Administration Of UFT Research Articles

Long-term prophylactic effects of intravesical instillation of thiotepa and oral administration of UFT on the recurrence of superficial bladder cancer after transurethral resection

Background. We examined the long-term effects of two chemotherapeutic agents, thiotepa and UFT, a 4 : 1 mixture of uracil and tegafur (a 5-fluorouracil pro-drug), in preventing postoperative recurrence of superficial bladder cancer.

Chemosensitivity of micrometastases and circulating tumor cells to uracil and tegafur as evaluated using LacZ gene-tagged Lewis lung carcinoma cell

The chemosensitivity of the sequence of steps responsible for metastasis formation including circulating tumor cells and micrometastases to a 5-fluorouracil derivative (UFT) was examined with a novel micrometastasis model featuring Lewis lung carcinoma cells tagged with the bacterial LacZ gene and hygromycin R gene ( hyg R). Metastases in the lung could be specifically detected at the single-cell level by X-Gal staining after inoculation of LacZ-transfected tumor cells. Spontaneous metastasis in mice bearing subcutaneous primary tumors was significantly inhibited by UFT at doses of 15–20 mg/kg when it was orally administered from day 14, during the early stage of micrometastasis formation, but not by late administration from day 22. Experimental pulmonary metastasis was also inhibited without significant toxic side effects by oral administration of UFT at a daily dose of 20 mg/kg from day 4, when the tumor cells start new growth in the lung, but not by daily treatment from 8 days after intravenous injection. Oral administration of UFT had no effect on tumor cell arrest in the lung as detected by X-Gal staining. Furthermore, PCR analysis revealed that circulating tumor cells in the peripheral blood of mice bearing primary tumors after subcutaneous injection of hyg R-tagged tumor cells were significantly reduced by the oral administration of UFT for 7 days in a dose-dependent manner. These results indicate that circulating tumor cells in the peripheral blood and micrometastases in the initial growth phase in the lungs are sensitive to this chemotherapeutic agent, and suggest that micrometastasis formation can be effectively inhibited by long-term oral administration of anticancer agents with minimal toxic side effects.

Induction of apoptosis in human tumour xenografts after oral administration of uracil and tegafur to nude mice bearing tumours.

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.

Advantage of postoperative oral administration of UFT (Tegafur and Uracil) for completely resected p-Stage I–IIIa non-small cell lung cancer (NSCLC)

Advantage of postoperative oral administration of UFT (Tegafur and Uracil) for completely resected p-Stage I–IIIa non-small cell lung cancer (NSCLC)

Effects of the anticancer drug cocktail "UFT" on metastatic potentials of squamous cell carcinoma (O-1N) in a hamster model.

UFT, a mixture of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) and uracil, is one of the most widely used anticancer agents. The tissue localization and the efficacy of UFT in preventing lymph node metastasis were studied in hamsters transplanted with oral squamous cell carcinoma (termed "O-1N") which has high lymph node metastatic potency. After UFT administration for 14 consecutive days, the incidence of lymph node metastasis was significantly decreased (16% vs 58%). When UFT was administered orally for 3 consecutive days to hamsters bearing O-1N, and tissue concentrations of tegafur and 5-FU were measured by gas chromatography, the value of 5-FU was significantly higher in the primary transplant tumour, cervical lymph nodes with or without metastasis, and liver, than in the normal oral tissues. When 14C-UFT(14C-tegafur + uracil, a uracil/FT molar ratio of 4) was administered orally for 3 consecutive days to hamsters bearing O-1N, the 14C-tegafur level of tissue homogenates in the buccal and metastatic tumours was within the range of normal oral tissues, but the localization of silver grains was significantly higher in tumour cells than in the oral normal tissues. The results suggest that UFT would be useful for treatment and prevention of lymph node metastasis of oral carcinomas because of the high accumulation of active metabolites in metastatic and non-metastatic lymph nodes.

Disposition of Components of New Anti-cancer Drug S-1 (7): Metabolism of Components of S-1 after Administration to Tumor bearing Rats.

1. S-1, a new oral anti-tumor drug, is composed of 5-fluoro-1-(tetrahydro-2-furanyl)-2, 4(1H, 3H)-pyrimidinedione (Tegafur, FT), 5-chloro-2, 4-dihydroxypyridine (Gimestat, CDHP) and potassium 1, 2, 3, 4-tetrahydro-2, 4-dioxo-1, 3, 5-triazine-6-carboxylate(potassium otastat, Oxo) at a molar ratio of 1 : 0.4 : 1. FT which is masked compound of 5-Fluorouracil (5-FU) plays a role as an effector compound. Both CDHP and Oxo which do not have antitumor activity themselves play roles as modulators. After administration of S-1 or FT to tumor bearing rats, the Cmax and AUC of 5-FU were 20.8 pmol/ml and 207.6 pmol·hr/ml, in FT group and 1, 192.0 pmol/ml and 5, 203.0 pmol·hr/ml, in S-1 group. Thus, the S-1 group showed higher plasma 5-FU levels by 57 times in Cmax and by 25 times in AUC than those in the FT group. Similar to the plasma concentration, the concentration of 5-FU in tumor in the S-1 group was also higher than that in the FT group by 23 times in Cmax and by 16 times in AUC. 2. After administration of S-1 to tumor bearing rats, the plasma concentratio n of CDHP, the reversible competitive inhibitor of dihydropyrimidine dehydrogenase (EC1.3.1.2), showed a Cmax value of 2, 054.8 pmol/ml at 30 min post-dose. The concentration of Oxo, the inhibitor of orotate phosphoribosyltransferase (EC2.4.2.10), in small intestine showed a Cmax value of 36, 156.5 pmol/g at 30 min post-dose, and showed still high concentration of 2, 813.6 pmol/g even at 3 hr post-dose. 3. AUC of 5-FU in plasma and various tissues after a dministration of S-1 were found to be greater than those AUC after administration of UFT (combination of FT and uracil). AUC of fluoroureidopropionic acid (FUPA) and fluoro-β-alanine (FBAL) in the S-1 group were smaller than those in the UFT group.

ＵＦＴ内服治療が奏効した高齢者下顎歯肉癌の１例

症例は左側下顎臼歯部歯肉癌の80歳の女性である。病理組織学的診断は扁平上皮癌であった。UFTの経口単独投与を行ったところ, 腫瘤は徐々に消失し, 投与開始3週間後には臨床的にも組織学的にも腫瘍の消失がみられた。本症例のメタロチオネイン (MT) およびPCNAの発現について免疫組織化学的に検討をした。MTの発現は癌胞巣の周辺部に認められ, その陽性率は約18%と非常に低い値を示した。また, MTの分布様式はPCNAの分布様式と非常に似た分布を示していた。

Pilot trial of a combination comprising of consecutive oral administration of UFT, and two-divided administration of CDDP in non-small cell lung cancer: Gemma A, Kudoh S, Yoshimura A, Ono Y, Takenaka K, Hayashihara K et al. Fourth Department Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113. Anticancer Res 1995;15:2691–2695

Pilot trial of a combination comprising of consecutive oral administration of UFT, and two-divided administration of CDDP in non-small cell lung cancer: Gemma A, Kudoh S, Yoshimura A, Ono Y, Takenaka K, Hayashihara K et al. Fourth Department Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113. Anticancer Res 1995;15:2691–2695

The significance of measuring RNA 5-fluorouracil content in gastrointestinal tract tumors after oral administration of UFT

Background Prior to surgery, UFT [combination of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) and uracil in a 1∶4 molar ratio] was orally administered to 32 patients with cancer of the gastrointestinal tract. During the operation the amount of 5-fluorouracil (5FU) concentration in the RNA (F-RNA) was mesured in normal and tumor tissues. Simultaneously, the 5FU concentration and thymidylate synthase (TS) inhibition rates were determined.

Prolongation of survival period and improvement of cancer cachexia by long-term administration of UFT.

We assayed the antitumoral and anticachectic activity of an oral fluoropyrimidine, UFT using the Colon-26-bearing murine cachexia model in terms of the survival period and parameters corresponding to clinical symptoms. Tumor growth was inhibited by UFT dose-dependently at the dose range of 12.5-25.0 mg/kg per day. Although UFT did not show significant growth inhibition at 15.0 and 12.5 mg/kg to which UFT gave little toxicity, the survival period was shown to be superior to the case of maximum tolerated dose (25.0 mg/kg per day). Next, we compared the maximum increase of life span (ILS) value for an administration schedule of continuous 9 days and 5 weeks which mimics the clinical schedule and found that the ILS value in the latter group was superior to the former and UFT improved cachexia, in the same manner. In the following experiments, we have clarified that UFT decreased the level of both plasma interleukin-6 (IL-6) and tumorous prostaglandin E2 (PGE2) and it highly accelerated IL-6 production from Colon-26. These findings suggest that UFT therapy, in low-toxic dose, could be useful to cachectic patients with poor performance status.

1-(2-Tetrahydrofuryl)-5-fluorouracil in combination with uracil suppresses mammary carcinogenesis and growth of tumors induced with 7,12-dimethylbenz[a]anthracene in rats.

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.

Use of flow cytometry for evaluating breast cancer cell proliferation after chemotherapy

We studied the change in cell proliferation after preoperative oral administration of an anticancer drug using flow cytometry for aspirated breast cancer cell specimens. Thirty-six patients with breast cancer received 400 mg/d of oral UFT (a 1:4 mixture of tegafur and uracil) for 1 to 2 weeks preoperatively. Cells aspirated from the tumor using a fine needle were evaluated for changes before and after administration of the drug. Ki-67, a nuclear-associated proliferation related antigen, staining and DNA ploidy were studied using flow cytometry and compared with cytologic and histologic (mastectomy specimen) changes. After administration of UFT, the number of cells stained with Ki-67 antigen decreased (from 69.2 ± 21.0 to 47.7 ± 28.6), but DNA ploidy was unchanged. The decreasing number of Ki-67-stained cells was well correlated with cell and tissue damage ( P = 0.0170 and P = 0.0090, respectively). These results suggest that flow cytometry is a simple and effective method for evaluating changes in cell proliferation after chemotherapy. This method also would be useful for selecting an effective anticancer drug for postoperative adjuvant chemotherapy.

Experimental evaluation of combination chemotherapy with UFT and cisplatin for the lung cancer: Uchida J, Satake H, Saito H, Nakano K, Takeda S, Unemi N. Anticancer and Antimicrobials, Research Laboratory, Taiho Pharmaceutical Co., Ltd., Taiho. Jpn J Cancer Chemother 1994;21:1001–1008

Combined treatment of UFT with cisplatin (CDDP) achieved remarkable elongation of survival time of BDF1 mice, which were intravenously transplanted with Lewis lung carcinoma (LLC). Three cycles of weekly iv administration of CDDP and vindesine (VDS), and daily oral administration of UFT were scheduled. Combination UFT (18 mg/kg/day) with CDDP (6.0 mg/kg/day) yielded tumor-free survivors in all of the treated animals with slight body weight loss. Its efficacy was superior to that of the combination of CDDP with VDS. Supra-additive cytotoxic activity against LLC cells was observed by Isobologram method on the schedule of the exposure to 5-fluorouracil preceding the exposure to CDDP. Additive effect was observed by the reversed schedule of the treatment. Using human non-small-cell lung cancer (NSCLC) cell lines which derived from histologically different type, additive or greater additive sensitivity to both of the sequential treatment schedules with 5-FU and CDDP was observed. These results suggest that the combination chemotherapy of UFT with CDDP for lung cancer may show high antitumor efficacy with low toxicity in a clinical setting.

Effects of preoperative chemotherapy on DNA ploidy patterns, cell cycle, and histological findings in gastric and colonic cancer patients.

The effects of preoperative chemotherapy on gastric and colonic cancers have yet to be evaluated fully. In this study, its effects were assessed by studying DNA ploidy patterns, cell cycles, and histological findings in such patients. Thirty-nine patients with gastric or colonic cancer were given preoperative chemotherapy with UFT (an admixture of tegafur and uracil). Biopsy specimens for analysis were obtained before chemotherapy through a gastroscope or colonoscope and after chemotherapy from resected tumors. The DNA ploidy patterns and cell cycles were evaluated using a flow cytometer and the tissues were examined histologically. The DNA ploidy pattern was diploid (D) in 12 gastric and 13 colonic cancer patients and aneuploid (A) in 10 and 4 patients, respectively. After chemotherapy, the pattern changed in nine gastric (A-->D: 7, D-->A: 2) and six colonic cancer patients (A-->D: 3, D-->A: 3) and was unchanged in the remaining patients. Cell cyclic analysis showed decreased G1- and increased S-phase fractions in 10 of 12 patients with gastric and 6 of 10 patients with colonic cancer. Histologically, decreased tumor cellularity, increased fibrosis, and/or cytological changes were observed in both cancers after chemotherapy. Gastric and colonic cancers in which the DNA ploidy pattern changed from aneuploid to diploid, G1- decreased and S-phase increased, and/or histological changes were observed, were considered to have responded to preoperative UFT administration.

INHIBITORY EFFECTS OF COMBINED ADMINISTRATION OF UFT AND KRESTIN ON INTRAPERITONEAL METASTASES IN MICE

In this study we investigated the effect of combined administration of UFT and Krestin (PSK) on the growth of intraperitoneal metastasis and temporal changes in the immune-endocrine system under this immunochemotherapy. At 7 days, Plasma ACTH levels of the PSK group were significantly lower than that of the control group (p<0.01). At 14 days, the tumor weight in the combined and the PSK alone group was significantly decreased, compared to the control group (p<0.05). Serum IAP levels of the UFT group were significantly lower than that of the control group (p<0.05). Serum cortisol levels of the combined group were lower than that of the other groups.

Comparison between intravenous and oral postoperative adjuvant immunochemotherapy in patients with stage III colorectal cancer

The present study was designed to retrospectively examine the efficacy of postoperative adjuvant chemotherapy in 107 patients with stage II primary colorectal cancer who underwent curative resection. The chemotherapy regimen was intravenous 5FU/LV in 30 patients (FL-IV group) and oral UFT/PSK in 77 patients (oral group). There were no significant differences between the FL-IV and the oral group with respect to the 3-year relapse-free survival rate, 5-year relapse-free survival rate, and 5-year overall survival rate, which were 82.4 vs. 83.0% (p=0.8546), 78.8 vs. 80.0% (p=0.756), and 81.6 vs. 92.8% (p=0.1609), respectively. Grade 3 adverse events that occurred in the FL-IV group were leukopenia in one patient (3.3%), nausea/vomiting in two (6.6%), anorexia in two (6.6%), diarrhea in one (3.3%), and fatigue in one (3.3%). No grade 3 or 4 adverse events were observed in the oral group. These results suggest that the oral regimen achieved equivalent efficacy to the FL-IV regimen in patients with stage II colorectal cancer, while improving their postoperative quality of life.

Effect of cyclic cisplatin and etoposide therapy with continuous UFT administration on the recurrence of endometrial cancer in nude mice.

Effects of cisplatin and etoposide chemotherapy and/or continuous administration of oral anticancer agent UFT following the initial chemotherapy with cisplatin and etoposide on the tumor recurrence rate were studied in endometrial cancer-bearing mice. Complete response (CR) rate of cyclic administration of cisplatin and etoposide (91%) was significantly higher than that in the control group (60%; p < 0.05). Continuous UFT administration raised a CR rate of 75%, which was not significantly higher than that of the control group. When cyclic administration of cisplatin and etoposide was combined with continuous UFT administration, 100% of CR rate was obtained (p < 0.01). Our results suggest that cisplatin-based cyclic chemotherapy has a therapeutic effect on gynecologic malignancies and is particularly effective in preventing tumor recurrence in mice. Combining this therapy with continuous administration of an oral anticancer agent enhances its therapeutic effect.

Metabolic basis of the synergistic antitumor activities of 5-fluorouracil and cisplatin in rodent tumor models in vivo

The biochemical mechanism of the synergy of 5-fluorouracil (FUra) and cisplatin (CDDP) was studied using transplantable tumors in rodents in vivo. The reduced folate 5,10-methylenetetrahydrofolate (CH2FH4) and its precursor tetrahydrofolate (FH4) are essential cofactors for the formation of a tight ternary complex of thymidylate synthase (TS) and 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) derived from FUra. Intraperitoneal administration of CDDP (5 mg/kg) inhibited the incorporation of exogenous L-methionine into ascitic tumor cells and increased the levels of CH2FH4 and FH4 in ascitic Yoshida sarcoma and P-388 cells transplanted into rats and mice to levels about 2-3 times those measured in cells from animals that were not treated with CDDP. Preincubation with 10(-6) M FUra in Hanks' medium inhibited [6-3H]-2'-deoxyuridine incorporation into DNA of tumor cells from CDDP-treated rats 3 times more than that into cells from untreated rats, indicating that the inhibition of TS by FdUMP derived from FUra was enhanced in the presence of CH2FH4. Intraperitoneal administration of CDDP on day 1 and continuous infusion of FUra from day 1 to day 6 had synergistic effects in inhibiting tumor growth in Yoshida sarcoma-bearing rats. Oral administration of UFT, a combined form of 1 M tegafur and 4 M uracil, for 7 consecutive days beginning at 24 h after tumor implantation and a single i.p. injection of CDDP on day 1 had a significantly greater effect than did either agent alone. These results suggest that CDDP significantly enhances FUra cytotoxicity by inhibiting intracellular L-methionine metabolism and consequently increasing the reduced folate pool in mammalian tumor models in vivo.

慢性関節リウマチに対するｂｉｏｃｈｅｍｉｃａｌ ｍｏｄｕｌａｔｉｏｎ製剤の有用性 ｕｒａｃｉｌ‐ｔｅｇａｆｕｒ配合剤（ＵＦＴ）

Anti-rheumatic effects of UFT, in which tegafur and uracil were mixed at the molar ratio of 1 to 4, were studied experimentally and clinically.Ratio of 5-FU concentrations in plasma, inoculated foot and non-inoculated of adjuvant arthritic rat after administration of UFT were examined in comparison with those of tegafur (FT) . Concentrations of FT in plasma, inoculated foot or non-inoculated foot after oral administration of FT or UFT (15 mg/kg) were nearly equal, whereas 5-FU levels on plasma, inoculated foot and non-inoculated foot after UFT administration were significantly higher than those of FT.Clinical trial of UFT was carried out in 6 RA patients and the clinical response was evaluated according to the Lansbury index and other inflammatory parameters. The dose of UFT was 300 mg/ day.Clinical response was observed in all 6 cases consisted of 2 marked improvement, 2 moderate improvement and 2 slightly improvement. Lansbury index and ADL showed a significant improvement as com-pared with pretreatment and UFT decreased the titer of RAHA and level of IgM.The present study suggests that UFT may be useful in the treatment of RA.

A CASE OF HEPATOMA WITH MULTIPLE PULMONARY METASTASIS WHICH COULD BE RESECTED AFTER SUCCESSFUL MULTIDISCIPLINARY TREATMENT

We experienced a case of hepatoma with multiple pulmonary metastasis, in which the primary lesion could be resected after one year when the metastatic lesions had disappeared by combined therapy with TAE, PTPE and HAL for the primary lesion and systemic administration of UFT. The patient is now, 3 years and 7 months after hepatectomy, doing well and serum AFP is within normal limit. The complete disappearance of pulmonary metastatic lesions is seemed to be caused by the improvement of the host cellular immunoactivity, which would have been occurred by resection of the primary lesion and decreased serum AFP level. Systemic chemotherapy with UFT would be also effective against primary and metastatic lesions. This case suggests that active multidisiplinary treatment should be performed even in the case of hepatoma with multiple metastasis.