FUra was comparable to S-1, it was not sustained. The sustained level of apoptosis appears to correlate with tumor growth inhibition. Mitotic figures were more greatly suppressed with S-1 treatment than with FUra. Studies on TS inhibition indicated that, although both S-1 and FUra caused a 4- to 6-fold induction of total TS protein, single oral administration of S-1 was superior to 24-h infusion of FUra in suppressing free TS. The data are consistent with the observation that the therapeutic efficacy of S-1 (100% cure) over FUra is associated with high and sustained levels of drug-induced apoptosis, greater suppression of mitosis, and inhibition of free TS in tumor tissues. (+info)
Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor drug.
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S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), which is a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits dihydropyrimidine dehydrogenase (DPD) activity; and potassium oxonate (Oxo), which reduces gastrointestinal toxicity. Phase I and early Phase II clinical trials have already been completed. On the basis of the results of these trials, 80 mg/m2/day, given daily in two divided doses after breakfast and supper, a 28-day consecutive oral regimen is recommended. In this study, we investigated the pharmacokinetics of 5-FU, intact FT, CDHP, and Oxo, after administration of S-1, at a standard dose of 80 mg/m2/day, in advanced cancer patients. Twelve patients were recruited to the study; 5 patients with gastric cancer, 4 with colorectal cancer, and 3 with breast cancer. Among them, analysis was conducted on 12 patients for single administration and on 10 patients for consecutive administration. The initial dose of S-1 for each patient was determined according to his/her body surface area (BSA) as follows: for BSA < 1.25 m2, 80 mg/body/day; for 1.25 m2 < or = BSA < 1.5 m2, 100 mg/day; and for 1.5 m2 < or = BSA, 120 mg/day. For single administration, half of the standard dose was used. For 28-day consecutive administration, the standard dose was given daily in two divided doses. The average single dose per BSA was 35.9 mg/m2 (31.7-39.7 mg/m2). Pharmacokinetic parameters of plasma 5-FU were as follows: Cmax, 128.5 +/- 41.5 ng/ml; Tmax, 3.5 +/- 1.7 h; AUC(0-14), 723.9 +/- 272.7 ng x h/ml; and T(1/2), 1.9 +/- 0.4 h. In the 28-day consecutive regimen, there were no fluctuations in pharmacokinetics nor any drug accumulation. Because the pharmacokinetics of orally administered S-1 is almost similar to that of continuous i.v. infusion of 5-FU, we concluded that S-1 may improve patients' quality of life. (+info)
Complete response of a gastric primary after a short but toxic course of 'S-1' EORTC Early Clinical Studies Group.
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We report the case of an unresected, metastatic gastric cancer, which was treated with a very short course of the oral 5-fluorouracil (5-FU) prodrug S-1. The patient had to discontinue chemotherapy during the first treatment cycle due to severe toxicity, but achieved a pathologically confirmed, long-term complete response of her primary tumour, a diffuse-type poorly differentiated adenocarcinoma. (+info)
Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors.
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PURPOSE: To investigate the side effects, determine the maximum-tolerated dose (MTD), and study the pharmacokinetics of S-1, an oral fluoropyrimidine-based antineoplastic agent consisting of the fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. PATIENTS AND METHODS: Patients with advanced solid tumors received S-1 bid for 28 days, followed by 1 week of rest. 5-FU pharmacokinetics were investigated after a single initial dose of S-1 during the first 24 hours and weekly thereafter. RESULTS: Twenty-eight patients received S-1 at the four consecutive dose levels of 25, 45, 35, and 40 mg/m(2). The MTD was initially found at 45 mg/m(2), with diarrhea as the dose-limiting toxicity (DLT). Diarrhea was also the DLT at the dose of 40 mg/m(2), which was the MTD for patients exposed to extensive prior chemotherapy. Other toxicities were generally mild. Two patients had a reduction of more than 50% in tumor dimension. Plasma pharmacokinetics of 5-FU were linear; at the highest S-1 dose level, 5-FU plasma peak concentrations reached 1 to 2 micromol/L, and the half-life of 5-FU was 3 to 4 hours. A statistically significant relationship was observed between the severity of diarrhea and pharmacokinetic parameters of 5-FU. CONCLUSION: The recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m(2) bid on 28 consecutive days, every 5 weeks. In heavily pretreated patients, the recommended dose is 35 mg/m(2) bid. Phase II trials are warranted in tumors known to be responsive to 5-FU treatment. (+info)
Phase II study of S-1, a novel oral fluorophyrimidine derivative, in patients with metastatic colorectal carcinoma. S-1 Cooperative Colorectal Carcinoma Study Group.
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This study set out to evaluate, in patients with metastatic colorectal carcinoma, the efficacy and toxicity of S-1, which contains tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate, based on a biochemical modulation of 5-fluorouracil (5-FU) targeted at inhibition of dihydropyrimidine dehydrogenase (DPD). Sixty-three patients with measurable metastatic colorectal carcinoma were enrolled into the study. None of the patients had received prior chemotherapy except for adjuvant setting. S-1 was administered orally twice daily at a standard dose of 80 mg m(-2) day(-1) for 28 days followed by a 14-day rest. This agent is continued until disease progression, unaccepted toxicity, or patient refusal. Twenty-two (35%) of the 62 eligible patients achieved PR with a 95% confidence interval of 25-48%. Five of the 10 patients with a history of adjuvant chemotherapy achieved partial remission. The median survival time was 12 months. Major adverse reactions included myelosuppressive and gastrointestinal toxicities, though their incidence of grade 3 or 4 being 13% in neutropenia and less than 10% in the others. None of the 53 patients treated as outpatients required hospitalization due to adverse reactions: These results suggest that S-1 achieves similar responses to those of infusional 5-FU plus leucovorin and shows the potential of another biochemical modulation with easily manageable toxicity. (+info)
Tissue distribution and biotransformation of potassium oxonate after oral administration of a novel antitumor agent (drug combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate) to rats.
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S-1, a new oral 5-fluorouracil (5-FU)-derivative antitumor agent, is composed of tegafur, 5-chloro-2,4-dihydropyridine, and potassium oxonate (Oxo). Oxo, which inhibits the phosphorylation of 5-FU, is added to reduce the gastrointestinal (GI) toxicity of the agent. In this study, we investigated the tissue distribution and the metabolic fate of Oxo in rats after oral administration of S-1. Oxo was mainly distributed to the intracellular sites of the small intestines in a much higher concentration than 5-FU, but little distributed to other tissues, including tumorous ones in which 5-FU was observed after oral administration of S-1. Plasma concentration-time profiles of Oxo and its metabolites after i.v. and oral administration of S-1 revealed that Oxo was mainly converted to cyanuric acid in the GI tract. Furthermore, the analysis of drug-related radioactivity in GI contents and in vitro studies suggested that Oxo was converted to cyanuric acid by two routes, the first being direct conversion by the gut flora in the cecum, and the second, conversion by xanthine oxidase or perhaps by aldehyde oxidase after degradation to 5-azauracil (5-AZU) by the gastric acid. These results indicate that, although a part of the administered Oxo was degraded in the GI tract, Oxo was mainly distributed to the intracellular sites of the small intestines in a much higher concentration than 5-FU and that little was distributed to other tissues, including tumors. We conclude that this is the reason why Oxo suppresses the GI toxicity of 5-FU without affecting its antitumor activity. (+info)
Effects of 5-fluorouracil on the drug-metabolizing enzymes of the small intestine and the consequent drug interaction with nifedipine in rats.
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5-Fluorouracil (5-FU) is a widely used antineoplastic agent. 5-FU therapy often causes gastrointestinal toxicity, which is suppressed by concomitant administration of potassium oxonate (Oxo). Here, we investigated the effect of 5-FU on the small-intestinal drug-metabolizing enzymes, which play important roles in the first-pass metabolism of drugs, in rats, by enzyme measurements and immunoblot analyses. During repeated administration of a combination of 1-(2-tetrahydrofuryl)-5-fluorouracil, an oral 5-FU-derivative drug, and 5-chloro-2,4-dihydroxypyridine (FCD), an inhibitor of 5-FU degradation, the activities of 7-ethoxyresorufin-O-deethylase, testosterone 6beta-hydroxylase, 4-methylumbelliferone UDP-glucuronyltransferase, and 1-chloro-2,4-dinitrobenzene glutathione S-transferase decreased significantly on day 4, and the activity of NADPH-cytochrome P450 (CYP) reductase decreased significantly on day 7. These effects were found to be attributable to a reduction in the enzyme protein contents in the small-intestinal mucosa. The enzymatic alterations significantly increased the plasma concentrations of orally administered nifedipine, which was prevented by concomitant administration of Oxo with FCD. However, consecutive administration of FCD for 4 days did not cause any alterations in the activity of the hepatic CYP isozyme-supported testosterone hydroxylase. These results suggest that continuous exposure to 5-FU leads to a decrease in the activities of drug-metabolizing enzymes in the intestinal mucosa by decreasing their enzyme protein contents, and increases the plasma concentrations of orally administered nifedipine, and that the sensitivity of these enzymes to the drug is greater than that of the enzymes of the liver. These effects were prevented by concomitant administration of Oxo. (+info)
Case report: hand-foot syndrome induced by the oral fluoropyrimidine S-1.
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Hand-foot syndrome (HFS) is a relatively common side effect of fluorouracil (5-FU) chemotherapy that has also been associated with the oral fluoropyrimidine capecitabine. Interestingly, HFS is virtually unknown to result from treatment with UFT, a combination of tegafur and uracil. Tegafur is a prodrug of 5-FU and is a component of S-1, another oral fluoropyrimidine active in a variety of solid tumors. We know of only one previously described case of S-1-induced HFS and the case reported here is the first to provide full documentation of this occurrence. The pathophysiology of chemotherapy-induced HFS remains unknown and very little pathological information is available. Treatment consists of topical emollient therapy, although pyridoxine has occasionally been beneficial. The study of HFS may provide an important insight into the pharmacology of fluoropyrimidines and allow for effective preventive strategies for this side effect of chemotherapy. (+info)