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T Shirasaka

Publications and source records attributed to T Shirasaka.

At least 91 records · Page 5Linked to original sources
PubMed1994

[Innate resistance to thymidylate synthase inhibition after 5-fluorouracil treatment--a rationale of combined use of cisplatin and its optimal administration dose].

We examined the changes of the number of FdU MP binding sites of thymidylate thynthase (TS-BS) in Yoshida sarcoma after administration of 5-FU to the tumor bearing rats. We also investigated the optimal dose of CDDP for the increase of intracellular folate level. In the group received consecutive 7-days administration of UFT (U-7 group), total TS-BS was significantly increased compared with non-treatment group and the group received only UFT (U-1 group). For free TS-BS, however, there was no difference despite of UFT administration. Thymidylate synthase inhibition rate (TSIR) was, therefore, significantly high in U-7 group compared with U-1 group. It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when 5-FU chemotherapy was performed. The optimal dose of CDDP as a modulator of 5-FU was 1 mg/kg in rat when it was estimated from the changes of intracellular folate levels after administration, which was less than the dose to reveal its own anticancer effect.

Animals↗
PubMed1994

[The clinical effect of chemotherapy with 5-FU and low-dose CDDP in patients with advanced gastric cancer].

A trial of FP therapy, a novel systemic chemotherapy consisting of 5-FU and low-dose CDDP, was carried out in patients with advanced gastric cancer and the clinical effects were evaluated. Five hundred mg/body/day of 5-FU was continuously administered via the central venous catheter for 7 consecutive days and 10mg/day of CDDP was rapidly administered with 500ml saline on days 1-5. The regimen was repeated for at least 4 weeks. The FP therapy was carried out in 22 cases, including several patients who underwent FP as an adjuvant therapy; 1 CR, 2PR's 1MR and 2NC's were obtained among the 6 patients with clinically evaluable lesions, resulting in a response rate of 50%. In four cases, the FP therapy was given as a neoadjuvant therapy, and histopathological examination of the resected specimen revealed histological effects exceeding Grade 2 in all 4 cases. Bone marrow suppression was the most commonly observed side effect, but renal dysfunction and nausea were not found. FP therapy is considered an effective therapy against advanced gastric cancer, from the viewpoint of both the clinical and adverse effects, in comparison with conventional regimen consisting of 5-FU and a single and large dose of CDDP.

Adenocarcinoma↗
PubMed1993

Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats.

The possibility of decreasing the gastrointestinal (GI) toxic effects of 5-fluorouracil (5-FU) on the digestive tract such as its injury of cells and induction of diarrhea, without reducing its antitumor activity, was investigated in rats. Oxonic acid was found to inhibit the phosphorylation of 5-FU to 5-fluorouridine-5'-monophosphate catalyzed by pyrimidine phosphoribosyl-transferase in a different manner from allopurinol in cell-free extracts and intact cells in vitro. On p.o. administration of 5-FU (2 mg/kg) and a potent inhibitor of 5-FU degradation to Yoshida sarcoma-bearing rats, oxonic acid (10 mg/kg) was found to inhibit the formation of 5-fluorouridine-5'-monophosphate from 5-FU and its subsequent incorporation into the RNA fractions of small and large intestine but not of tumor and bone marrow tissues. This selective inhibition of 5-FU phosphorylation in the GI tract was due to the much higher concentrations of oxonic acid in GI tissues than in other tissues and the blood. On p.o. administration with the 5-FU derivative, UFT, which is a combined form of 1 M tegafur and 4 M uracil and usually administered p.o. to cancer patients in Japan, oxonic acid (10-50 mg/kg) markedly reduced injury of GI tissues and/or severe diarrhea without influencing the antitumor effect of UFT. These findings suggest that coadministration of oxonic acid suppresses the GI toxicity of 5-FU and its derivatives without affecting their antitumor activity and thus prolongs the life span of cancer-bearing rats.

Administration, Oral↗
PubMed1993

Changes in drug sensitivity of human immunodeficiency virus type 1 during therapy with azidothymidine, dideoxycytidine, and dideoxyinosine: an in vitro comparative study.

Human immunodeficiency virus type 1 (HIV-1) strains were isolated from nine patients before and after prolonged therapy with either an alternating regimen of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC) (AZT/ddC) or 2',3'-dideoxyinosine (ddI) alone. All strains obtained from four patients who received AZT/ddC for up to 41 mo were highly insensitive to AZT in vitro. Only one strain obtained after AZT/ddC therapy showed reduced susceptibility to ddC in addition to AZT and had previously unreported amino acid substitutions in the viral polymerase-encoding pol region, whereas three other strains had one or more of the five previously reported AZT-related mutations. In five HIV-1 strains from patients who received ddI for up to 29 mo, no appreciable decrease in sensitivity to ddI was detected. Two strains isolated after ddI therapy had no significant amino acid mutations, although three strains had a mutation reportedly associated with ddI administration. These data suggest that HIV-1 develops reduced susceptibility to AZT more readily than to ddC and ddI and/or that the reduced susceptibility to ddC and ddI is modest in degree. Moreover, the present data suggest that an alternating regimen of AZT and ddC does not block the emergence of AZT-insensitive variants. It should be noted, however, that the current results do not provide a basis for concluding that AZT/ddC or ddI is inferior, equivalent, or superior to AZT as therapy of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1993

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.

Animals↗
PubMed1993

High-level resistance to zidovudine but not to zalcitabine or didanosine in human immunodeficiency virus from children receiving antiretroviral therapy.

Human immunodeficiency virus type 1 (HIV-1) isolates from children receiving long-term therapy with an alternating regimen of zidovudine and zalcitabine, or with didanosine monotherapy, were evaluated for resistance to zidovudine, zalcitabine, and didanosine, and for mutations known to be associated with zidovudine or didanosine resistance. HIV-1 from four of six patients receiving zidovudine with zalcitabine developed high-level resistance to zidovudine. A mutation in the HIV-1 reverse transcriptase that is highly associated with zidovudine resistance was identified in all four zidovudine-resistant posttherapy isolates. In contrast, none of the HIV-1 isolates from the seven patients receiving didanosine developed high-level resistance to this agent, despite the identification of a didanosine-associated mutation in six of these posttherapy isolates, although small decreases in sensitivity to didanosine were observed. These results indicate that nucleoside analog-associated mutations in HIV-1 occur frequently in children receiving long-term antiretroviral therapy and that alternating combination therapy does not prevent the development of resistance to zidovudine. They also suggest that there may be differences in the degree of resistance conferred by mutations that result from therapy with different nucleoside analogs. These findings underscore the need for studies to define the clinical importance of these mutations, and for treatment strategies to overcome the emergence of viral resistance in vivo.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Monitoring the activity of antiviral therapy for HIV infection using a polymerase chain reaction method coupled with reverse transcription.

AIM: To monitor the anti-HIV-1 activity of antiretroviral agents in patients with HIV-1 infection. METHOD: Quantification of viral RNA copy in plasma or serum using a polymerase chain reaction method coupled with reverse transcription. CONCLUSIONS: The HIV-1 RNA copy number represents the HIV-1 viremia status in patients with HIV-1 infection. This copy number is likely to be useful in monitoring the effectiveness of antiviral therapy and the method is likely to be built into every clinical trial of anti-HIV-1 therapy in the near future.

Antiviral Agents↗
PubMed1993

In vitro anti-human immunodeficiency virus (HIV) activities of transition state mimetic HIV protease inhibitors containing allophenylnorstatine.

Transition state mimetic tripeptide human immunodeficiency virus (HIV) protease inhibitors containing allophenylnorstatine [(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] were synthesized and tested for activity against HIV in vitro. Two compounds, KNI-227 and KNI-272, which were highly potent against HIV protease with little inhibition of other aspartic proteases, showed the most potent activity against the infectivity and cytopathic effect of a wide spectrum of HIV strains. As tested in target CD4+ ATH8 cells, the 50% inhibitory concentrations of KNI-227 against HIV type 1 LAI (HIV-1LAI), HIV-1RF, HIV-1MN, and HIV-2ROD were 0.1, 0.02, 0.03, and 0.1 microM, respectively, while those of KNI-272 were 0.1, 0.02, 0.04, and 0.1 microM, respectively. Both agents completely blocked the replication of 3'-azido-2',3'-dideoxythymidine-sensitive and -insensitive clinical HIV-1 isolates at 0.08 microM as tested in target phytohemagglutinin-activated peripheral blood mononuclear cells. The ratios of 50% cytotoxic concentrations to 50% inhibitory concentrations for KNI-227 and KNI-272 were approximately 2,500 and > 4,000, respectively, as assessed in peripheral blood mononuclear cells. Both compounds blocked the posttranslational cleavage of the p55 precursor protein to generate the mature p24 Gag protein in stably HIV-1-infected cells. The n-octanol-water partition coefficients of KNI-227 and KNI-272 were high, with log Po/w values of 3.79 and 3.56, respectively. Degradation of KNI-227 and KNI-272 in the presence of pepsin (1 mg/ml, pH 2.2) at 37 degrees C for 24 h was negligible. Current data warrant further careful investigations toward possible clinical application of these two novel compounds.

Antiviral Agents↗
PubMed1993

Differential phosphorylation of azidothymidine, dideoxycytidine, and dideoxyinosine in resting and activated peripheral blood mononuclear cells.

The antiviral activity of azidothymidine (AZT), dideoxycytidine (ddC), and dideoxyinosine (ddI) against HIV-1 was comparatively evaluated in PHA-stimulated PBM. The mean drug concentration which yielded 50% p24 Gag negative cultures were substantially different: 0.06, 0.2, and 6 microM for AZT, ddC, and ddI, respectively. We found that AZT was preferentially phosphorylated to its triphosphate (TP) form in PHA-PBM rather than unstimulated, resting PBM (R-PBM), producing 10- to 17-fold higher ratios of AZTTP/dTTP in PHA-PBM than in R-PBM. The phosphorylation of ddC and ddI to their TP forms was, however, much less efficient in PHA-PBM, resulting in approximately 5-fold and approximately 15-fold lower ratios of ddCTP/dCTP and ddATP/dATP, respectively, in PHA-PBM than in R-PBM. The comparative order of PHA-induced increase in cellular enzyme activities examined was: thymidine kinase > uridine kinase > deoxycytidine kinase > adenosine kinase > 5'-nucleotidase. We conclude that AZT, ddC, and ddI exert disproportionate antiviral effects depending on the activation state of the target cells, i.e., ddI and ddC exert antiviral activity more favorably in resting cells than in activated cells, while AZT preferentially protects activated cells against HIV infection. Considering that HIV-1 proviral DNA synthesis in resting lymphocytes is reportedly initiated at levels comparable with those of activated lymphocytes, the current data should have practical relevance in the design of anti-HIV chemotherapy, particularly combination chemotherapy.

5'-Nucleotidase↗
PubMed1993

Antiallergic profile of the novel H1-antihistaminic compound levocabastine.

Levocabastine hydrochloride (R50 547, CAS79516-68-0) caused no inhibitory effect on the histamine release from rat peritoneal mast cells induced by compound 48/80, A23187 and concanavalin A. However, the drug inhibited histamine release from passively sensitized mast cells and passive peritoneal anaphylaxis in rats, though higher concentrations or doses were required. Moreover, levocabastine provided a relatively potent inhibitory effect on histamine release from lung pieces of actively sensitized guinea pigs exposed to antigen, and simultaneously the drug prevented a decrease in the cyclic AMP (cAMP) content. Levocabastine potently inhibited histamine-induced cutaneous reactions in rats and the drug also prevented histamine-induced contraction of isolated guinea pig ileum. Levocabastine did not induce any significant changes in platelet aggregation or in the contraction of guinea pig ileum induced by platelet activating factor (PAF). However, the drug inhibited eosinophil migration induced by PAF. The chemotaxis of neutrophils induced by N-formyl-methionyl-leucylphenylalanine (fMLP) was also inhibited by levocabastine in a dose-dependent fashion. Levocabastine has no influence on the order parameter tested with liposomes, suggesting that the drug provides no significant effect on the membrane fluidity of lipid bilayer. These results seem to indicate that the antiallergic effect of levocabastine is mainly dependent on its potent antihistaminic activity.

Anaphylaxis↗
PubMed1993

[Plasma amino acid levels in alcoholics].

Plasma aromatic amino acid (AAA) and branched-chain amino acid (BCAA) concentrations were determined in 197 alcoholics. The BCAA/AAA molar ratio in patients with alcohol withdrawal symptoms was compared with the ratio in patients without such symptoms. The BCAA/AAA molar ratio in patients with emotional disturbance or with transient hallucination was significantly lower than that in patients without these symptoms. The BCAA/AAA molar ratio tended to be lower in patients with alcohol withdrawal convulsion or with delirium tremens as compared to patients without such symptoms. The BCAA/AAA molar ratio had a negative correlation with plasma total bilirubin and LDH and had a positive correlation with plasma choline esterase and albumin. Oral administration of amino acid preparations (Aminoleban EN) to the patients elevated the BCAA/AAA molar ratio and normalized liver function. These results indicate that abnormalities of amino acid metabolism caused by liver damage in alcohol dependence may have an important role in the pathogenesis of alcohol withdrawal syndrome.

Adult↗
PubMed1992

Phosphorylation of smg p21B in rat peritoneal mast cells in association with histamine release inhibition by dibutyryl-cAMP.

IP3 formation and histamine release from rat peritoneal mast cells stimulated by compound 48/80 were dose-dependently inhibited by Bt2cAMP. These inhibitions were restored to the control level in the presence of H-8, a protein kinase A inhibitor. The 22 kDa protein in mast cells was revealed as a markedly phosphorylated protein by incubating with Bt2cAMP, and this phosphorylation was also diminished by H-8. The 22 kDa phosphoprotein of rat mast cells comigrated with phosphorylated smg p21B, purified from human platelets and phosphorylated by protein kinase A in cell-free system, in both one- and two-dimensional PAGE analysis. Moreover, 22 kDa protein in mast cells was identified as smg p21B by immunoblot analysis using an antibody against smg p21B. From the present study, it became clear that smg p21B is phosphorylated by means of protein kinase A system in rat peritoneal mast cells, and it was assumed that phosphorylated smg p21B plays some important role in the suppression of IP3 formation and histamine release from rat peritoneal mast cells.

Animals↗
PubMed1992

Chemistry and anti-HIV properties of 2'-fluoro-2',3'-dideoxyarabinofuranosylpyrimidines.

The synthesis, chemistry, biochemistry, and anti-HIV activity of a series of 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)pyrimidines have been studied in an attempt to find useful anti-AIDS drugs. Synthesis is carried out via a 2,3-dideoxyribose intermediate which facilitates the preparation of analogues by removing the sugar 3'-hydroxyl group prior to, rather than after, condensation with a uracil or cytosine aglycon. The 2'-F-dd-uridine analogues 7a-d (with H, F, Cl, and CH3 substitution in the 5-position) as well as the 4-deoxy compound (12b) are nonprotective to ATH8 or CEM cells infected with HIV-1. In the corresponding cytidine series, the 5-chloro analogue (11) is inactive. However, 2'-fluoro-2',3'-dideoxyarabinosylcytosine, 10a, and its 5-fluoro analogue, 10b, are both active. While neither compounds is a potent as ddC or 5-F-ddC (2b), 10b gives complete protection against the cytopathic effects of HIV in both host cell lines. 2'-Fluoro substitution confers increased chemical and enzymatic stability on dideoxynucleosides. Even though dideoxy pyrimidine nucleosides are inherently more stable than the corresponding purine analogues toward acid-catalyzed cleavage of the glycosidic bond, 2'-fluoro substitution (10a) still increases stabilization relative to ddC (2b). No detectable deamination by partially purified cytidine deaminase is observed with the 2'-fluoro compounds 10a, 10b, or 11 under conditions which rapidly deaminate cytidine. A small amount of 2'-F-dd-ara-U (7a) is formed from 10a in monkey plasma after greater than 24 h of exposure. The octanol-water partition coefficients for the dideoxynucleosides in this study indicate their hydrophilic character, with log P values varying from -0.28 to -1.18.

Animals↗
PubMed1992

In vitro inhibition of human immunodeficiency virus (HIV) type 1 replication by C2 symmetry-based HIV protease inhibitors as single agents or in combinations.

C2 symmetry-based human immunodeficiency virus (HIV) protease inhibitors were examined in vitro as single agents or in combination with 3'-azido-2',3'-dideoxythymidine (AZT) or 2',3'-dideoxyinosine for activity against HIV type 1 (HIV-1). Ten C2 symmetry-based or pseudo-C2 symmetry-based HIV protease inhibitors were active against a laboratory strain (HIV-1IIIB) in the HIV-1 cytopathic effect inhibition assay. Three inhibitors, A75925, A76928, and A77003, selected to represent a range of aqueous solubility and antiviral activity, were active against four different HIV-1 strains tested. These three inhibitors exhibited a significant inhibition of the cytopathic effect of HIV-1 against the CD4+ ATH8 cell line, with 90% inhibitory concentrations ranging from 0.1 to 4 microM. Cellular toxicity was negligible at up to 20 microM. Furthermore, they completely inhibited the replication of monocytotropic strain HIV-1Ba-L in purified monocytes and macrophages at 0.75 to 2 microM. Potent inhibitory activity against a primary HIV-1 isolate and an AZT-resistant HIV-1 variant was also observed for all three inhibitors in phytohemagglutinin-activated peripheral blood mononuclear cells. When these three HIV protease inhibitors and AZT or 2',3'-dideoxyinosine were used in combinations against a primary HIV isolate in phytohemagglutinin-activated peripheral blood mononuclear cells and the results were analyzed with the COMBO program package, their antiviral activities were identified to be synergistic in some cases and additive in others. The present data warrant further investigations of these compounds as potential antiviral agents for the therapy of HIV infections.

Didanosine↗
PubMed1991

Escherichia coli mediated biosynthesis and in vitro anti-HIV activity of lipophilic 6-halo-2',3'-dideoxypurine nucleosides.

A series of 6-substituted 2',3'-dideoxypurine ribofuranosides (ddP) was enzymatically synthesized with live E. coli in an effort to enhance the lipophilicity of this class of anti-human immunodeficiency virus (HIV) compounds and thereby facilitate drug delivery into the central nervous system. All 6-halo-substituted ddPs were substantially more lipophilic, as defined by their octanol-water partition coefficient (P), than their nonhalogenated congeners 2',3'-dideoxyinosine (ddI) or 2',3'-dideoxyguanosine (ddG). For this class of compounds, log P's ranged from +0.5 to -1.2 in the following order: 6-iodo, 2-amino-6-iodo greater than 6-bromo, 2-amino-6-bromo greater than 6-chloro, 2-amino-6-chloro greater than 6-fluoro, 2-amino-6-fluoro much greater than ddG greater than ddI. These compounds were evaluated in vitro for ability to suppress the infectivity, replication, and cytopathic effect of HIV. 2-Amino-6-fluoro-, 2-amino-6-chloro-, and 6-fluoro-ddP exhibited a potent activity against HIV comparable to that of ddI or ddG and completely blocked the infectivity of HIV without affecting the growth of target cells. The comparative order of in vitro anti-HIV activity was 2-amino-6-fluoro, 2-amino-6-chloro, 6-fluoro greater than 2-amino-6-bromo greater than 2-amino-6-iodo, 6-chloro greater than 6-bromo greater than 6-iodo. These compounds also exhibited potent in vitro activity against HIV-2 and 3'-azido-3'-deoxythymidine-resistant HIV-1 variants. All 2-amino-6-halo-ddPs and 6-halo-ddPs were substrates for adenosine deaminase (ADA) and were converted to ddG or ddI, respectively. In the presence of the potent ADA inhibitor 2'-deoxycoformycin, 6-halo-substituted ddPs failed to exert an in vitro antiretroviral effect. These dideoxypurine nucleoside analogues represent a new class of lipophilic prodrugs of ddG and ddI that possess the potential for more effective therapy of HIV-induced neurologic disorders.

Adenosine Deaminase↗