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.
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.
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)
UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice.
UFT, an anticancer agent that is composed of tegafur (FT) and uracil at a molar ratio of 1:4, is widely used in clinical practice in Japan to treat cancer patients requiring a long-term chemotherapy, and it is associated with few side effects, if any. In this study, we have evaluated the inhibitory effect of UFT against RENCA cell-induced angiogenesis by a dorsal air sac assay. Marked angiogenesis is induced by implantation of a chamber containing RENCA cells into mice. In this model, UFT showed a strong angiogenesis-inhibitory effect, whereas 5-fluorouracil (5-FU) and doxifluridine were less effective. Additional experiments revealed FT to be effective component of UFT; uracil remained ineffective in the inhibition of angiogenesis. Moreover, we have found that gamma-hydroxybutyric acid and gamma-butyrolactone, the metabolites of FT, possess a potent angiogenesis inhibitory effect that is amplified when the compounds are administered by a continuous infusion. This may reflect a transition in blood concentration of each metabolite resulting from the administration of UFT. Similar results were also obtained with respect to 5-FU. It was suggested that UFT has a stronger angiogenesis-inhibitory effect than did other fluorinated pyrimidines, partly due to its pharmacokinetic properties characterized by maintaining of higher and long-lasting blood levels of 5-FU and partly due the inhibitory effects derived from gamma-hydroxybutyric acid and gamma-butyrolactone, UFT-specific metabolites. (+info)
The oral fluoropyrimidines in cancer chemotherapy.
A classic example of a rationally developed class of anticancer drugs, the fluoropyrimidines are now the focus of further rational approaches to cancer chemotherapy as they are transformed into oral formulations. Given alone, oral 5-fluorouracil (5-FU) has erratic absorption and nonlinear pharmacokinetics. However, when oral 5-FU is given as a prodrug and/or paired with a dihydropyrimidine dehydrogenase inhibitor, the resultant 5-FU has linear pharmacokinetics that may approximate the less myelosuppressive continuous i.v. infusion schedule of 5-FU administration without the use of infusion catheters and pumps. We review the preclinical and clinical experience of several of the oral fluoropyrimidines. (+info)
A review of the pharmacology and clinical activity of new chemotherapy agents for the treatment of colorectal cancer.
Colorectal carcinoma is an important cause of cancer morbidity and mortality. 5-fluorouracil has been the major chemotherapeutic agent for the treatment of colorectal carcinoma for the past four decades. This regimen is noncurative, and its impact on survival is unclear. Attempts at identifying more effective chemotherapeutic agents for colorectal cancer have yielded oral formulations and prodrugs of 5-fluorouracil with apparently equivalent efficacy. Specific thymidylate synthase inhibitors are now available. Platinum analogues with activity in colorectal carcinoma, and no cross-resistance to the antimetabolites have also been developed. The topoisomerase I inhibitors represent a new class of agents with a novel mechanism of action. These agents are in phase II and Phase III clinical trials, others have been approved for clinical use within the last 3 years. (+info)
Complete response of a gastric primary after a short but toxic course of 'S-1' EORTC Early Clinical Studies Group.
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)
Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer.
PURPOSE: The efficacy of adjuvant chemotherapy in gastric cancer is controversial. We conducted a phase III, randomized, multicentric clinical trial with the goal of assessing the efficacy of the combination of mitomycin plus tegafur in prolonging the disease-free survival and overall survival of patients with resected stage III gastric cancer. PATIENTS AND METHODS: Patients with resected stage III gastric adenocarcinoma were randomly assigned, using sealed envelopes, to receive either chemotherapy or no further treatment. Chemotherapy was started within 28 days after surgery according to the following schedule: mitomycin 20 mg/m(2) intravenously (bolus) at day 1 of chemotherapy; 30 days later, oral tegafur at 400 mg bid daily for 3 months. Disease-free survival and overall survival were estimated using the Kaplan-Meier analysis and the Cox proportional hazards model. RESULTS: Between January 1988 and September 1994, 148 patients from 10 hospitals in Catalonia, Spain, were included in the study. The median follow-up period was 37 months. The tolerability of the treatment was excellent. The overall survival and disease-free survival were higher in the group of patients treated with chemotherapy (P =.04 for survival and P =.01 for disease-free survival in the log-rank test). The overall 5-year survival rate and the 5-year disease-free survival rate were, respectively, 56% and 51% in the treatment group and 36% and 31% in the control group. CONCLUSION: Our positive results are consistent with the results of recent studies; which conclude that there is a potential benefit from adjuvant chemotherapy in resected gastric cancer. (+info)
Epirubicin, cisplatin and oral UFT with leucovorin ('ECU'): a phase I-II study in patients with advanced upper gastrointestinal tract cancer.
BACKGROUND: ECF (epirubicin, cisplatin, protracted venous fluorouracil) is superior to FAMTX in gastroesophageal cancer, but protracted fluorouracil adds to its morbidity and cost. In this dose-escalation pilot study, fluorouracil was replaced by oral UFT and leucovorin. PATIENTS AND METHODS: Thirty unpretreated patients with advanced upper gastrointestinal cancers received epirubicin 50 mg/m2 and cisplatin 60 mg/m2 i.v. on day 1, and leucovorin 45 mg p.o. on days 1, 8 and 15, of a 21-day cycle for up to 8 cycles. UFT was taken 12-hourly throughout, at escalating doses in four cohorts ranging from 150-325 mg/m2 per day. RESULTS: The maximum tolerable dose of UFT, recommended for further study, was 200 mg/m2 per day. At higher doses, more than two-thirds patients required dose reductions, although mostly for persistent mild (CTC grade 2) nausea, diarrhoea or fatigue, rather than for severe acute toxicity. Myelotoxicity was mild. Twenty patients, including 15 with gastroesophageal cancer, had assessable disease. Among these there were nine WHO objective responses, all in gastroesophageal patients, including two radiological complete responses. CONCLUSIONS: ECU is well tolerated at the defined dose, with activity comparable to ECF in gastroesophageal cancer. UFT and other oral 5FU dosing strategies make promising components of combination chemotherapy, deserving further, randomised evaluation. (+info)