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.     

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.     

Protracted Intravenous Infusion of 5-Fluorouracil in Combination Treatments

5-fluorouracil (5-FU) administered by protracted intravenous infusion has been shown to have clinical utility against colorectal cancer and several other advanced tumors. However, additional therapeutic strategies are needed to further improve treatment results. Although the addition of low-dose cisplatin appeared to improve the clinical activity of 5-FU infusion in early phase 11 studies, subsequent evaluation has failed to substantiate these early reports. in addition, toxicity has been significantly increased. Combinations of cisplatin and other drugs with 5-FU infusion are currently being evaluated. Phase I studies demonstrate that only low doses of concomitant leucovorin are necessary to potentiate 5-FU infusion; phase II studies to evaluate efficacy are underway. Although combinations of 5-FU and biological therapies such as alpha 2a-interferon appear to be very promising, they will require extensive phase II and 111 testing to define their clinical utility and toxicity.     

Effects of intravenous feeding on adjuvant chemotherapy--an experimental study on the distribution of 5-FU after injection of tegafur (1)

Forty-eight male Donryu rats inoculated with Sato lung cancer were used to experimentally determine the effects of intravenous feeding on the concentrations of the chemotherapeutic agents FT-207 and 5-FU in the blood, as well as in the liver and tumorigenic tissue. Following FT-207 administration, the blood, tumor and liver tissue levels were lower than in the IVH group (oral administration). The liver 5-FU concentration, at 0.10 +/- 0.02 microgram/g, was significantly higher in the intravenous feeding group than in the p.o. group (0.05 +/- 0.01 micrograms/g). The 5-FU blood concentration rose quickly, reaching 0.051 +/- 0.013 micrograms/ml and 0.035 +/- 0.004 micrograms/ml at 9 and 12 hours, respectively, following treatment. This was significantly higher than in the p.o. group, which showed corresponding levels of 0.031 +/- 0.004 microgram/ml and 0.022 +/- 0.002 microgram/ml, respectively. The increase in the 5-FU level within the tumor was markedly high in the IVH group compared to the p.o. group, and it peaked at 9 hours following administration. The concentration in the IVH group was thus higher than in the p.o. group at any given time. At 24 hours after treatment, the IVH group level was 0.35 +/- 0.09 microgram/g, against 0.27 +/- 0.05 microgram/g in the p.o. group. The blood concentration of 5-FU following intravenous feeding maintained a high value for a long time, and the 5-FU tumor concentration also remained at a high level. The intravenous route was therefore considered to be advantageous for antitumor chemotherapy.     

Oral Administration of BOF-A2 to Rats with Lung Transplanted Tumors Results in Increased 5-Fluorouracil Levels

A new tumor model was developed in which solid Yoshida sarcoma tissue injected intravenously developed into tumors in the lungs of about 30% (13/42) of the inoculated rats. Histological examination revealed that alveoli were occupied with tumor cells and the tumors were similar to those obtained by subcutaneous inoculation. Using this model, the concentrations of 5-fluorouracil (5-FU) in tumor tissue 12 h after oral administration of 3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)-benzoyl]-1-ethoxymethyl-5-fluorouracil (BOF-A2, 36 μmol/kg) or a combination of tegafur and uracil in a molar ratio 1 to 4 (UFT, 50 μmol/kg) were found to be 129.8 ng/g and 19.2 ng/g, respectively. Thus, compared to treatment with UFT, BOF-A2 resulted in higher levels of 5-FU in lung tumor tissues. Increased concentrations of 5-FU should have a superior anti-tumor effect and so BOF-A2 merits clinical trial in the treatment of patients with lung cancer.     

5-Fluorouracil induces arterial vasocontractions.

BACKGROUND: From 2% to 10% of cancer patients treated with 5-fluorouracil (5-FU) will develop symptomatic cardiotoxicity. Nevertheless, the underlying pathophysiology is mostly unknown. Patients and METHODS: We investigated the influence of intravenous chemotherapy (CTX) on the diameter of the brachial artery using high resolution ultrasound in patients with malignant tumors, mostly gastrointestinal cancer. Cytostatic drugs included 30 cases with 5-FU and 30 cases with non-5-FU CTX (cis/carboplatin, anthracycline and cyclophosphamide). In addition, plasma levels of big endothelin were assessed prior to and after CTX. RESULTS: Fifteen of 30 patients (50%) showed a contraction of the brachial artery after the end of 5-FU application (median 11%, range 4.3-18.5), whereas no single contraction was noticed in 30 patients following non-5-FU-based CTX. Vessel tonus generally normalized within 30 min after stopping 5-FU. Five patients positive for 5-FU associated vessel contraction were repeatedly exposed to 5-FU. Vessel contractions reoccurred in 86% (18/21) of these administrations. When patients with 5-FU bolus application were pre-treated with glyceroltrinitrate no contraction of the brachial artery was detected in five out of five occasions. There was a trend towards increased big endothelin plasma levels after 5-FU application (median 1.52 versus 1.99 fmol/ml; P = 0.07), whereas big endothelin levels remained unchanged after non-5-FU CTX (1.83 versus 1.83 fmol/ml; P = 0.99). CONCLUSIONS: Application of 5-FU is commonly accompanied by arterial vessel contractions, which is likely to represent the first step in 5-FU-induced cardiotoxicity. 5-FU-associated vessel contractions were highly reproducible on re-exposure and were in the case of bolus application completely preventable by glyceroltrinitrate.     

Effects of the Plasma Concentration of 5-Fluorouracil and the Duration of Continuous Venous Infusion of 5-Fluorouracil with an Inhibitor of 5-Fluorouracil Degradation on Yoshida Sarcomas in Rats

The correlations of the 5-fluorouracil (5-FU) level in the plasma and the duration of continuous 5-FU infusion with the antitumor activity of 5-FU on Yoshida sarcomas in rats were examined. The circadian variation in the plasma level of 5-FU during continuous infusion was prevented by treatment with 3-cyano-2,6-dihydroxypyridine (CNDP), which strongly inhibits 5-FU degradation. On continuous venous infusion of 2 to 30 mg/kg of 5-FU over 24 h with CNDP at a molar ratio of 1:10 into normal rats, the 5-FU level in the blood was linearly proportional to the dose of 5-FU. The optimum schedule for antitumor activity on Yoshida sarcomas in rats was found to be infusion of 5-FU at 5 mg/kg over 24 h for 6 consecutive days, which gave a plasma 5-FU level of 176 ng/ml. Continuous infusion of 5-FU to give a plasma level of 300 ng/ml for 6 consecutive days from day 5 after implantation of tumor cells, when the tumors weighed about 1.0 g, resulted in complete regression of the tumors in all rats.     

Enhanced accumulation of 5-Fluorouracil in human tumors in athymic mice by co-administration of Ftorafur and Uracil

Human colonic tumors grown in athymic mice were tested for the effect of coincident uracil (U) and Ftorafur (FT) exposure versus FT alone on 5-Fluorouracil (5-FU) metabolism. Serum and tumor FT and 5-FU levels were studied as a function of time after FT +/? U injections. The combination of U + FT led to significantly higher tumor/serum 5-FU ratios than FT alone. The data indicate that the metabolism of 5-FU released from FT can be modulated by coincident U exposure in human tumor cells in vivo. Such combinations may be of use in the development of oral 5-FU pro-drugs for applications using 5-FU as an out-patient non-invasive radiosensitizer.     

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.     

A case report of unresectable gastric cancer that responded to 5-FU plus paclitaxel (FT) therapy

We report a case of a 63-year-old man who has been treated by FT therapy (5-fluorouracil (5-FU) plus paclitaxel therapy). The regimen includes 600 mg/m2/day of 5-FU by continuous i.v. administration from day 1 to 5 and consequent administration of paclitaxel (90 mg/m2/day) on days 8, 15, and 22 for 28 days repetitively. Before the therapy was started, that occurred were obstructive jaundice, ascites, and poor performance status due to gastric cancer were observed. After percutaneous transhepatic drainage was performed, the patient was started on the above-mentioned regimen even before full recovery from the hepatic dysfunction. As the treatment proceeded, he showed good response (ascites disappeared and the size of swollen perigastric lymph node was reduced, which were confirmed as a partial response by sequential CT examination) to the therapy and his QOL and PS also improved. He has continued to receive this regimen for over 1 year and 4 months without any sign of progressive disease by CT examination. No adverse event greater than grade 1 by the NCI-CTC criteria was seen, except for alopecia (grade 2). Considering the favorable response and mild toxicity, this regimen is useful even for the patients with poor performance status and severe hepatic dysfunction.     

5-Fluorouracil cardiotoxicity induced by alpha-fluoro-beta-alanine

Cardiotoxicity is a rare complication occurring during 5-fluorouracil (5-FU) treatment for malignancies. We herein report the case of a 70-year-old man with 5-FU-induced cardiotoxicity, in whom a high serum level of alpha-fluoro-beta-alanine (FBAL) was observed. The patient, who had unresectable colon cancer metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of 5-FU (1000 mg/day), during which precordial pain with right bundle branch block occurred concomitantly with a high serum FBAL concentration of 1955 ng/ml. Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of 5-FU. As the precordial pain in this patient was considered to have been due to 5-FU-induced cardiotoxicity, the administration of 5-FU was abandoned. Instead, oral administration of S-1 (a derivative of 5-FU), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on dihydropyrimidine dehydrogenase, which catalyzes the degradative of 5-FU into FBAL. The serum FBAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no cardiac symptoms were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that FBAL is related to 5-FU-induced cardiotoxicity. S-1 may be administered safely to patients with 5-FU-induced cardiotoxicity.     

Severe Acute Metabolic Acidosis and Wernicke's Encephalopathy Following Chemotherapy with 5-Fluorouracil and Cisplatin: Case Report and Review of the Literature

A 28-year-old woman with inoperable gastric carcinoma was givencontinuous infusion of 5-fluorouracil (5-FU) and low-dose cisplatin(CDDP) for 4 weeks while receiving intravenous hyperalimentation(IVH). Eleven days after her last treatment, she developed acutediplopia, deafness and gait ataxia, followed by severe confusion.She became markedly acidotic and hypotensive with a systolicblood pressure of 60 mmHg, necessitating intubation, dopaminetreatment and hemodialysis for 7 h. She was also given thiamine.Thereafter, her blood pressure stabilized, the acidosis improved,and her deafness, diplopia, and confusion were resolved. Thiscase suggests that FP (5-FU/CDDP) therapy toxicity, manifestedas acute metabolic acidosis and Wernicke's encephalopathy, maybe associated with IVH and thiamine deficiency.     

Oral Ftorafur Versus Intravenous 5-Fluorouracil: A comparative study in patients with colorectal cancer

The toxicities of ora] Ftorafur (1 g/m²/day 1-21) and intravenous 5-fluorouracil (5-FU) (500 mg/m²/day 1-5) were compared in a prospective randomized study in patients with colorectal cancer. The treatment courses were repeated every 6th week. Leu-copenia was more common after 5-FU. Leucocyte nadir in connection with first treatment cycle was on average seen on day 15 in patients receiving 5-FU and on day 28 in patients receiving Ftorafur. Significantly more patients on 5-FU developed stomatitis. There was no difference in the number of patients with diarrhea or nausea/vomiting. Median survival and response rates were not significantly different after the two treatment schedules.     

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.     

5-Fluorouracil incorporation into RNA and DNA in relation to thymidylate synthase inhibition of human colorectal cancers.

BACKGROUND: The mechanism of action of 5-fluorouracil (5-FU) has been associated with inhibition of thymidylate synthase (TS) and incorporation of 5-FU into RNA and DNA, but limited data are available in human tumor tissue for the latter. We therefore measured incorporation in human tumor biopsy specimens after administration of a test dose of 5-FU alone or with leucovorin. PATIENTS AND METHODS: Patients received 5-FU (500 mg/m(2)) with or without high-dose leucovorin, low-dose leucovorin or l-leucovorin, and biopsy specimens were taken after approximately 2, 24 or 48 h. Tissues were pulverized and extracted for nucleic acids. 5-FU incorporation was measured using gas chromatography/mass spectrometry after complete degradation to bases of isolated RNA and DNA. RESULTS: Maximal incorporation into RNA (1.0 pmol/micrograms RNA) and DNA (127 fmol/micrograms DNA) of 59 and 46 biopsy specimens, respectively, was found at 24 h after 5-FU administration. Incorporation into RNA but not DNA was significantly correlated with intratumoral 5-FU levels. However, DNA incorporation was significantly correlated with the RNA incorporation. Primary tumor tissue, liver metastasis and normal mucosa did not show significant differences, while leucovorin had no effect. Neither for RNA (30 patients) nor DNA (24 patients) incorporation was a significant correlation with response to 5-FU therapy found. However, in the same group of patients, response was significantly correlated to TS inhibition (mean TS in responding and non-responding groups 45 and 231 pmol/h/mg protein, respectively; P=0.001). CONCLUSIONS: 5-FU is incorporated at detectable levels into RNA and DNA of human tumor tissue, but no relation between the efficacy of 5-FU treatment and incorporation was found, in contrast to TS.     

Clinical Effect of 1-Hexylcarbamoyl-5-Fluorouracil (HCFU) in Patients with Disseminated Gastric Cancer

A randomized trial of chemotherapy was made in patients withdisseminated gastric cancer. Thirty-two patients were randomlyallocated to three treatment groups. Eleven patients were treatedwith 1-hexylcarbamoyl-5-fluorouracil (HCFU), 600 mg with dividedoral administration, three times a day. Eleven patients weretreated with 1-(2-tetrahydrofuryl)-5-fluorouracil (FT 207),600 mg with divided oral administration, three times a day.Ten patients did not receive chemotherapy. The survival ratewas significantly higher in patients treated with HCFU thanin those treated with FT 207 or in those with no chemotherapyduring the first 80 to 100 days after diagnosis. HCFU mightbe more effective than FT 207 for patients with disseminatedgastric cancer.     

5-Fluorouracil plus leucovorin as adjuvant treatment of an experimental liver tumor in rats

Recent experimental and clinical work has shown that leucovorin potentiates the cytotoxic effect of 5-fluorouracil (5-FU). To investigate the adjuvant role for this combination, 5-FU, 30 mg/kg, combined with leucovorin, 15 mg/kg, was administered intraperitoneally on 3 consecutive days beginning on the same day as tumor cell inoculation in the liver. Tumor take and tumor volume were registered on day 14, followed by recording of survival time. The results of the combined treatment were compared with treatment with 5-FU alone. Leucovorin in combination with 5-FU, but not 5-FU alone, significantly reduced the tumor take compared with untreated animals (p less than 0.01). The combination also resulted in smaller tumors compared with untreated animals (p less than 0.001) or with animals given 5-FU alone (p less than 0.01). The present study supports the use of leucovorin in combination with 5-FU as adjuvant treatment of patients with primary colorectal cancer.     

Pharmacokinetic Modulation of Plasma 5-Fluorouracil Concentrations to Potentiate the Antitumor Activity of Continuous Venous Infusion of 5-Fluorouracil

Methods for pharmacokinetic modulation of the plasma 5-fluorouracil (5-FU) level to increase antitumor activity during continuous venous infusion (CVI) of low doses of 5-FU were examined in Yoshida sarcoma-bearing rats. These methods were additional infusion of 5-FU for a short period (4 h) or oral administration of LIFT or Tegafur during long-term CVI of 5-FU that alone gave a plasma 5-FU level of about 50 ng/ml. The antitumor effect on Yoshida sarcoma was markedly potentiated when an additive dose of 5-FU combined with 3-cyano-2,6-dihydroxypyridine (CNDP), a potent inhibitor of 5-FU degradation, giving a plasma level of about 500 ng/ml, was infused for 4 h. A similar increase in the antitumor effect was observed with oral administration of a conventional dose of UFT during CVI of 5-FU without CNDP, giving a plasma level of 30 to 60 ng/ml. These results suggest that the antitumor effect of CVI of 5-FU can be potentiated by pharmacokinetic modulation of the 5-FU concentration in the blood.     

Cyclophosphamide, Methotrexate, and 5-Fluorouracil (CMF)-Induced Ocular Toxicity

Ocular toxicity is a common, but poorly understood, sequela from CMF chemotherapy. We investigated this toxicity in patients receiving CMF therapy. Detailed interviews in 210 patients revealed that new, unpleasant ocular symptoms developed in 42% of patients receiving CMF, in 39% of subjects receiving other regimens containing 5-fluorouracil (5-FU), and only in 18% of subjects receiving a variety of chemotherapy regimens not containing 5-FU. CMF-associated ocular symptoms usually consisted of mild to marked tearing, ocular pruritis, and/or burning. These toxicities usually began 11-17 days after starting a cycle of CMF and lasted for 10-15 days. 5-FU was detected in the tears of 12 tested patients within several minutes after intravenous 5-FU (peak concentrations as high as 60 µg/ml). 5-FU tear concentrations did not correlate with the presence or absence of ocular toxicity. There is no established antidote for this toxicity although some patients have reported subjective benefit from cryotherapy, applied around the period of 5-FU injections, or cromolyn sodium eye drops.