UFT is an active anticancer drug in patients with colorectal
cancer. UFT is composed of a fixed molar ratio (1:4) of tegafur
and uracil. In this pilot study, with a translational clinical
pharmacology design, previously untreated patients with advanced
colorectal cancer (Table 1)
were treated with UFT plus oral leucovorin (a combination being
developed under the trade name Orzel). Patients were treated for 7
days with UFT (300 mg/m²/d) plus leucovorin (90 mg/d) in three
daily doses. The patients enrolled in this study were candidates for
partial or total resection of tumor.
Tumor and blood samples were obtained less than 1 week before drug
administration and within 1 to 4 hours after the last drug intake (at
time of tumor resection). Approval was obtained from the local ethics
committee and all patients gave informed consent.
Thymidylate synthase (TS) levels were determined by a slightly
modified FdUMP binding assay, and dihydropyrimidine dehydrogenase
(DPD) activity was determined by radioenzymatic assay, using (14C)
fluorouracil (FU) as substrate.[3,4] Drugs and metabolites were
measured by gas chromatography and mass spectrometry (5-FU, m/z =
301; uracil, m/z = 283; fluoro-b-alanine
[FBAL], m/z = 278) or by high-performance liquid chromatography (tegafur).
Table 2 shows the impact of the
7-day UFT treatment on tumor thymidylate synthase levels (FdUMP
binding) and dihydropyrimidine dehydrogenase activity. The rate of
tumoral inhibition after the 7-day UFT treatment sequence varied
between 5% (patient 5) and 31% (patient 4). UFT treatment induced a
systematic decrease in tumor dihydropyrimidine dehydrogenase activity
ranging from 13% (patient 4) to 60% (patient 3). In comparison, the
changes in lymphocytic dihydropyrimidine dehydrogenase activity were
less consistent (only three of six patients exhibited a marked
decrease after UFT treatment).
Table 3 illustrates the
patient-to-patient variations in drug concentrations. UFT treatment
induced a systematic increase in uracil concentrations both in plasma
and tumors. Tegafur, 5-FU, and FBAL were found in plasma and tumors
at variable concentrations; the highest drug concentrations were
those of FBAL in plasma.
This pilot study demonstrated that a short, 7-day sequence of UFT
treatment is able to induce measurable and variable effects on
thymidylate synthase intratumor activity, resulting in 5% to 31%
occupation of thymidylate synthase binding sites and a 13% to 60%
decrease in intratumor dihydropyrimidine dehydrogenase activity. Drug
and metabolite concentrations were detected at variable levels in
both plasma and tumor, with FBAL exhibiting the highest
concentrations in plasma.
1. Sulkes A, Benner SE, Canetta RM: Uracil-Ftorafur: An oral
fluropyrimidine active in colorectal cancer. J Clin Oncol
2. Omura K, Kawakami K, Kanehira E, et al: The number of
5-fluoro-2-deoxyuridine-5-monophosphate binding sites and
reduced folate pool in human colorectal carcinoma tissues: Changes
after tegafur and uracil treatment. Cancer Res 55:3897-3901, 1995.
3. Harris BE, Song R, Soong SJ, et al: Relationship between
dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil
levels with evidence for circadian variation of enzyme activity and
plasma drug levels in cancer patients receiving 5-fluorouracil by
protracted continuous infusion. Cancer Res 50:197-201, 1990.
4. Beck A, Etienne MC, Cheradame S, et al: A role for
dihydropyrimidine dehydrogenase and thymidylate synthase in tumour
sensitivity to fluorouracil. Eur J Cancer 30:1517-1522, 1994.