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Other Fluorinated Pyrimidines in the Treatment of Solid Tumors

Other Fluorinated Pyrimidines in the Treatment of Solid Tumors

ABSTRACT: Researchers, primarily in Japan, Europe, and the United States, have evaluated several new fluorinated pyrimidines in recent years. Most of these drugs are orally active prodrugs of fluorouracil (5-FU), and some also contain modulators of its pharmacological properties. S-1 is a rationally developed combination of tegafur, a prodrug of 5-FU; CDHP, an inhibitor of 5-FU catabolism; and potassium oxonate, an inhibitor of 5-FU-induced diarrhea. S-1 underwent phase I and II trials in Japan, where it is now approved for use in the treatment of advanced gastric cancer. Two phase I studies conducted recently in Europe and the United States identified diarrhea as the dose-limiting toxicity of S-1. BOF-A2, which contains a 5-FU prodrug and CNDP, an inhibitor of 5-FU catabolism, demonstrated clinical activity in preliminary studies in Japan. This article summarizes the preclinical and clinical development of S-1 and BOF-A2. [ONCOLOGY 15(Suppl 2):65-68, 2001]

Introduction

Since its introduction in 1957,
fluorouracil (5-FU) has been used
in the treatment of breast, head and neck, and gastrointestinal malignancies.[1]
The prototype fluorinated pyrimidine, 5-FU works as an antimetabolite to disrupt
nucleic acid synthesis and thus kill cells.[2] 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.

S-1

Pharmacology and Preclinical Evaluation of S-1

S-1 is a combination of 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.[3]
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.[8] After being absorbed by the
gastrointestinal tract, tegafur is converted to 5-FU by the hepatic microsomal
enzyme system.[9] 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.[10] When
CDHP is combined with tegafur, the resulting 5-FU levels are maintained both in
plasma and in tumor tissue.[8]

Gastrointestinal Toxicity

Early research attributed the gastrointestinal toxicity of 5-FU
to its phosphorylation.[11] 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.[12]

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[13], 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.[13]

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.[16]

Phase I Studies of S-1

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.[17] 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.[18] 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.[19] 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.[20]

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.[21] 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

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%.[22] 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.[23]

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.[24] 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.[25]
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.[26] 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.[24] S-1
produced objective responses in 41% of 27 evaluable patients with advanced
breast cancer,[27] and in 46% of 26 evaluable patients with advanced head and
neck tumors.[28]

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