Hyperthermia enhances the inhibition of tumor growth by 1-(2-tetrahydrofuryl)-5-fluorouracil/uracil (1:4) in tumors in mice and humans.

The cytotoxicity of several antitumor drugs is enhanced by hyperthermia (HT). Using mouse Sarcoma-180 (S-180) tumors, the authors examined the effects of 5-fluorouracil (5-FU) and a combined oral preparation of 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) and uracil in a molar ratio of 1:4 (UFT), in combination with HT. The antitumor effect of 5-FU was not enhanced significantly by HT. Growth inhibition by UFT plus HT was significantly greater than that by UFT alone, whereas inhibition by UFT alone was significantly greater than that by 5-FU. The intracellular metabolism of 5-FU and FT in whole homogenates of S-180 cells, human tumor cell lines (SC-2 and Lu-99), and five fresh human tumor tissues also was investigated. Conversion of FT to 5-FU, phosphorylation, and degradation of 5-FU were assayed with [3H]FT or [3H]5-FU, and the products were separated by thin-layer chromatography. The conversion of FT to 5-FU and the phosphorylation of 5-FU were more rapid at 43 degrees C than at 37 degrees C, whereas the degradation of 5-FU to 2-fluoro-beta-alanine remained unchanged. This acceleration of the active metabolism of FT and 5-FU may be one explanation for the enhanced effect of UFT by HT.     

Sensitivity test for 5-fluorouracil and its analogues, 1-(2-tetrahydrofuryl)-5-fluorouracil, uracil/1-(2-tetrahydrofuryl)-5-fluorouracil (4:1) and 1-hexylcarbamoyl-5-fluorouracil, using the subrenal capsule assay

The chemosensitivity of 20 human neoplastic tissues including 13 gastric and 7 colorectal cancers was tested using 5-fluorouracil (5-FU) and its analogues: 1-(2-tetrahydrofuryl)-5-FU (FT), uracil/FT (UFT) and 1-hexylcarbamoyl-5-FU (HCFU), and the in vivo subrenal capsule (SRC) assay. The relative variation of tumor size (delta TS/TSo) was calculated as follows: delta TS/TS0 = (TS6-TS0/TS0) x 100%, where TS6 was the tumor size on day 6 and TS0 on day 0, and the chemosensitivity was considered to be sensitive when delta TS/TS0 in the treated group was decreased to below -10%. The mean tumor size was -10.9 +/- (SD) 10.9% for 5-FU, -12.3 +/- 17.1% for FT, -18.4 +/- 15.8% for UFT and -17.9 +/- 15.4% for HCFU. The decrease of tumor size was marked when exposed to UFT (p less than 0.01) or HCFU (p less than 0.02), compared with that to 5-FU. Positive correlations were noted between the tumor sizes of 5-FU and its analogues (5-FU vs. FT, r = 0.851; 5-FU vs. UFT, r = 0.746; 5-FU vs. HCFU, r = 0.685). In 9 tissues resistant to 5-FU, 2 (22%) were sensitive to FT, 4 (44%) to UFT, 5 (56%) to HCFU and 7 tissues (78%) to at least one of these analogues. These results suggest that the SRC assay is useful for predicting the effective drug among 5-FU and 5-FU analogues, for individual patients with cancer.     

Continuous Intravenous Administration of l-(2-Tetrahydrofuryl)-5-Fluorouracil [FT] by Intravenous Hyperalimentation (IVH) -- Stability of FT in IVH Solution and Tumor Levels of 5-Fluorouracil (5-FU) --

The continuous intravenous administration of l-(2-tetrahydrofuryl)-5-fluorouracil(FT) to colorectal cancer patients was studied in regard tothe stability of FT in intravenous hyperalimentation (IVH) solutionsand tumor levels of 5-fluorouracil (5-FU). FT was very compatiblewith IVH solutions, because the decomposition of FT in IVH solutionwas very low, 3%. High levels of 5-FU, which is an active metaboliteof FT, were obtained in the tumors, averaging 0.369 mcg/g. Theratios of 5-FU levels in the tumor to those in serum and normaltissues were 13.6 and 3.7. respectively. The difference in 5-FUlevels between normal tissues and the tumors was statisticallysignificant (P<0.01). Therefore, continuous intravenous administrationof FT should be widely used to treat patients with colorectalcancer, as the method of administration of antitumor agents.     

Continuous intravenous administration of 1-(2-tetrahydrofuryl)-5-fluorouracil [FT] by intravenous hyperalimentation (IVH)--stability of FT in IVH solution and tumor levels of 5-fluorouracil (5-FU)

The continuous intravenous administration of 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) to colorectal cancer patients was studied in regard to the stability of FT in intravenous hyperalimentation (IVH) solutions and tumor levels of 5-fluorouracil (5-FU). FT was very compatible with IVH solutions, because the decomposition of FT in IVH solution was very low, 3%. High levels of 5-FU, which is an active metabolite of FT, were obtained in the tumors, averaging 0.369 mcg/g. The ratios of 5-FU levels in the tumor to those in serum and normal tissues were 13.6 and 3.7, respectively. The difference in 5-FU levels between normal tissues and the tumors was statistically significant (P less than 0.01). Therefore, continuous intravenous administration of FT should be widely used to treat patients with colorectal cancer, as the method of administration of antitumor agents.     

Relationship of in vivo antitumor activities of fluorinated pyrimidines to thymidylate synthase activity and intratumoral concentrations of 5-fluorouracil and uracil

MOPC-104E plasmacytomas were subcutaneously transplanted into BALB/c mice and after 7 days the mice were administered different fluorinated pyrimidines at 4 times the clinical doses, 5-fluorouracil (5-FU, 15 mg/kg), tegafur (FT, 100 mg/kg) or UFT (FT, 20 mg/kg + uracil, 44.8 mg/kg) daily for 7 days. Tumor growth was most effectively inhibited in the UFT group. The % inhibition of tumor growth on day 14, while not correlating with the concentration of 5-FU in the tumor, negatively correlated with the concentration of uracil, which was lowest in the UFT group. The activity of thymidylate synthase (TS) was measured using a 5-fluoro-deoxyuridine monophosphate (FdUMP) binding assay. The total and free TS activities in the tumor negatively correlated with the % inhibition of tumor growth, and were lowest in the UFT group. However, the % inhibition of TS activity in the tumor, which was about 80% in all 3 groups, did not correlate with the tumor-inhibitory effect. These results suggest that uracil in the tumor may play an important role in the metabolism of fluorinated pyrimidines, and that exogeneously administered uracil may decrease the amounts of uracil and TS in the tumor, and subsequently cause 5-FU accumulation.     

5-FU concentration in blood and tissue of patients with renal cell carcinoma after administration of UFT

UFT (3 capsules; 300mg FT) was administered to five of 10 patients with renal cell carcinoma, and concentrations of FT, 5-FU and uracil in the serum and tissues (normal renal tissues, renal tumor tissues and liver) were determined 5.2 hours on average, after administration. The levels were also compared with these in the five patients administered 300 mg of FT. There was no difference in FT concentration between the serum and the tissues in the group administered UFT, but the concentration of 5-FU in tumor tissues was significantly higher (25.6 times) than that in the serum. The level was also higher (3.2 times) than that in normal renal tissues. There was a positive correlation between the concentration of 5-FU in the tissues and the concentration of uracil in the tissues. Although there was no difference in the concentration of FT between serum and tissues in patients administered UFT or FT, the concentration of 5-FU in patients administered UFT was definitely higher than that in patients administered FT; the concentration of 5-FU in the tumor tissues of patients given UFT was 3.9 times higher than in those given FT. Thus, UFT induced a concentration of 5-FU in tumor tissues that was maintained at a high level, suggesting that an excellent antitumor effect on renal cell carcinoma can be expected with UFT.     

Study on the concentrations of 5-fluorouracil (5-FU), tegafur (ET) and uracil in bile: comparison of UFT or FT

The serum and bile tegafur (FT), 5-fluorouracil (5-FU) and uracil levels after administration of UFT were assessed in 13 cases of malignant biliary tumor accompanied by biliary obstruction in comparison with FT alone. The serum and bile FT and 5-FU levels showed almost the same transition pattern in both groups, reaching to the plateau in 1-2 weeks and revealing cumulative effect by continual administration. Correlation was obtained between serum and bile levels except for 5-FU level in UFT group (p less than 0.05). Correlation between 5-FU and uracil was obtained in the serum in both groups (p less than 0.05), but no effect of uracil was observed. In bile, correlation was seen only in UFT group (p less than 0.05), and the effect of uracil was observed in bile 5-FU level.     

Pharmacokinetic studies on fluorinated pyrimidine in cancer cell and tissue]

A number of the studies on pharmacokinetics of fluorinated pyrimidines have been precisely reported. In mice bearing Ehrlich ascites carcinoma, 5-FU showed highest concentration in the lung and kidney immediately after i.v. administration of 5-FU, and in the liver, it showed rather lower concentration but for a longer period. 5-FU in blood was transferred into ascites fluid rapidly, and thus, the level of 5-FU in ascites fluid became higher than that in blood. FT is a masked compound of 5-FU, having a tetrahydrofuryl group. Drug metabolizing enzyme, natural degradation, and thymidine phosphorylase are considered to be responsible for the molecular conversion of FT into 5-FU. In order to increase the level of drug metabolizing enzyme, P450 in the liver of tumor bearers, of which P450 level was extremely lower as compared to normal individuals, phenobarbital was very effective from our previous experiment. Clinically, phenobarbital 200mg/day for 3 successive days was administered in prior to FT, and a better response was obtained than FT alone. Prevention from degradation of 5-FU in the liver by uracil kept higher level of 5-FU in blood. HCFU and 5'DFUR are also masked form of 5-FU and are converted to 5-FU in the liver.     

Dipyridamole augments the antitumor effects of fluorinated pyrimidines.

The antitumor effects of 5-fluorouracil (5-FU) and its analogues when combined with dipyridamole (DP) were investigated using B16 melanoma cells, in vitro and in vivo. First, the enhancement of 5-FU cytotoxicity by DP was examined in vitro. Cell growth was suppressed significantly by combining 5-FU and a nontoxic dose of DP (2.5 micrograms/ml) as compared to 5-FU alone. Next, the effect of DP was examined in vivo in combination with 5-FU, tegafur (FT) and UFT. UFT had the most remarkable antitumor effect when given in a single equimolar dose. Although DP alone did not affect tumor growth, the growth inhibition by antitumor drugs was augmented by DP. DP enhanced the antitumor effect of UFT significantly (P less than 0.05), and combination treatment with UFT and DP proved to be the most effective regimen for inhibiting growth of B16 melanoma. Combination treatment with UFT and DP shows promise for clinical cancer.     

Chemotherapy with fluoropyrimidines for MOPC-104E plasmacytoma transplanted in mice with CCl4 induced chronic liver dysfunction

The masked compounds of 5-fluorouracil (5-FU) have been widely used for chemotherapy in digestive organ cancer. Among them it has been considered that FT (Tegafur) is metabolized into the active form by the drug-metabolizing enzyme P-450 in the microsomes of hepatocytes, and that their activation and anti-tumor activity may decrease under the condition of chronic liver dysfunction. However, this hypothesis has never been experimentally proved. In the present study the therapeutic effect and metabolism of 5-FU and its masked compounds: FT, UFT (uracil + FT), HCFU (Carmofur), 5'-DFUR (Doxifluridine) were assessed by using MOPC-104E plasmacytoma transplanted subcutaneously in BALB/c mice with CCl4-induced chronic liver dysfunction. Agents were administered daily directly into the stomach with stainless steel canule over days 7 to 13 after tumor transplantation, and the tumor weights, drug concentrations in the liver or the tumor, and serum levels of GOT, GPT and LDH were measured on day 14. In mice with chronic liver dysfunction the tumor-inhibitory effect of 5-FU, FT, UFT and HCFU did not necessarily decrease and serum levels of GOT, GPT and LDH of mice administered with 5-FU, FT, HCFU and 5'-DFUR were higher than in normal animals treated with them. By contrast UFT had no influence on them. The most remarkable difference was observed in uracil concentrations, which were significantly lower in the tumor and the liver of mice with chronic liver dysfunction than in those of normal mice.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhancement of the antitumour activity of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase activity (DPD) using 5-chloro-2,4-dihydroxypyridine (CDHP) in human tumour cells

The purpose of this study was to evaluate the use of 5-chloro-2,4-dihydroxypyridine (CDHP), a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), to enhance the antitumour activity of the fluoropyrimidines. In an in vitro study, CDHP did not influence cell proliferation by itself. However, CDHP did inhibit 5-fluorouracil (5-FU) degradation and enhanced 5-FU cytotoxicity in a concentration-dependent manner in two human tumour cell lines (MIAPaCa-2 and HuTu80) with relatively high basal DPD activity. CDHP exhibited a maximum effect at a molar ratio (CDHP:5-FU) of more than 0.2. However, CDHP did not have any effect on 5-FU cytotoxicity in the CAL27 tumour cell line, which has a relatively low basal DPD activity, even at concentrations where the DPD activity is almost completely inhibited. In an in vivo study, the maximal tolerable doses (MTD) of tegafur (FT) and a combination of FT and CDHP at a molar ratio of 1:0.4 (FT/CDHP) for nude mice were determined by oral administration for 14 consecutive days. After a single oral administration of either FT or FT/CDHP at the MTD, the 5-FU serum concentration-time profiles were almost the same for both treatment strategies. When nude mice bearing subcutaneous (s.c.) MIAPaCa-2 cells were treated with either FT or FT/CDHP at the MTD, the FT/CDHP treatment showed a significantly higher antitumour effect than the FT treatment (tumour growth inhibition: FT/CDHP, 51+/-12%; FT, 21+/-25%; P<0.05). However, the host-body weight suppression induced by FT/CDHP and FT was equivalent. These findings suggest that the combination of fluoropyrimidine and CDHP for the treatment of tumours with a high basal DPD elicits a greater antitumour effect than treatment with fluoropyrimidines alone and we suggest that CDHP inhibits the degradation of 5-FU in the tumour.     

Phase I and pharmacologic study of 72-hour infused 5-fluorouracil and hyperfractionated cyclical radiation

We have studied 21 patients infused for 72 hours with 5-Fluorouracil (5-FU) at progressive doses combined with hyperfractionated radiation. The schedule was chosen as being one capable of inducing 5-FU radiosensitization (RS). All patients were started at a daily 5-FU dose of 40 mg/kg/24 hours; doses were then escalated with each subsequent treatment cycle to limiting toxicity or until taken off study. Patients received between one and six infusion cycles. Every treatment cycle included coincident hyperfractionated radiation to various body areas including the abdomen, chest, and head and neck region. Radiation fractionation was invariant; 1,000 rad were delivered in four equal fractions. Two fractions of 250 rad each were given on days 1 and 2 of each three day 5-FU cycle, i.e. at approximately 0, 8, 24, and 32 hours into the drug infusion. Patients were followed for toxicity; serum 5-FU concentrations were determined using a high pressure liquid chromatographic assay. 5-FU clearances were calculated from the mean serum drug levels and the infused drug dose. The toxicity spectrum was not found to be significantly different from infused drug alone in this dose range save when the head and neck region received coincident irradiation. In that region the two anticipated toxicities combined in what appears to be a synergistic fashion to enhance mucositis. Most toxicities including gastrointestinal and bone marrow appeared dependent on the mean serum 5-FU level as did mucositis itself. 5-FU clearance was found to be non-linear in this dose region but did not appear influenced by radiation to any part of the body. This study shows that 72-hour infused 5-FU can be combined with external beam radiation and will produce reasonably predictable toxicity patterns which depend on the region of the body being irradiated. 5-FU toxicity correlates with mean serum drug level which is itself dependent on 5-FU clearance. Minor variations in 5-FU clearance therefore probably contribute to the natural range found in the dose-response relationship for infused 5-FU toxicities. Future studies should integrate this understanding of 5-FU pharmacokinetics into treatment regimens. The combination of infused 5-FU and coincident radiation appears useful in treating several tumor types, particularly squamous and squamous-like cancers. However, further scheduling and radiation fractionation studies are desirable to optimize 5-FU RS in man and to quantify late effects.     

Preoperative treatment of FT-207 suppository in cervical cancer-- serum and tumor tissue content of FT-207

A 750 mg FT suppository was inserted daily for seven days prior to surgery of uterine cervical carcinoma. The concentrations of FT and 5-FU in the serum, tumor tissue, adjacent normal tissues and regional lymph nodes were then measured. In addition, the concentrations of FT and 5-FU in the serum of patients who had been receiving chemotherapy for long term (an average of 15 months) after the initial remission were measured. The results are as follows: The 5-FU concentration in the serum of patients following short duration of administration was 0.014 +/- 0.006 micrograms/micromilligram. The 5-FU concentration in the tumor tissue was 0.209 +/- 0.132 microgram/g. This was approximately 3.2 times higher than the concentration in the normal tissue which was 0.065 +/- 0.017 microgram/g, and approximately 2.4 times higher than in the regional lymph nodes of 0.088 +/- 0.055 microgram/g. Relatively higher concentrations of 5-FU were seen in the non-keratinizing type than in the keratinizing type suggesting. The correlation between the concentration in the tumor tissue and the histologic findings of the carcinoma tissue. The 5-FU concentration in the serum of patients receiving long-term chemotherapy was 0.019 +/- 0.015 microgram/micromilligram, showing no significant difference from the patients receiving short-term chemotherapy.     

Phase I and pharmacologic study of oral ftorafur and X ray therapy in advanced gastrointestinal cancer

We have treated 15 patients with advanced gastrointestinal carcinoma with a cyclical regimen of combined Ftorafur (N1-((2-furanidyl-))-5-Fluorouracil, a 5-FU pro-drug) and external beam radiation. The Ftorafur (FT) was administered orally in daily doses of between 1.0 and 2.5 g/m2/day in 3 divided doses in a Phase I format. The drug was given daily for 5 days along with conventional X ray treatment portals and daily radiation doses of 250 rad on each of the first 4 days of each treatment cycle. The patients were then rested for a minimum of 10 days or until all significant side effects had passed. The total number of 1,000 rad cycles and radiation dose were dictated by tolerance and by normal organ dose limitations. The most common toxicity in general, and the most common limiting toxicity was nausea and vomiting, in contrast to oral FT alone where diarrhea is more prominent. Stomatitis was seen only once and no other form of serious toxicity was encountered. Two-thirds of the patients responded in subjective terms (pain relief). There was 1 partial response to FT alone (pulmonary metastases outside the treatment field). The sole patient whose treatment field was outside the abdomen (chest portals for esophageal carcinoma) developed pneumonitis which contributed to his death. No other delayed effects were noted. Serum FT levels were related to the ingested dose and in the microgram range while serum 5-FU levels were in the nanogram range indicating slow decomposition of FT into 5-FU. The therapy was reasonably well tolerated at doses of 2.0 g/m2/day or lower with abdominal radiation. FT offers the potential for replacing intra-venous infused 5-FU as a clinical radiosensitizer.     

Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur,in experimental tumor models in rats

 S-1, a new oral antitumor agent, is composed of 1-(2-tetrahydrofuryl)-5-fluorouracil (Tegafur, FT), 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) in a molar ratio of 1 : 0.4 : 1. FT which is a masked compound of 5-fluorouracil (5-FU) acts as an effector, while both CDHP and Oxo which do not have antitumor activity themselves act as modulators. In this study, the antitumor activity and intestinal toxicity of S-1 were investigated using experimental tumor models in rats, and compared with those of other oral fluoropyrimidines, namely 5-FU, FT, FCD (1 M FT/0.4 M CDHP) and UFT (combination of FT and uracil). In rats bearing subcutaneous Yoshida sarcoma, S-1 inhibited tumor growth at the lowest dose (ED₅₀ value: S-1 5, UFT 22, FT 82, FCD 5, and 5-FU 19 mg/kg per day), and induced the least host body weight suppression, leading to the highest therapeutic index (TI) (S-1 4.5, UFT 1.4, FT 1.8, FCD 2.0, and 5-FU 1.4). S-1 also showed a higher therapeutic effect than UFT against AH-130 and Sato lung carcinoma. After administration of S-1 and UFT at equitoxic doses, S-1 showed a higher and more prolonged concentration of 5-FU than UFT both in plasma (AUC_0-∞: S-1 28 nmol h/ml, UFT 15 nmol⋅h/ml) and in tumor tissue (AUC_0-∞: S-1 95 nmol h/g tissue, UFT 52 nmol h/g tissue), leading to a higher 5-FU level incorporated into the RNA fraction (F-RNA level) in tumor tissue (AUC_0-24: S-1 7.0 nmol h/mg RNA, UFT 4.3 nmol h/mg RNA) and 5–8% higher thymidylate synthase (TS) inhibition in tumor tissue at every time-point through 24 h. Compared with other oral fluoropyrimidines after administration of the maximal tolerable dose (MTD), S-1 caused the lowest rates of intestinal toxicities, such as diarrhea and occult blood in feces. S-1 also showed a higher antitumor effect on Yoshida sarcoma implanted intracolonically than UFT at an equitoxic dose (tumor weight: S-1 64±30 mg, UFT 133±52 mg; P<0.05). These results suggest that CDHP, which is a potent inhibitor of 5-FU degradation, increases the antitumor activity of FT, and that Oxo, which is an inhibitor of 5-FU phosphorylation, locally protects the gastrointestinal tract from 5-FU-induced toxicity without decreasing the antitumor activity. Received: 13 October 1996/Accepted: 18 May 1996     

Randomised study of tegafur and oral leucovorin versus intravenous 5-fluorouracil and leucovorin in patients with advanced colorectal cancer

This randomised, open-label trial compared oral tegafur (FT)/leucovorin (LV) with the intravenous bolus 5-fluorouracil (5-FU)/LV as first-line chemotherapy for advanced colorectal cancer (CRC). Patients were randomised to receive oral FT 750 mg/m2/day for 21 days and LV 15 mg/m2 every 8 h in cycles repeated every 28 days (n=114), or intravenous LV 20 mg/m2 followed by 5-FU 425 mg/m2 daily for 5 days every 4 weeks for 2 cycles, and later every 5 weeks (n=123). Response rate was significantly higher in the FT/LV arm (27%, 95% CI 19-35) than in the 5-FU/LV arm (13%, 95% CI 7-19) (p<0.004). The median time to progression was 5.9 months (95% CI, 5.3-6.5; FT/LV arm) and 6.2 months (95% CI, 5.4-6.9; 5-FU/LV arm). Median overall survival was 12.4 months (95% CI, 10.3-14.5 months; FT/LV arm) and 12.2 months (95% CI, 8.9-15.7 months; 5-FU/LV arm) (p=n.s.; hazard ratio FT/LV:5-FU/LV=1.02). 5-FU/LV showed a higher incidence of grade 3/4 neutropenia (4.1 vs. 0%). Non-hematological toxicities showed similar incidences in the two treatment arms. Oral FT/LV was more active than IV 5-FU/LV in terms of objective response rate with similar overall survival, and with a favorable toxicity profile. This makes FT/LV a valid alternative to the IV 5-FU schedule in CRC patients.     

Recent advances is surgical adjuvant chemotherapy for colorectal cancer

To evaluate the significance of surgical adjuvant chemotherapy, randomized controlled trials (RCTs) of adjuvant chemotherapy after curative resection for colorectal cancer were reviewed. Several multi-drug systemic chemotherapies (MOF, MMC/FT, 5-FU, UFT p.o.) were useful as adjuvant treatment to improve survival or disease-free survival of patients with colorectal cancer. Moreover, a worldwide meta-analysis suggested that continuous intraportal 5-FU infusion improves survival. Combination chemotherapy trials utilizing 5-FU and levamisol (LEV) demonstrated a survival advantage in patients with high risk colon cancer. Recently, many RCTs have substantiated the benefits of treatment with 5-FU/Leucovorin (LV) and this treatment is widely used as adjuvant treatment for the patients with Dukes C resected colon cancer in Europe and the U.S.A. Now, with the increasing use of oral chemotherapy drugs, new trials comparing oral UFT/LV with intravenous 5-FU/LV are being implemented to investigate these drugs in terms of QOL, toxicity and cost. Furthermore, the new drug irinotecan (CPT-11) is now under investigation to see if it brings added efficacy to 5-FU/LV. In Japan, two major groups (N-SAS-CC and TAC-CR) are comparing surgery alone and UFT alone in patients with Dukes C colon and rectal cancer. From these results, surgical adjuvant chemotherapy seems to be effective in the treatment of patients with high risk colon cancer and those with rectal cancer.     

Comparison of pharmacokinetics of 5-FU and alpha-fluoro-beta-alanine, a metabolite of 5-FU, in plasma after administration of UFT, tegafur, 5-FU or doxifluridine to rats

Toxic effects (neurotoxicity and cardiotoxicity) of 5-FU and its derivatives have been reported by many investigators. These toxicities are considered to be caused by the inhibition of the TCA cycle by alpha-fluoro-beta-alanine (FBAL), a metabolite of 5-FU, and later metabolites. In this study, we focused on FBAL as an index of the above toxicities. We compared the concentrations of 5-FU and FBAL in plasma after administration of UFT, tegafur (FT), 5-FU or doxifluridine (5'-DFUR) to rats (75 mumol/kg) in order to evaluate which compound has the better balance of efficacy and toxicity. UFT exhibited the lowest FBAL concentration in plasma followed by FT, 5'-DFUR and 5-FU. The ratio of FBAL to 5-FU in Cmax and AUC after dosing of UFT was the lowest among these four test compounds. These data indicate that the lowest ratio of FBAL to 5-FU resulted from the inhibitory effect of uracil, a component of UFT, on the metabolism of 5-FU. In conclusion, the present results suggest that UFT has a better balance of efficacy and toxicity than FT, 5-FU and 5'-DFUR.     

Effect of fluoropyrimidine, drugs of tegafur and UFT on transplanted tumor in liver-damaged mice

1-(2-Tetrahydrofuryl)-5-fluorouracil (FT) and UFT are masked compounds of 5-fluorouracil (5-FU) and considered to be gradually metabolized and converted to 5-FU in the liver. Therefore, it is important clinically to classify whether or not these anti-cancer drugs are effective in individuals with liver diseases. BALB/c mice were injected 4 ml/kg of 10% CCl4 intraperitoneally twice a week for two months to induce liver damage. On the 49th day after starting of giving CCl4, mouse sarcoma 180 was transplanted to the right thigh of mice and from the next day 5-FU (10, 20, 30 mg/kg/day), FT (50, 100, 200 mg/kg/day), UFT (10, 20, 30 mg/kg/day) or physiological saline solution for control were orally administered daily for 7 days. On the 61st day, all mice were sacrificed and the weight of excised tumor was measured to judge the effect of anti-cancer drugs. Dose-dependent effect of 5-FU was observed in the liver-damaged mice. FT was more effective in liver-damaged mice than control. It was assumed that the suppression of 5-FU decomposition was due to the insufficient liver function. Effect of UFT was similar in liver-damaged mice to control. These data show that the effects of FT and UFT were not reduced in tumor-bearing mice by liver damage.     

5-Fluorouracil modulation of radiosensitivity in cultured human carcinoma cells

We evaluated conventional pulse exposure versus continuous exposure models of 5-fluorouracil (5-FU) radiosensitization in HT-29 (human colon adenocarcinoma) and DU-145 (human prostate cancer adenocarcinoma) cell lines. Cell survival following treatment with drug and/or radiation was determined by colony formation assays. Radiation was delivered either by itself, approximately midway through a 1-hr exposure to 5-FU (10 micrograms/ml), or at various times following initiation of exposure to 5-FU (0.5 microgram/ml) present throughout the entire period of incubation. Drug concentrations were selected to approximate those achieved in vivo in humans. HT-29 cells showed a plating efficiency of 87% and similar cytotoxicity (survival reduced to 0.57-0.71) for all 5-FU conditions. The Do's of the radiation survival curves were not different for 1 hr of 5-FU exposure versus radiation alone. However, continuous exposure conditions demonstrated statistically significantly different Do's from radiation alone and pulse 5-FU exposure. DU-145 cells displayed a plating efficiency of 17% and cytotoxicities of 0.10-0.91 for the 5-FU conditions. DU-145 cells showed different radiation 5-FU interactions: 5-FU produced statistically significant changes in Do well as the differences between cell lines insofar as their radiosensitization by 5-FU underscore the caution required in extrapolating these radiobiologic models to the clinical setting.