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In Japan, oral administration of tegafur-uracil is recommended as postoperative adjuvant chemotherapy for patients diagnosed with primary lung adenocarcinomas of >2 cm size and staged as IA, IB, and IIA. Reports on chemotherapy-induced pericardial effusion are rare. Herein, we report a rare case of tegafur-uracil-induced pericardial effusion during postoperative adjuvant chemotherapy for primary lung cancer. A 60-year-old man underwent left lower lobectomy and mediastinal lymph node dissection for left lower lung adenocarcinoma. Lung cancer was staged as IB, and tegafur-uracil was administered as postoperative adjuvant chemotherapy from 1 month after the surgery. A computed tomography (CT) scan revealed a pericardial effusion 5 months after the surgery. A malignant pericardial effusion was suspected, and tegafur-uracil was discontinued. Pericardiocentesis could not be performed owing to a small amount of pericardial effusion. An 18 F-fluorodeoxyglucose (FDG) positron emission tomography/CT scan revealed no abnormal FDG uptake. During a short follow-up period after discontinuation of tegafur-uracil, a CT scan revealed a decrease in pericardial effusion, suggesting that the pericardial effusion was induced by tegafur-uracil. Follow-up of pericardial effusion is required while administering tegafur-uracil. In cases of pericardial effusion without symptoms and no suspicious metastatic lesions in other organs, we should be concerned about tegafur-uracil-induced pericardial effusion., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Metronomic chemotherapy using the 5-FU prodrug uracil-tegafur (UFT) and cyclophosphamide (CTX) was previously shown to only modestly delay primary tumor growth, but nevertheless markedly suppressed the development of micro-metastasis in an orthotopic breast cancer xenograft model, using the metastatic variant of the MDA-MB-231 cell line, 231/LM2-4. Furthermore, a remarkable prolongation of survival, with no toxicity, was observed in a model of postsurgical advanced metastatic disease. A question that has remained unanswered is the seemingly selective anti-metastatic mechanisms of action responsible for this treatment. We assessed the in vivo effect of metronomic UFT, CTX or their combination, on vascular density, collagen deposition and c-Met (cell mediators or modulators of tumor cell invasion or dissemination) via histochemistry/immunohistochemistry of primary tumor sections. We also assessed the effect of continuous exposure to low and non-toxic doses of active drug metabolites 5-fluorouracil (5-FU), 4-hydroperoxycyclophosphamide (4-HC) or their combination, on 231/LM2-4 cell invasiveness in vitro. In the in vivo studies, a significant reduction in vascular density and p-Met[Y1003] levels was associated with UFT+CTX treatment. All treatments reduced intratumoral collagen deposition. In the in vitro studies, a significant reduction of collagen IV invasion by all treatments was observed. The 3D structures formed by 231/LM2-4 on Matrigel showed a predominantly Mass phenotype under treated conditions and Stellate phenotype in untreated cultures. Taken together, the results suggest the low-dose metronomic chemotherapy regimens tested can suppress several mediators of tumor invasiveness highlighting a new perspective for the anti-metastatic efficacy of metronomic chemotherapy., Competing Interests: The authors have declared that no competing interests exist.

To identify the genes and clinical parameters associated with efficacy of uracil and tegafur/leucovorin (UFT/LV) chemotherapy in colorectal cancer (CRC), we compared the levels of reduced folate in tumors between patients receiving LV and those not receiving LV (study I), and explored the changes in the expression levels of 14 genes after two weeks of UFT/LV chemotherapy in 73 patients with CRC (study II). In study I, the reduced folate levels after LV administration were approximately 3-fold higher than those without LV administration in patients with right-sided tumors or aged >75 years old (p=0.019). In study II, the reduction in γ-glutamyl hydrolase (GGH) expression in responders and in patients with right-sided tumors or aged >75 years old was significantly greater than that in non-responders (p<0.001) and in other patients, respectively (p=0.003). Increase of reduced folate and reduction in GGH expression were associated with response to UFT/LV chemotherapy in patients with right-sided tumors or aged >75 years old.

We evaluated the antitumor effect of combined therapy with tegafur/uracil (UFT) plus leucovorin (LV) (UFT/LV) and protein-bound polysaccharide, PSK, in three mouse models of transplantable tumors. UFT/LV showed antitumor effect against Meth A sarcoma, and the antitumor effect was enhanced when PSK given concomitantly. UFT/LV showed antitumor effect to Lewis lung carcinoma and PSK alone also showed antitumor effect at high dose, but a combination of UFT/LV and PSK resulted in no enhanced antitumor effect. Colon 26 carcinoma was weakly responsive to UFT/LV, and no enhancement of antitumor effect was found even PSK was used in combination. In conclusion, while the effect of PSK varies depending on tumor, combined use of UFT/LV and PSK may be expected to augment the antitumor effect.

Systemic and local immunological responses were studied in patients with or without preoperative administration of chemotherapeutic and/or immunotherapeutic drugs for colorectal cancer. The plasma TGFbeta and other cytokines such as IL-2, IL-4, IL-6, IL-10, IL-12, IFN-gamma in the supernatant fluid of culture of peripheral blood mononuclear cell (PBMC) and regional lymph node were measured by the ELISA method. A systemic response of cytokines was as follows: the production of plasma TGFbeta increased in many cases by chemotherapeutic drugs with a significant elevation of the mean production. Productions of IFN-gamma, IL-2, IL-12 in the supernatant fluid of culture of PBMC increased in many cases by immunotherapeutic drugs, and that of IL-4, IL-6 increased in many cases by chemotherapeutic drugs. A local response of cytokines was as follows: the production of IL-2 by immunotherapeutic drugs was greater than that without immunotherapeutic drugs whereas the production of IL-10 by immunotherapeutic drugs was smaller than that without immunotherapeutic drugs.

Purpose: To evaluate the efficacy and toxicity of a novel combination treatment using concurrent radiotherapy with cisplatin plus UFT, which is comprised of uracil and tegafur, in locally advanced non-small cell lung cancer (NSCLC) patients., Experimental Design: In this Phase II trial, patients with unresectable stage III NSCLC were treated with the oral administration of UFT (400 mg/m(2)/d tegafur) on days 1-14 and days 29-42 whereas 80 mg/m(2) cisplatin was administered i.v. on days 8 and 36. Radiotherapy, with a total dose of 60 Gy, was delivered in 30 fractions from day 1., Results: Seventy patients were enrolled and eligible, as follows: 57 males/13 females; mean age 61 ranging from 36 to 74; performance status 0/1:45/25; stage IIIA/IIIB, 14/56. A complete response was observed in two patients and a partial response in 54 patients, and the overall response rate was 81% (95% confidence interval; 70-89%). The median survival, the 1- and 2-year survival rates were 16.5 months, 67% and 33%, respectively. Grade 3/4 leukopenia occurred in 14%/1% of the patients. Grades 3 non-hematological toxicities were only reported in three patients with nausea, two with esophagitis and one with pneumonitis whereas no grade 4 non-hematological toxicity was observed., Conclusions: UFT plus cisplatin with concurrent radiotherapy is considered to be a feasible and effective treatment for locally advanced NSCLC patients. Additional study of this concurrent chemoradiotherapy is warranted.

Background/aims: Some patients are candidates for neo-adjuvant use of Tegafur, a prodrug of 5-fluorouracil, and Uracil combination (UFT). The purpose of this study is to assess the effect of preoperative UFT use on the strength of colonic anastomosis., Methodology: Forty Wistar albino rats were randomly divided into a control (group 1, n=10) and three study (Group 2, 3 and 4, 10 animals in each group) groups. Animals in control and study groups were given saline or UFT which included 50 mg/kg of Tegafur via an oral-gastric tube for 28 days. A segmental colonic resection and end-to-end anastomosis was performed on all animals 1, 1, 7 and 14 days after the treatments had ended in groups 1, 2, 3 and 4, respectively. On postoperative day 7 the animals were killed and bursting pressure and breaking strength were measured., Results: Three animals in the treatment groups died during the preoperative period, and one in the control group died after surgery. The animals in groups 2 and 3 had lesser bursting pressures than the control group (p<0.001), but no statistical difference was observed in bursting pressures of the control group and group 4 (p>0.05). The breaking strengths of each group were statistically different from the other groups (p<0.001 for each comparison)., Conclusions: UFT use during the preoperative period affected the anastomosis strength in this animal experiment. Current study suggests that an operation should not be performed during the 14 days after UFT use has ended.

Background: Although intestinal permeability is known to increase in conditions of stress (such as endotoxemia, septic shock, and ischemia-reperfusion), the mechanism of gut barrier dysfunction during chemotherapy remains to be elucidated. We designed an experiment in which a gastrectomy and anticancer drugs were administered to rats to assess the extent of damage or an increase in permeability of the intestinal mucosa., Methods: The rats were separated into the following groups: group A, no operation without an anticancer drug (control rats); group B, a gastric operation; group C, chemotherapy; and group D, a gastric operation followed by chemotherapy. Six rats were placed in each group. The groups that were given the anticancer drug received 45 mg/kg for 7 and 14 days, respectively. Intestinal permeability was determined by an injection of fluorescein isothiocyanate-dextran (FITC-D) intravenously and the measurement of the amount of FITC-D leakage in the luminal lavage. The plasma nitric oxide concentrations were measured spectrophotometrically by the Griess reaction. The cell surface expression of CD44 in the rat small intestine was evaluated immunohistochemically., Results: During the entire experimental period, the FITC-D levels in the anticancer drug that was administrated to rats (groups C and D) were significantly higher than the levels in groups A and B (P <.001). Similarly, the plasma nitric oxide concentration increased significantly not only in groups C and D but also in group B (P <.05). A linear regression analysis revealed a positive significant correlation between FITC-D and the plasma nitric oxide levels (r = 0.617; P <.001). When the anticancer drug was administered, the intestine histologically revealed so-called mucosal atrophy and a decreased expression of CD44 within the intestinal mucosa., Conclusions: The administration of anticancer drugs impairs the gut barrier function, possibly by reducing the cell-cell and cell-matrix interactions. This may contribute to the development of hyperpermeability that is induced by an overexpression of nitric oxide.

Although 5-FU administered as a single agent in different intravenous bolus schedules has been shown to have minimal activity in non-small cell lung cancer (NSCLC), several lines of experimental evidence suggest that 5-FU in combination regimens may be synergistic with the 'anchor' drug of the combination. Moreover, the recent availability of oral formulations of 5-FU together with the ability to modulate the anabolic and catabolic metabolism of 5-FU with leucovorin and dihydropyrimidine dehydrogenase (DPD) inhibitors, respectively, may provide a substantial improvement in the ease of administration and the efficacy of fluoropyrimidine therapy. Several oral fluoropyrimidines are under investigation. Orzel [UFT (uracil:tegafur) plus oral leucovorin] is the first oral DPD-inhibitory fluoropyrimidine. Orzel administered daily achieves similar concentrations of 5-FU obtained with continuous-infusion 5-FU. This paper reviews the clinical experience with UFT and Orzel in the treatment of NSCLC.

Background: Low dose oral Folinic acid was used together with uracil with ftorafur (UFT) producing some response with low toxicity in advanced colorectal cancer. However, the 28 day regimen produced 20 per cent severe (grade III, IV) diarrhea. This study required 21 days' treatment to evaluate the response rate and toxicity in advanced colorectal cancer., Method: UFT 300 mg/m2/day together with oral Folinic acid 7.5 mg/dose for 21 days with 7 days rest were required to treat 28 cases of recurrent or metastatic colorectal cancer., Results: Partial response was seen in 13.6 per cent of 22 evaluable cases and minimal response seen in 18.2 per cent. The majority (77%) of these patients had previously been treated with 5-fluorouracil (5-FU). These results are comparable to other studies. Toxicity was low with 3.3 per cent grade III, IV diarrhea., Conclusion: This regimen produced some activity in metastatic colorectal cancer with low toxicity.

We have investigated the correlation between the in vitro chemosensitivity to 5-FU, measured using the collagen gel droplet embedded culture drug sensitivity test (CD-DST), and the anti-tumor effect of UFT, a prodrug of 5-FU, in metastatic tumors from orthotopic implanted colon cancer in nude rats. Human colon cancer cells (KM12SM) were injected into the cecal wall of the nude rats. Five weeks later, the implanted cecal tumors were removed. Oral UFT (a daily dose of 30 mg/kg) was administered postoperatively for four weeks. After the UFT administration period, the lung and lymph nodes were analyzed macroscopically and microscopically. In vitro chemosensitivity to 5-FU in the lung and lymph node metastases was tested using CD-DST, and the enzymatic activities of thymidine synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) in the lung and lymph node metastases were measured. A daily administration of UFT produced an inhibitory effect on lung metastasis compared with the control group. However, there was no difference in the frequency of lymph node metastasis. The inhibition rate produced by 5-FU in CD-DST was significantly higher for lung metastases than for lymph node metastases. There was no difference in the TS and DPD activities between the metastatic tumoral tissues. These results suggest that the organ specificity of the anti-tumor effects of UFT on colon metastases may be determined by CD-DST of 5-FU for individual tumors. The TS and DPD activity in the tumoral tissues may not affect the organ specificity of the anti-tumor effect of UFT on colon metastases.

The fluorinated pyrimidines have played a major role in the treatment of many common tumors since 5-fluorouracil (5FU) was first introduced. Studies of the cellular and clinical pharmacology of 5FU have led to an improved understanding of the mechanisms of action of this agent. This knowledge has allowed the optimal and rational development of fluoropyrimidine therapy, with significant therapeutic advances in recent years. Efforts to improve the therapeutic index of 5FU have included alteration of schedule, and the addition of biochemical modulators such as folinic acid. Although protracted continuous infusion of 5FU has led to better response rates and decreased toxicity, the administration of 5FU by protracted infusion is not only costly, but also inconvenient to the patient. Furthermore it is often associated with infectious and thrombotic complications related to the required indwelling intravenous catheter. Protracted oral administration is a rational route for administering 5FU, being preferred by the patient and the pharmaco-economist. The unpredictable and low oral bioavailability of 5FU initially discouraged this form of treatment. This problem has now been overcome by the new generation of oral fluoropyrimidines. Two main strategies have been pursued: 1) The administration of an inactive prodrug of 5FU, which is absorbed intact, and subsequently converted to 5FU. Capecitabine is converted to 5FU by a 3 step enzymatic process. 2) The administration of 5FU with an inhibitor of dihydropyrimidine dehydrogenase (DPD) to minimise the erratic absorption and variable clearance of 5FU: the preparations UFT, S1, and ethinyluracil/5FU contain an oral fluoropyrimidine co-administered orally with inhibitors of this enzyme. The development and characteristics of these agents are discussed.

Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). DPD has an important role in regulating the availability of 5-FU for anabolism. It is now clear that DPD also accounts for much of the variability observed with the therapeutic use of 5-FU, including variable drug levels during 24-hour infusion, erratic pharmacokinetics, variable bioavaialability, inconsistent toxicity, and variability in drug response (resistance). The use of DPD inhibitors has been explored as a means to improve 5-FU pharmacology. This article describes how drugs that modulate DPD activity have been used to develop a new class of orally administered fluoropyrimidines, now referred to as DPD-inhibiting fluoropyrimidine (DIF) drugs. The biochemical basis for using four DIF drugs--uracil and tegafur (UFT), ethynyluracil, S-1, and BOF-A2--currently in clinical evaluation in the United States, is hereby reviewed. Early clinical data suggest that these drugs may achieve antitumor efficacy equivalent to that of conventional intravenously administered 5-FU therapy, with the additional advantages of reduced toxicity, less expense, and improved quality of life.

To elucidate the roles of chemotherapeutic agents in tumor progression, we examined whether cis-diamminedichloroplatinum (II) (cisplatin) and UFT would promote malignant progression of a weakly tumorigenic and poorly metastatic fibrosarcoma cell line OR-32SK in vivo. C57BL/6 mice, transplanted with QR32SK, were treated with either cisplatin or UFT alone and in combination. After treatment with or without cisplatin and/or UFT, we established in vitro culture cell lines from the tumors arising in the mice on day 21 and then i.v. injected the established cell lines into syngeneic mice. As a result, the cell lines established from cisplatin-treated mice and UFT-treated mice had significantly higher metastatic capacity in lung compared to the ones from control untreated mice (64 and 65%, respectively, versus 26.7%). The cell lines established from the mice with the combination therapy showed lower lung metastasis (11%) than the ones from control untreated mice. Furthermore, we found the incidences of these experimental metastases were closely related with in vitro chemotactic activities and the production of MMP-9 of the cultured cell lines. These results indicate that cisplatin and UFT as a single agent promote the chemotactic activities and the production of MMP-9 in non-metastatic fibrosarcoma cells, resulting in the conversion to highly metastatic ones, and that cisplatin and UFT in combination failed to promote the chemotactic activities and the conversion. These results suggest that the combination therapy with cisplatin and UFT is useful in preventing the emergence of more malignant tumor cells after chemotherapy.

Background: Thymidylate synthetase and thymidine kinase are key enzymes involved in de novo and salvage pathways for pyrimidine nucleotide synthesis, respectively., Materials and Methods: Weekly injections of 1,2-dimethyl-hydrazine induced high incidence of colorectal adenocarcinomas in rats., Results: An increased activity of thymidylate synthetase was found in the poorly differentiated adenocarcinomas of the chemically induced rat colorectal tumors. Six-week oral administration of 1-(2-tetrahydrofuryl)-5-fluorouracil in combination with uracil (UFT) reduced the total number of colorectal tumors, with the reduction of thymidylate synthetase activity in the poorly-differentiated type, though the mRNA expression of thymidylate synthetase and thymidine kinase differed little between the groups with or without UFT treatment., Conclusions: These results indicate that the long-term oral administration using UFT suppresses colorectal carcinogenesis and the growth of the poorly-differentiated type tumors.

Various types of anti-neoplastic agents induce apoptosis in vitro, but less is known of the role of this mode of cell death in tumours treated in vivo. We examined the induction of apoptosis by oral anti-neoplastic agents, tegafur and uracil (UFT, a combined preparation of 1 mol tegafur and 4 mol uracil), and the relationship of effects on tumour growth. Seven different human gastrointestinal tumour xenografts were transplanted into nude mice, including two colon adenocarcinomas (KM20C and Col-1), three gastric carcinomas (SC-6, St-40 and 4-1ST) and two pancreatic carcinomas (PAN-4 and PAN-12), followed by oral administration of UFT (24 mg kg(-1) day(-1)) for 9 days. The percentage of apoptotic cells in each tumour was scored in histological sections, chronologically, using a molecular biological-histochemical system and growth inhibition was examined in each tumour. A significant growth inhibition by UFT was observed for all tumours, except PAN-12. In KM20C and SC-6, growth inhibition rates were 61.7% and 60.6% respectively. Quantitative assay for apoptosis showed a remarkable induction of apoptosis in KM20C (4.2%) and SC-6 (3.5%), which were relatively sensitive to UFT. In addition, KM20C and SC-6 showed a higher incidence of spontaneous apoptosis. In five other tumours, which responded to a lesser extent than KM20C and SC-6, UFT altered little the changes in apoptosis (less than 2%) and spontaneous apoptosis was relatively low. Thus, tumours with a higher apoptosis induced by UFT had a higher response to UFT. Apoptosis observed in tumours might serve as a predictor of a preferable response to UFT.

Plasma 5-fluorouracil (5-FU) levels were compared in the same patients after approximately equimolar doses (1.9 mmol/ m2/day) of 5-day continuous i.v. infusion of 5-FU (CIFU) and oral administration of a formulation of two combined pharmacological agents, uracil (U) plus N1-(2'-tetrahydrofuryl)-5-fluorouracil (ftorafur or FT), a prodrug of 5-FU. Ten patients received CIFU for 5 days, then, after a week wash-out period, began the 28-day oral UFT regimen, which was given in three daily divided doses. Following 1 h of CIFU, the plasma 5-FU levels reached a steady state of 0.6+/-0.2 microM (mean+/-SD; day 1), which was maintained for the entire 5-day infusion period (0.6+/-0.1 microM). In contrast, the maximum 5-FU concentrations (Cpmax) generated from oral UFT at 1 h after dose administration on days 1 and 5 were 2.1+/-1.5 microM and 2.3+/-1.9 microM, respectively, which were higher than the steady-state levels during CIFU. These high 5-FU levels disappeared with an apparent elimination half-life (tl/2,beta) of 5.2+/-2.4 h (day 1) and 7.2+/-3.9 h (day 5). On day 1 of both regimens, CIFU patients had significantly larger 5-FU area under the concentration versus time curve (AUC0-8h) values (4.4+/-1.3 microM.h) than the AUC value when they received the UFT regimen (2.6+/-1.7 microM.h; P = 0.02). However, by day 5, there were no significant differences between AUC0-8 h values in patients receiving CIFU and UFT, respectively (4.8+/-1.5 microM.h versus 3.8+/-2.2 microM.h; P = 0.30)]. On day 5, the average concentration of the metabolite 5-FU at steady-state (Css,aver) within dose interval of 8 h (0.48+/-0.28 microM) for the oral UFT treatment is comparable with the Cpss values of 5-FU from CIFU-treated patients. The post-UFT generated 5-FU pharmacokinetic parameters (higher Cp(mx, comparable Css,aver, equal AUC values, and longer apparent t1/2,beta of 5-FU) may make oral UFT a preferred method of delivering this fluoropyrimidine over CIFU. In addition, oral UFT would eliminate the incidence of venous thrombosis and catheter-related infections sometimes seen in patients treated with CIFU. Furthermore, the convenience and decreased cost of oral administration may be preferable for many patients, particularly those receiving 5-FU for palliation.

UFT is an oral antineoplastic drug combining uracil and tegafur in a 4:1 molar ratio. Tegafur acts as a prodrug of 5-fluorouracil (5-FU), being slowly metabolized by cytochrome P450 to 5-FU. Uracil competitively inhibits the metabolism of 5-FU, resulting in increased plasma and tumor 5-FU concentrations. At equimolar doses, higher peak plasma 5-FU concentrations are achieved with UFT plus oral leucovorin with similar systemic 5-FU exposure compared with low-dose continuous 5-FU infusions. The elimination half-life of 5-FU following UFT administration is approximately 7 h compared with 0.2 h with i.v. 5-FU. In phase II studies of UFT plus oral leucovorin for the treatment of advanced colorectal cancer, response rates ranged from 25 to 42%. UFT plus oral leucovorin is well tolerated, with manageable diarrhea being the only dose-limiting toxicity; the regimen is not associated with significant myelosuppression, mucositis, hand-foot syndrome or alopecia. UFT, with or without leucovorin, has also been evaluated alone or in combination with other cytotoxic agents for the treatment of advanced lung, breast and gastric cancers. UFT has also been evaluated as adjuvant therapy for colorectal, breast, gastric, head and neck, and superficial bladder cancers. UFT plus leucovorin offers patients an entirely oral cancer treatment, and appears to provide potential advantages over bolus 5-FU regimens with regard to toxicity and convenience of administration. These benefits should be advantageous in the adjuvant setting, as well as in advanced disease settings in which palliation is an important consideration. Ongoing clinical trials will further define the role of this promising oral treatment regimen.

Thymidylate synthetase (TS) and thymidine kinase (TK) are key enzymes in de novo and salvage pathways for pyrimidine nucleotide synthesis, respectively. A high incidence of colorectal adenocarcinomas with varied grades of cell differentiation can be induced by 1,2-dimethylhydrazine (DMH) in rats. The marked increases of TS and TK activities were found in the poorly and well-differentiated adenocarcinomas of the colon, respectively. Oral administration of 1-(2-tetrahydrofuryl)-5-fluorouracil in combination with uracil (UFT) markedly reduced the number and accumulated area of colonic carcinomas, and TS activity in the poorly differentiated adenocarcinomas. A potential balance between the de novo and the salvage pathways for pyrimidine nucleotide synthesis was suggested to be related with the histopathological grades of cell differentiation. Suppression of colonic TS activity by UFT administration reduced the colonic carcinogenesis and the potency of the poorly differentiated adenocarcinomas of the colon.

For clinical cancers of esophagus (10 cases), stomach (7), colon and rectum (11) and breast (5), subrenal capsule assays (SRC) were performed using normal or AF nude mice. The sensitivity of anticancer drugs (UFT, CDDP) was evaluated by both the change in graft size under the renal capsule and the histological findings of these grafts. SRC was found to be a very reliable testing method for cancer of esophagus, colon and rectum because these grafts possessed remarkable viability. Evaluability of these two cancers was very high (approximately 80%). Sensitivity of UFT was 29% (2/7) for esophageal cancer, 50% (5/10) against colon and rectal cancer, and that of CDDP was 40% (2/5) and 17% (1/6), respectively. Evaluability of gastric and breast cancers was very low because of the poor growth of the grafts irrespective of the immunity of host animals. It was discussed why the evaluation rate depended on the type of cancer. These results suggest that indications for SRC are restricted, but that for colon and rectal or esophageal cancer SRC is a reliable testing method for anticancer drugs in clinical use.

The effects of 1-(2-tetrahydrofuryl)-5-fluorouracil in combination with uracil (UFT) on mammary carcinogenesis and growth of tumors induced with 7,12-dimethylbenz[a]anthracene (DMBA) were investigated in rats. Daily oral administration of UFT reduced the incidence and number of mammary tumors compared with those of the DMBA control group, resulting in lower activities in DNA synthesizing enzymes, thymidylate synthetase and thymidine kinase, and a reduction of bromodeoxyuridine-immunoreactive (S-phase) cells in mammary tumors of UFT-treated rats.

Thymidylate synthase (TS) is a target enzyme of 5-fluorouracil and is inhibited by 5-fluoro-dUMP (FdUMP) to form an inactive ternary complex. We investigated the changes in the number of FdUMP binding sites in human colorectal carcinoma tissues after treatment with 5-fluorouracil derivatives and also examined the mechanisms underlying these changes. The number of FdUMP binding sites was significantly increased in patients who received tegafur and uracil preoperatively [UFT (+) group, n = 14] compared with those who did not [UFT (-) group, n = 36; P < 0.0001]. No amplification of the TS gene was observed in the carcinoma tissues in either group. The level of TS mRNA in the carcinoma tissues showed no significant difference between UFT (-) and UFT (+) groups. There was a significant correlation between the level of TS mRNA and TS in the UFT (-) group, as shown by simple linear regression analysis (P < 0.05). In the UFT (+) group, 9 of 12 cases showed TSf corresponding to their level of TS mRNA. It seemed that the augmentation of TStot is the result of accumulation of ternary complex. Thus, TS inhibition by FdUMP will be insufficient in the absence of methylenetetrahydrofolate in the cytosol, because translation of TS from TS mRNA has been shown to continue in the presence of FdUMP.

Previous work in our laboratory showed that UFT (mixed compound of tegafur and uracil, molar ratio 1:4, respectively) caused the prolonged reduction of dTTP in L1210 leukemia cells in comparison with 5-fluorouracil (5-FU). The purpose of this study was to assess the effect of UFT on cell cycle distribution and thymidylate synthase activity of a leukemia cell line as compared with 5-FU. UFT and 5-FU were orally given to BDF1 mice bearing L1210 ascites tumor on day 3 after the tumor inoculation. Cell cycle distribution patterns at 24 hr after the drug administration showed a higher percentage of S phase in tumor cells treated with UFT than in those treated with 5-FU. Until 6 hr after the oral administration of the drugs, UFT inhibited the incorporation of [3H] deoxyuridine into DNA more long than 5-FU did. These results indicated that UFT has longer and stronger inhibitory effects on DNA replication than 5-FU in vivo under the employed experimental conditions (i.e., low and single doses of these fluorinated pyrimidines).

Changes in the deoxyribonucleotide pools following a single oral administration of 13 mg/kg of 5-fluorouracil (5-FU) or of 64.8 mg/kg of UFT (a mixed compound of tegafur and uracil) were investigated. We compared their pharmacodynamics and effects on nucleotide metabolism in L1210 ascites tumor on day 3 after intraperitoneal tumor inoculation. The intracellular dTTP pool decreased to half the control level 1-6 hr after the administration of 5-FU. The dTTP pools rapidly recovered after 6 hr. In contrast, UFT kept the intracellular dTTP level to 1/3 to 1/2 of the control level for 24 hr. Either drug elevated the intracellular dATP pools, but decreased dCTP pools. UFT influenced the intracellular dATP and dCTP levels longer than 5-FU. Orally administered UFT seemed to exert a longer and more potent inhibitory effect on thymidylate synthetase than equimolar 5-FU. In view of these results, we suggest that UFT could be a more potent chemotherapeutic drug than 5-FU in oral administration.

The pharmacological properties of a new type of anti-cancer agent, 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) and uracil (U), in a molar ratio of 1:4, were investigated and compared with those of FT, 5-fluorouracil (5-FU) and uracil. UFT at doses larger than 874.8 (FT: 270.0) mg/kg p.o. produced slight central nervous depression in mice and rats, as demonstrated by prolongation of the thiopental anesthesia, analgesic activity in the acetic acid stretching test, an anticonvulsant effect on maximal electroshock convulsions and decrease in body temperature. In rabbits UFT at a dose of 291.6 (FT: 90.0) mg/kg p.o. produced an increase in the drowsy EEG pattern. UFT at high dose produced clonic convulsions in mice and rats and cardiac fibrillation in rabbits. UFT had slight cardiorespiratory effects in anesthetized rabbits and dogs and at a dose of 291.6 (FT: 90.0) mg/kg i.v. it increased the voltage of the T-wave in ECG in anesthetized dogs. At high doses UFT inhibited gastrointestinal transit in mice and it caused emesis in dogs. At doses larger than 291.6 (FT: 90.0) mg/kg p.o. it had a diuretic effect and at higher doses it slightly increased the blood glucose level in rats. FT at equal doses to UFT had the same effects as UFT and the effect of 5-FU was similar to that of UFT. The pharmacological activity of uracil was much less potent. It was concluded that the pharmacological effect of UFT was almost entirely due to FT, however, UFT had much less effect than FT in inducing clonic convulsions, increasing the voltage of the T-waves in ECG and inducing emesis, its depressant effect is probably due to its constituent uracil.