Showing papers by "Nobuo Shimma published in 2000"
TL;DR: In tests with various human cancer xenograft models, capecitabine was more efficacious at wider dose ranges than either 5-FU or 5'-DFUR and was significantly less toxic to the intestinal tract than the others in monkeys.
156 citations
TL;DR: It appears that in C. albicans, inhibition of CaChs1p causes cell growth arrest, but simultaneous inhibition ofCaCHS1p and CaChS2p is lethal, and a novel inhibitor is identified and characterized that was highly specific to Ca chitin synthases.
55 citations
TL;DR: A novel Candida albicans chitin synthase 1 (CaChs1) inhibitor, RO-41-0986, was discovered by random screening and systematic modification led to the identification of a highly potent CaChS1 inhibitor,RO-09-3024, having strong antifungal activity against Candida spp.
30 citations
Patent•
25 Oct 2000
TL;DR: N-substituted carbamoyloxyalkyl-azolium derivatives have antifungal activity and are useful for the treatment of fungal diseases.
Abstract: N-substituted carbamoyloxyalkyl-azolium derivatives which have antifungal activity and are useful for the treatment of fungal diseases.
21 citations
Patent•
24 Mar 2000TL;DR: The 5′-deoxy-cytidine derivatives represented by the general formula (I) where R 1 is a hydrogen atom or a group easily hydrolyzable under physiological conditions; R 2 is an hydrogen atom, or CO-OR 4 group [wherein R 4 is a saturated or unsaturated, straight or branched hydrocarbon group consisting of one to fifteen carbon atoms as discussed by the authors.
Abstract: Novel 5′-deoxy-cytidine derivatives represented by the general formula (I) wherein R 1 is a hydrogen atom or a group easily hydrolyzable under physiological conditions; R 2 is a hydrogen atom, or —CO—OR 4 group [wherein R 4 is a saturated or unsaturated, straight or branched hydrocarbon group consisting of one to fifteen carbon atoms, or a group of the formula —(CH 2 ) n —Y (in which Y is cyclohexyl or phenyl; n is an integer from 0 to 4)]; R 3 is a hydrogen atom, bromo, iodo, cyano, a C 1-4 alkyl group [which may be substituted with halogen atom(s)], a vinyl or ethynyl group [which may be substituted with halogen atom(s), C 1-4 alkyl, cycloalkyl, aralkyl, or aromatic ring which may have one or more hetero atom(s)], or an aralkyl group which may be substituted for use in medical therapy, especially tumor therapy.
6 citations
1 citations
TL;DR: Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel oral fluoropyrimidine carbamate, which was designed to be sequentially converted to 5fluorouracil (5-FU) by three enzymes located in the liver and in tumors.
Abstract: Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel oral fluoropyrimidine carbamate, which was designed to be sequentially converted to 5-fluorouracil (5-FU) by three enzymes located in the liver and in tumors. N4-alkoxycarbonyl-5'-deoxy-5-fluorocytidine derivatives including capecitabine pass intact through the intestinal tract and are sequentially converted to 5-FU by a cascade of the three enzymes. The first step is the conversion to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase located in the liver, then to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase highly expressed in the liver and various solid tumors, and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in tumor tissues. Among large numbers of the derivatives, capecitabine was selected based on its susceptibility to hepatic carboxylesterase, oral bioavailability in monkeys and efficacy in a human cancer xenograft. Capecitabine given orally yielded substantially higher concentrations of 5-FU within tumors than in plasma or normal tissue (muscle). The tumor 5-FU levels were also much higher than those achieved by intraperitoneal administration of 5-FU at equi-toxic doses. This tumor selective delivery of 5-FU ensured greater efficacy and a more favourable safety profile than with other fluoropyrimidines. In 24 human cancer xenograft models studied, capecitabine was more effective at a wider dose range and had a broader spectrum of antitumor activity than 5-FU, UFT or its intermediate metabolite 5'-DFUR. The susceptibility of the xenografts to capecitabine correlated with tumor dThdPase levels. Moreover, the conversion of 5'-DFUR to 5-FU by dThdPase in tumor was insufficient in a xenograft model refractory to capecitabine. In addition, the efficacy of capecitabine was enhanced by dThdPase up-regulators, such as by taxanes and cyclophosphamide and by X-ray irradiation. The efficacy of capecitabine may, therefore, be optimized by selecting the most appropriate patient population based on dThdPase status and/or by combining it with dThdPase up-regulators. Capecitabine has additional characteristics not found with 5-FU, such as potent antimetastatic and anticachectic actions in mouse tumor models. With these profiles, capecitabine may have substantial potential in cancer treatment.
Patent•
25 Oct 2000
TL;DR: The authors concerne des derives carbamoyloxyalkyl-azolium N-substitues de formule generale (I) dans laquelle Q, Y, R?1, R2, R3 and X-? sont tels que definis dans les revendications et la description, ainsi que des sels de ces derniers.
Abstract: L'invention concerne des derives carbamoyloxyalkyl-azolium N-substitues de formule generale (I) dans laquelle Q, Y, R?1, R2, R3 et X-? sont tels que definis dans les revendications et la description, ainsi que des sels de ces derniers. Les composes de la presente invention presentent une activite antifongique et sont utiles dans le traitement de mycoses.