Search PubMed⌕ Search

Biomedical subjects

T Shirasaka

Publications and source records attributed to T Shirasaka.

143 records · Page 8Linked to original sources
PubMed1980

Effect of coadministration of thymine or thymidine on the antitumor activity of 1-(2-tetrahydrofuryl)-5-fluorouracil and 5-fluorouracil.

The antitumor activity of 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) on sarcoma was enhanced by oral coadministration of uracil, thymine, or thymidine. The activity was enhanced equally by thymine and by uracil than by thymidine, but thymine caused loss in body weight. The antitumor activity of 5-fluorouracil (5-FU) was also enhanced by thymine or uracil, but both caused loss in body weight. Degradation of 5-FU in vitro was inhibited more by thymine than by uracil. Phosphorylation of 5-FU, however, was not inhibited by uracil, thymine, or thymidine, even at 100 times the concentration of 5-FU. These results suggest that the mechanism of enhancement of the antitumor activity of FT-207 by thymine or thymidine was similar to that by uracil, and that uracil had more effect than thymine or thymidine in enhancing antitumor effect of these drugs to FT-207 without toxicity.

Administration, Oral↗
PubMed1980

DNA synthesis in tumor-bearing rats: purification of liver thymidine kinase stimulating factor from Yoshida sarcoma.

Yoshida sarcoma cells contain a factor that stimulates thymidine kinase activity in the liver of mice in vivo; intraperitoneal injection of an extract from Yoshida sarcoma into normal mice stimulated their liver thymidine kinase activity 2- to 3-fold, whereas injection of a crude extract of normal rat liver did not stimulate the activity at all. A factor that stimulates the de novo synthesis of thymidine kinase in the liver was partially purified from Yoshida sarcoma by ammonium sulfate fractionation, DEAE-cellulose column chromatography and gel filtration. It appeared to be thermolabile and sensitive to trypsin treatment. These results suggested that it was a high-molecular weight protein. Intraperitoneal injection of this factor into 67% hepatectomized rats stimulated thymidine kinase activity 2- to 3-fold. Increase of liver thymidine kinase activity after injection of the factor into mice was blocked by simultaneous injection of actinomycin-D. These results suggest that this factor stimulates de novo synthesis of thymidine kinase in the liver.

Animals↗
PubMed1979

Effect of coadministration of uracil or cytosine on the anti-tumor activity of clinical doses of 1-(2-tetrahydrofuryl)-5-fluorouracil and level of 5-fluorouracil in rodents.

Concentration of 5-fluorouracil (5-FU) in the tumor, blood, and various organs of AH130-bearing rats after administration of clinical doses of 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) and uracil was examined. The concentration of 5-FU in blood was less than 0.02 microgram/ml with all combinations of FT-207 and uracil except high molar ratios of uracil to FT-207 (ratio, 5 and 10), whereas high concentrations of up to a maximum of 0.200 microgram/g on administration of uracil plus 5 or 7.5 mg/kg of FT-207 (ratio, 4), was found in the tumor. On oral administration of FT-207 plus uracil in various combinations, the highest T/B (ratio of concentration of 5-FU in the tumor to that in blood) value was obtained at a ratio of uracil to FT-207 of 4. With this combination, 5-FU concentration in the tumor, muscle, and spleen was higher than that after administration of FT-207 alone (5 mg/kg). These results suggest that at the clinical doses the optimum molar ratio of uracil to FT-207 is 4. Coadministration of cytosine enhanced the antitumor activity of FT-207 on sarcoma-180 in mice. However, cytosine enhanced the antitumor activity of FT-207 less than uracil and its coadministration resulted in a lower concentration of 5-FU in the tumor than coadministration of uracil.

Administration, Oral↗
PubMed1979

Effect of uracil on metabolism of 5-fluorouracil in vitro.

The effect of uracil on the metabolism of 5-fluorouracil (5-FU) in vitro was studied. 5-FU was mainly phosphorylated in intact Yoshida sarcoma cells, whereas it was mainly degraded in liver slices. Uracil inhibited degradation of 5-FU much more than its phosphorylation; incubation of 2,500 microM of uracil with 2.5 microM of 5-FU (molar ratio, 1,000:1) inhibited the degradation of 5-FU by 70%, but did not affect its phosphorylation. With homogenates of Yoshida sarcoma or liver uracil inhibited degradation of 5-FU greatly, phosphorylation of 5-FU by alpha-D-ribose 1-phosphate (RiblP) and ATP to some extent, and phosphorylation by 5-phospho-alpha-D-ribosyl diphosphate (PPRibP) very little. The activities of the enzymes involved in the metabolism of 5-FU in various tissues were also determined. Degradation of 5-FU was much faster in liver than in other tissues and was very slow in tumor tissue. Phosphorylation of 5-FU with RiblP and ATP was rapid in Yoshida sarcoma and bone marrow. Phosphoribosyltransferase activity was high in Yoshida sarcoma and thymus, but low in bone marrow.

Animals↗
PubMed1979

Metabolism of 5-fluorouracil in sensitive and resistant tumor cells.

Thymidine kinase, dTMP kinase, and DNA polymerase activities were determined in cell lines of AH hepatoma, L1210 leukemia, and Yoshida sarcoma that were sensitive and resistant to 5-fluorouracil (5-FU). It was found that the levels of these enzymes in tumor cells were not consistently related to the property of sensitivity to 5-FU. A marked difference was observed between sensitive and resistant cell lines of L1210 leukemia and Yoshida sarcoma in the uptake of labeled 5-FU into the acid-soluble, nucleotide, and RNA fractions, the rate of incorporation of 5-FU into these fractions being 3 to 5 times greater in sensitive tumor cells than in resistant tumor cells. The radioactivities in the acid-soluble fractions of AH44 (sensitive) and AH109A (resistant) were similar after incubation of these cells with labeled 5-FU in vitro. However, a smaller volume of ascites and lower cell number were observed in AH44 (sensitive)-bearing rats than in AH109A (resistant)-bearing rats. These in vivo results indicate that the 5-FU injected intraperitoneally was diluted by ascites more in AH109A (resistant)-bearing rats than in AH44 (sensitive)-bearing rats.

Animals↗
PubMed1975

DNA synthesis in tumor-bearing rats.

Thmidine (TdR) incorporation into DNA increased in the livers and spleens of rats bearing Yoshida sarcoma (solid type) or AH130 (solid type). TdR kinase and DNA polymerase activities increased in the serum, liver, and spleen of these rats, while thymidine monophosphate kinase activity increased appreciably only in the liver and spleen. On diethylaminoethyl cellulose column chromatography, 2 peaks of TdR dinase activity were separated from the serum and tumor tissues of rats bearing Yoshida sarcoma (solid type) while only 1 peak was obtained from the liver. TdR kinase activity in the serum decreased abruptly 7 hr after removal of the Yoshida sarcoma, while that in the liver decreased more slowly.

Animals↗
PubMedDate not supplied

Feasibility study on protracted infusional 5-fluorouracil and consecutive low-dose cisplatin for advanced gastric cancer.

In this phase II trial 31 patients with advanced gastric cancer (21 with metastatic cancer and 10 with locally advanced cancer) were treated with a continuous 24-hour infusion of 5-fluorouracil (5-FU) 330 mg/m2/day plus low-dose cisplatin (CDDP) 6 mg/m2/day by bolus infusion on days 1-5. The regimen with a combination of 5-FU and low-dose CDDP (FLDP) was repeated weekly for two to four courses according to response and tolerance. In 24 (77%) of the 31 patients, four courses of this regimen were administered. The overall response rate was in 14/31 (45%) patients with measurable disease, including one complete response and 13 partial responses. An especially high response rate of 60% was seen in 10 patients with liver metastasis. Median survival time was 11 months (range 6-27+) in the 10 cases of locally advanced cancer and 11 months (range 6-24+) in the 21 cases of metastatic cancer. Toxicity was primarily hematologic. Leukopenia and thrombocytopenia of World Health Organization (WHO) grade 3 or 4 occurred in 4/31 (13%) and 4/31 (13%) of patients, respectively. Renal dysfunction, which is a major toxicity associated with CDDP, was not observed without hydration. The patients were able to eat during therapy and preserved a good quality of life. A randomized trial including the FLDP regimen is needed to compare it with other active regimens, particularly the use of high-dose CDDP.

Adult↗
PubMedDate not supplied

Combined effects of S-1, a new form of oral tegafur, plus modulators on ovarian cancer in nude rats.

We evaluated the efficacy of S-1 as a new oral antitumor agent in ovarian cancer-bearing nude rats. This drug consists of tegafur, 5-chloro-2,4-dihydroxypyridine, and oxonic acid in a molar ratio of 1:0.4:1.S-1 was given alone or in combination with cisplatin. When administered alone at a daily dose of 20 mg/ kg, S-1 produced a significant inhibition of tumor growth [inhibition rate (IR) 89%] in the treated versus the control animals (p < 0.05). The effects of S-1 resembled those of cisplatin-treated groups. The consecutive daily administration of S-1, 20 mg/kg, combined with cisplatin, 1 mg/kg, markedly inhibited cell growth (IR 99%), a significant difference relative to cisplatin alone (p < 0.05). The daily administration of S-1 combined with low-dose cisplatin induced tumor regression with a low toxicity.

Administration, Oral↗
PubMedDate not supplied

Soluble interleukin-2 receptors in pulmonary tuberculosis.

Serum levels of soluble interleukin-2 receptor (IL-2R) were measured in patients with pulmonary tuberculosis, nontuberculous pulmonary diseases (bacterial pneumonia, lower respiratory tract infection, lung cancer), and in normal volunteers. Patients with tuberculosis had increased levels of soluble IL-2R compared to normal controls. Abnormally elevated levels were also shown in patients with nontuberculous pulmonary diseases, suggesting that elevations of soluble IL-2R are not specific for tuberculosis. In patients with tuberculosis, elevated levels of soluble IL-2R were steadily decreased to normal levels during successful treatment. Additionally, soluble IL-2R levels in tuberculosis were closely correlated with adenosine deaminase levels. Thus, it seems possible that measurements of soluble IL-2R may be beneficial in the diagnosis and the management of patients with tuberculosis. Furthermore, we demonstrated that elevated levels of soluble IL-2R in tuberculosis appear to be a consequence of cellular activation of mononuclear cells and not to be the result of cell death with subsequent IL-2R release.

Adenosine Deaminase↗
PubMedDate not supplied

Chemoimmunosensitization of the T24 human bladder cancer line to Fas-mediated cytotoxicity and apoptosis by cisplatin and 5-fluorouracil.

Previous studies have demonstrated that cisplatin (CDDP) sensitizes bladder cancer cells to Fas-mediated cytotoxicity and that CDDP also enhances the cytotoxic effect of 5-fluorouracil (5-FU). These agents mediate apoptosis and may share common intracellular pathways leading to cell killing. We reasoned that combination treatment with CDDP, 5-FU and anti-Fas monoclonal antibody (mAb) might overcome the drug-resistance. We investigated whether CDDP, 5-FU and anti-Fas mAb synergize in cytotoxicity and apoptosis against the T24 bladder cancer line. Cytotoxicity was monitored by a one day microculture tetrazolium dye assay. Treatment of T24 cells with anti-Fas mAb in combination with CDDP or 5-FU resulted in a synergistic cytotoxic effect. In addition, combination treatment of T24 cells with CDDP, 5-FU and anti-Fas mAb further enhanced the synergistic cytotoxicity achieved by two agents. The synergy achieved in cytotoxicity with CDDP, 5-FU and anti-Fas mAb was also achieved in apoptosis. The current study demonstrates that combination treatment of bladder cancer cells with CDDP, 5-FU and anti-Fas mAb overcomes their resistance. In addition, the sensitization required low concentrations of CDDP and 5-FU, and thus supporting the potential in vivo application of combination of CDDP, 5-FU and immunotherapy in the treatment of drug-resistant bladder cancer.

Antibodies, Monoclonal↗
PubMedDate not supplied

An in vitro examination of a 5-fluorouracil regimen involving continuous venous infusion using cultured cell lines derived from ovarian cancers.

To examine the antitumor effectiveness of continuous venous infusion of 5-fluorouracil (5-FU), such a regimen was mimicked in vitro using cultured ovarian cancer cell lines. Two ovarian carcinoma cell lines, HRA and KK with cell doubling times (DT) of 16 h and 45 h, respectively, were grown under three incubation conditions with respect to 5-FU exposure, and the extent of growth inhibition was compared among the three conditions and between the two cell lines. Protocol I: 6 h-intermittent exposure to 5-FU, protocol II: 24 h-intermittent exposure to 5-FU, protocol III: uninterrupted exposure to 5-FU. The 50% growth inhibitory concentrations (IC50) of 5-FU obtained for KK cells grown under protocols I and II were both two times higher than that obtained under protocol III. Regarding HRA cells, IC50 obtained under protocol I was two times higher than that obtained under protocol III, while that obtained under protocol II was 3.7 times higher than that obtained under protocol III. Results obtained from the present in vitro examination suggested that the drug-free interval in the intermittent infusion of 5-FU should be shorter than the DT of the targeted tumor cells to obtain an efficacy corresponding to that obtained by uninterrupted exposure to the drug. In establishing an effective intermittent continuous infusion therapy with 5-FU with fewer side effects, the drug-free interval should be shorter than the DT of tumor cells, but longer than the DT of proliferating cells in normal tissues, including gastrointestinal mucosa cells assuming that these normal cells possess shorter DT than tumor cells.

Cell Division↗
PubMedDate not supplied

Possible regulation of 5-fluorouracil-induced neuro- and oral toxicities by two biochemical modulators consisting of S-1, a new oral formulation of 5-fluorouracil.

S-1 is a new oral formulation of 5-fluorouracil (5-FU) containing 1 M tegafur and 0.4 M 5-chloro-2,4-dihydroxypyridine (CDHP) and 1 M potassium oxonate (Oxo). It has been reported to have a high antitumor activity and low gastrointestinal toxicity in rats bearing murine and human tumors. We further studied the possible inhibition of the toxicities caused by the products of 5-FU metabolism with the use of CDHP, a new inhibitor of 5-FU degradation and Oxo, an inhibitor of 5-FU phosphorylation. In a model of pentylenetetrazole-induced convulsions in mice, intravenous injection of fluoroacetate (3 mg/kg), 2-fluoro-b-alanine (30 mg/kg) and 5-FU (over 300 mg/kg) significantly augmented the occurrence of convulsion. However coadministration of an equivalent dose of CDHP with 5-FU almost completely suppressed the 5-FU-augmented convulsions, suggesting that inhibition of 5-FU catabolism by CDHP may lead to a decreased risk of development of 5-FU neurotoxicity. Another advantage of the use of S-1 was protection through Oxo against the development of 5-FU-induced mucositis, which occurs frequently in cancer patients. When 6 mg/kg of S-1 was administered orally to beagle dogs for 5 days, the incidence of stomatitis decreased markedly compared to that in dogs receiving the same dose of S-1 not containing Oxo, in which severe stomatitis was frequently observed. One of the possible mechanisms of the decreased incidence of mucositis associated with oral S-1 administration is the decreased formation of 5-fluoronucleotides from 5-FU in the mucosal tissues of the oral cavity. These results suggest that oral S-1 could be employed for the treatment of cancer patients with marked reduction in the incidence of toxicities including encephalopathy, stomatitis and diarrhea.

Animals↗
PubMedDate not supplied

Enhanced inhibition of thymidylate synthase by 5-fluorouracil and [6S]leucovorin combination therapy for breast cancer.

The influence of the addition of [6S]leucovorin (LV) to 5-fluorouracil (5-FU) preoperative chemotherapy was examined in patients with surgically resectable breast cancer who had had no prior treatment. The patients underwent one of the following three treatments at their will: (1) 5-FU 500 mg/m2 administered by an i.v. bolus; (2) [6S]LV 250 mg/m2 infused intravenously over two hours, with 5-FU 500 mg/m2 as an IV bolus at the midpoint of [6S]LV infusion, (3) no drug treatment. Tumors were resected 24 hours after the dose of 5-FU with or without [6S]LV. These studies confirmed an increased stabilization of 5-fluorodeoxyuridine monophosphate (FdUMP)-thymidylate synthase(TS)-folate ternary complex with the addition of [6S]LV. An increase of total TS activity was also found.

Adolescent↗