Since its introduction in 1957, fluorouracil(Drug information on fluorouracil) (5-FU) has been used in the treatment of breast, head and neck, and gastrointestinal malignancies. The prototype fluorinated pyrimidine, 5-FU works as an antimetabolite to disrupt nucleic acid synthesis and thus kill cells. Over the past few years, researchers have developed and tested several new oral fluorinated pyrimidines, which are starting to gain wider application. Most of these agents are oral prodrugs of 5-FU, and some also contain biochemical modulators of 5-FU. Two of these prodrugs, S-1 and BOF-A2, have shown promising preliminary results. This article summarizes the preclinical and clinical development of S-1 and BOF-A2.
Pharmacology and Preclinical Evaluation of S-1
S-1 is a combination of tegafur(Drug information on tegafur), 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (potassium 1,3,5-triazine-2,4(1H,3H)-dione-6-carboxylate) at a fixed molar ratio of 1:0.4:1. Tegafur (5-fluoro-1-(tetrahydro-2-furanyl)-2,4-(1H,3H)-pyrimidinedione), a prodrug of 5-FU, was developed in the former Soviet Union and introduced in 1967. Evaluation of tegafur in the 1970s by the United States National Cancer Institute revealed that, when administered by short intravenous infusion, the drug caused significant gastrointestinal and neurologic toxicity despite demonstrated activity in a variety of solid tumors.[4,5] Because tegafur is well absorbed via the oral route, Japanese investigators pursued an alternative strategy of prolonged oral administration. Further development of tegafur took place mainly in Japan, although researchers in the United States conducted additional phase I and II studies of oral tegafur.[6,7]
The development of S-1 represents a rational approach to the pharmacologic modulation of fluoropyrimidines. After being absorbed by the gastrointestinal tract, tegafur is converted to 5-FU by the hepatic microsomal enzyme system. CDHP reversibly inhibits dihydropyrimidine dehydrogenase (DPD), the chief enzyme regulating 5-FU degradation. In vitro, CDHP is almost 200 times more potent than uracil, another reversible inhibitor of DPD. When CDHP is combined with tegafur, the resulting 5-FU levels are maintained both in plasma and in tumor tissue.
Early research attributed the gastrointestinal toxicity of 5-FU to its phosphorylation. In animal models, potassium oxonate inhibits the activity of orotate phosphoribosyltransferase, the enzyme that catalyzes 5-FU phosphorylation in the gastrointestinal tract, thus leading to decreased gastrointestinal toxicity without loss of antitumor activity.
Researchers in Japan conducted preclinical evaluation of S-1 and demonstrated its antitumor activity in experimental models of rodent tumors and human xenografts. S-1 significantly inhibited tumor growth in rats with subcutaneous Yoshida sarcoma, and in rats and nude mice orthotopically implanted with human colon cancer cell lines.[14,15] The animal studies also confirmed that the gastrointestinal toxicity of S-1 is low, most likely because of the protection afforded by potassium oxonate.
Pharmacological data derived from these studies indicated high concentrations of 5-FU in the plasma and tumor tissue of animals treated with oral S-1. In addition, S-1 compared favorably with intravenous 5-FU, showing similar levels of tumor inhibitory activity and gastrointestinal toxicity.
Phase I trials of S-1 have been conducted in Japan, Europe, and the United States. Japanese investigators administered S-1 for 28 consecutive days, followed by a 14-day rest period. In a phase I study using two dosing schedules of S-1, Taguchi et al identified the maximum tolerated doses as 75 to 100 mg twice daily or 150 to 200 mg once daily. Toxicity was mainly hematologic, and gastrointestinal side effects were generally mild.
In another phase I study, Hirata et al treated 12 patients with fixed doses prespecified according to body surface area. Patients with a body surface area < 1.25 m2 received 40 mg twice daily; those with a body surface area of 1.25 to 1.5 m2 received 50 mg twice daily; and those with a body surface area > 1.5 m2 received 60 mg twice daily. Dose escalation was not included in the protocol of this study; rather the primary objective was to investigate the pharmacokinetics of S-1. The only grade 3 or 4 toxicity was hematologic and occurred in three patients.
Dosing Based on Actual Measurement vs Body Surface Area
Phase I studies of S-1 conducted in Europe and the United States employed a dosing schedule based on actual body surface areas. The European Organization for the Research and Treatment of Cancer (EORTC) reported the preliminary findings of a phase I study of S-1. Fifteen patients received the drug for 28 days, followed by a 7-day rest period. The starting dose was 25 mg/m2 twice daily, and dose-limiting toxicity was reached, at 45 mg/m2 twice daily. Although the Japanese study reported only mild gastrointestinal side effects, the EORTC data identified grade 3 or 4 diarrhea as the primary dose-limiting toxicity. An analysis of 13 of 28 patients receiving 25, 35, 40, or 45 mg/m2 once daily showed linear pharmacokinetics for S-1 components, such as 5-FU and CDHP, and for endogenous uracil.
We, at The University of Texas M. D. Anderson Cancer Center, conducted a phase I study of S-1 administered for 28 days, followed by a 7-day rest period. Consecutive cohorts of patients received escalating doses of S-1. The starting dose of 30 mg/m2 twice daily was found to be the maximum tolerated dose, and, as in the EORTC study, diarrhea was the dose-limiting toxicity. In contrast to the findings of the Japanese study, our study documented infrequent hematologic toxicity. The pharmacokinetic profiles of S-1 constituents suggested linear kinetics, and measurement of endogenous uracil confirmed the transient nature of DPD inhibition.
Phase II studies of S-1 conducted in Japan used a fixed-dose schedule adjusted to the ranges of body surface areas. Three trials among patients with advanced gastric cancer were reported. In a study of 51 patients with no history of previous chemotherapy, Sakata et al documented an objective response rate of 49%. In a second study, reported in abstract form, 50 patients evaluable for efficacy demonstrated an overall response rate of 40%, confirming the activity of S-1 in advanced gastric cancer.
Sugimachi et al treated 28 patients, of whom 9 had received previous chemotherapy. Objective responses, documented in 12 of 23 patients (52%) with measurable disease, did not differ, irregardless of whether patients had or had not received prior chemotherapy. Based on the good results observed in patients with advanced gastric cancer treated with S-1, the drug received approval for this indication in Japan.
The EORTC Early Clinical Studies Group has launched an early phase II study of S-1 in patients with advanced/metastatic gastric and colorectal cancer. It recently reported that a patient with gastric cancer who could only tolerate only one cycle of S-1 therapy experienced a durable complete pathologic response in the primary tumor, with stable metastatic disease. Although anecdotal, the experience with this patient clearly illustrates the activity of the drug and suggests that it should be evaluated further in disease-specific settings.
Phase II studies of S-1 in patients with other types of solid tumors have yielded promising results. S-1 produced an overall response rate of 36% in 62 patients with previously untreated, advanced colorectal cancer. In another trial of S-1 in 29 patients with measurable advanced colorectal cancer, only 4 (14%) responded. However, in the latter study, 25% of patients (4 of 16), who had not received prior chemotherapy, achieved a partial response. S-1 produced objective responses in 41% of 27 evaluable patients with advanced breast cancer, and in 46% of 26 evaluable patients with advanced head and neck tumors.