Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats

The purpose of this study was to establish a nude rat orthotopic (organ-specific) human colorectal cancer model as an in vivo secondary screen for general evaluation of new anticancer agents against colorectal cancer and to evaluate practically the antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1), a new p.o. fluoropyrimidine, in comparison to 1 M tegafur-4 M uracil [(UFT) effective on colorectal tumor in clinical]. After implantation of KM12C, a human colorectal cancer cell line, into the subserosal layer of the colon as a single-cell suspension, extensive local tumor growth and invasion to both the mucosal and the serosal sides were observed in all rats. Metastatic foci were also formed in both lymph nodes and lungs following local tumor growth in all of them. Using this method, an equitoxic dose of S-1 (15 mg/kg/day) and UFT (30 mg/kg/day) was administered p.o. for 14 consecutive days from 7 days after tumor cell implantation. S-1 showed a higher tumor growth inhibition than UFT did [S-1, 57% (significantly different from the tumor weight of the untreated group at P < 0.05) and UFT, 18% (P > 0.05)]. When both drugs were administered to nude rats bearing KM12C injected into the cecal wall for 28 consecutive days at equitoxic doses, the mean survival in the S-1 group was 16 days longer than that in the untreated group (P < 0.01) but that in the UFT group was only 8 days longer (P > 0.05). After the administration of an equitoxic dose of both drugs, S-1 gave the higher levels than UFT in various pharmacokinetic parameters as follows: area under the curve 0-24 h of 5-fluorouracil in plasma (3.5-fold), area under the curve 0-24 h of 5-fluorouracil incorporated into RNA in the tumor (1.3-fold), and thymidylate synthase inhibition rate (percentage) in the tumor (about 20%). Collectively, these findings suggested that this orthotopic human colorectal tumor model in nude rats is useful to evaluate the clinical therapeutic efficacy of drugs or therapies for colorectal cancer, and that S-1 had a higher therapeutic effect on human colorectal tumor than UFT did.     

Optical and electrical anisotropies of polydiacetylene derivative film aligned by shear stress

The molecular alignment of polydiacetylene (PDA) derivatives and their optical and electrical properties of thin films based on PDA derivatives have been studied. The PDA derivatives were aligned depending on the direction of applied shear stress in the film. From measurements of the polarized absorption and current–voltage characteristics, the optical and electrical anisotropies have been observed, that was discussed by taking the PDA main chain alignment into consideration.     

5-Fluorouracil prodrug: role of anabolic and catabolic pathway modulation in therapy of colorectal cancer

Following p.o. administration to rats bearing advanced colorectal carcinoma, Ftorafur (FT) is converted to 5-fluorouracil (FUra) by microsomal P450 in the liver. To optimize the therapeutic selectivity of the FUra generated from FT, three approaches were utilized: (a) inhibition of FUra degradation to dihydrofluorouracil by uracil as an alternative substrate for uracil reductase in the molar ratio of 4 uracil:1 FT (UFT); (b) modulation of drug inhibition of thymidylate synthase by leucovorin (LV); and (c) by increasing the level of FUra incorporation into cellular RNA by N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartate transcarbomylase. The maximum tolerated dose (MTD) of FT and UFT, administered 3 times a day for 28 days, was 150 mg/kg/day and 60 mg/kg/day, respectively. The MTDs were not significantly modified by LV (150 or 600 mg/kg/day), administered by the p.o. route with the drugs, or by PALA (100 mg/kg) administered weekly by the i.v. route. The dose-limiting toxicity of FT alone and in combination with the modulators was stomatitis. The severe alopecia observed with FT alone was reduced significantly by uracil. At the MTD, the antitumor activity of UFT was superior to those of FT and FUra alone and in combination with LV and/or PALA. The 3-month sustained complete tumor regression for UFT, FT, and FUra was 38%, 0%, and 13% (for the weekly schedule), respectively. Although uracil, LV, and PALA individually increased the antitumor activity of FT at its MTD, the combination of the three modulators produced the highest therapeutic efficacy in rats bearing advanced colorectal carcinoma, in which 100% of the treated animals achieved complete and sustained tumor regression. The therapeutic efficacy observed with FT modulation could not be achieved with FUra administered by different schedules, each at its MTD alone or in combination with either LV or PALA. In brief, modulation of FT produced greater therapeutic efficacy and selectivity than FUra. Furthermore, the combined use of modulators capable of inhibiting the degradation pathway of FUra and potentiating the effects of the anabolic metabolites action appears to offer the greatest therapeutic potential.     

Pressure-drop reduction and heat-transfer deterioration of slush nitrogen in horizontal pipe flow

Cryogenic slush fluids such as slush hydrogen and slush nitrogen are two-phase, single-component fluids containing solid particles in a liquid. Since their density and refrigerant capacity are greater than those of liquid-state fluid alone, there are high expectations for the use of slush fluids in various applications such as clean-energy fuels, spacecraft fuels for improved efficiency in transportation and storage, and as refrigerants for high-temperature superconducting equipment. Experimental tests were performed using slush nitrogen to obtain the flow and heat-transfer characteristics in two different types of horizontal circular pipes with inner diameters of 10 and 15 mm. One of the primary objectives for the study was to investigate the effect of pipe diameter on the pressure-drop reduction and heat-transfer deterioration of slush nitrogen according to changes in the pipe flow velocity, solid fraction and heat flux. In the case of an inner diameter of 15 mm, pressure drop was reduced and heat-transfer characteristics deteriorated when the pipe flow velocity was higher than 3.6 m/s. On the other hand, in the case of an inner diameter of 10 mm, pressure drop was reduced and heat-transfer characteristics deteriorated when the pipe flow velocity was higher than 2.0 m/s. From these results, it can be seen that a larger pipe diameter produces a higher onset velocity for reducing pressure drop and deteriorating heat-transfer characteristics. Furthermore, based on observations using a high-speed video camera, it was confirmed that pressure drop was reduced and heat-transfer characteristics deteriorated when the solid particles migrated to the center of the pipe and the flow pattern of the solid particles inside the pipe was pseudo-homogeneous.     

Invention of a tumor-selective 5-fluorouracil derivative named S-1 by biochemical modulation of 5-fluorouracil

A new oral type of 5-fluorouracil (5-FU) derivative possessed of both potent antitumor activity and less gastrointestinal (GI) toxicity was investigated and developed in the form of a combination of tegafur (FT), a masked form of 5-FU, and its two peculiar biochemical modulators. One is 5-chloro-2,4-dihydroxypyridine (CDHP), a new potent inhibitor of 5-FU degradation in vivo, and another is potassium oxonate (Oxo), a characteristic inhibitor of 5-FU phosphorylation, which distributes much higher in GI tract after p.o. administration. 5-FU levels in blood of rats following administration of FT, were markedly elevated and persisted for a long-time by co-oral CDHP corresponding to over 0.4 molar ratio to FT, like the case in continuous infusion of 5-FU, which resulted in an augmentation of antitumor efficacy in Yoshida sarcoma-bearing rats, although severe GI toxicity simultaneously occurred. To reduce 5-FU-induced toxicities such as diarrhea and body weight loss and to maintain the augmented antitumor activity, 0.5 to 2 molar Oxo was orally given to rats with one molar FT plus 0.4 molar CDHP. As a result, both severe GI injury and body weight loss were markedly inhibited by coadministration of 0.5 to 1.0 molar Oxo while high antitumor efficacy (about 90% inhibition of tumor growth) was maintained. However, such almost complete antitumor effect was reduced to about 50% inhibition of tumor growth by over 2 molar Oxo combined with one molar FT plus 0.4 molar CDHP. Based on these results, a novel 5-FU derivative, named S-1, was composed of one molar FT, 0.4 molar CDHP and one molar Oxo. S-1 showed an antitumor activity over 3-fold stronger than UFT (one molar FT plus 4 molar uracil) against Yoshida sarcoma and Sato lung carcinoma in rats and human colon carcinoma (KM12C) xenografted in nude rats when its minimum toxic dose was administered. Co-oral Oxo also significantly reduced the incidence of diarrhea and stomatitis induced by administration of FT-CDHP in beagle dogs. These results suggest that high antitumor activity and less GI toxicity of S-1 was brought about by the elevation in blood and tumor tissues and by selective decrease of 5-fluoronucleotides, an active metabolite of 5-FU, in GI tract.     

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.     

Production of eicosapentaenoic acid bySaprolegnia sp. 28YTF-1

Saprolegnia sp. 28YTF-1, isolated from a freshwater sample, is a potent producer of 5,8,11,14,17-cis-eicosapentaenoic acid (EPA). The fungus used various kinds of carbon sources, such as starch, dextrin, sucrose, glucose, and olive oil for growth, and olive oil was the best carbon source for EPA production. The EPA content reached 17 mg/g dry mycelium (0.25 mg/L) when the fungus was grown in a medium that contained 2.5% olive oil and 0.5% yeast extract, at pH 6.0 and 28°C for 6 d with shaking. Accompanying production of arachidonic acid (AA; 3.2 mg/g dry mycelia, EPA/AA = 5.1) and other ω6 polyunsaturated fatty acids was low. Both EPA content and EPA/AA ratio increased in parallel by lowering growth temperature. Triglyceride was the major mycelial lipid (ca. 84%), but EPA comprised only 2.2% of the total fatty acids of this lipid. About 40% of the EPA produced was found in polar lipids, such as phosphatidylethanolamine (EPA content, 28.2%), phosphatidylcholine (13.6%), and phosphatidylserine (21.2%).     

Adsorption and reaction of cyclohexene and 1-hexene on nascent gold surface formed by friction

Adsorption and reaction of cyclohexene, 1-hexene and benzene on nascent gold surface formed by friction were investigated using an adsorption test apparatus in high vacuum at room temperature. Chemisorption of cyclohexene, 1-hexene and benzene was observed during the sliding processes by a quadrupole mass spectrometer. It is found that nascent gold surface has catalytic activity for hydrogenation of cyclohexene and 1-hexene, and for dehydrogenation of the olefins and benzene. The adsorbed cyclohexene and 1-hexene molecules were hydrogenated on the surface to form cyclohexane and hexane, respectively. As dehydrogenation products, hydrogen from all the sample gases, and benzene from cyclohexene desorbed. Adsorption rate of the olefins was higher than that of benzene, and hydrogenation activity of 1-hexene is higher than that of cyclohexene. However, on nascent Pd–Ag alloy surface, the desorption of hydrogenation products was not detected, although adsorption of the sample gases and desorption of the dehydrogenation products were also observed.     

Photocatalytic hydrogen production from water with nonfood hydrocarbons as oxidizing sacrifice agents

To enhance photocatalytic water splitting, various oxidizing sacrifice agents (OSA) have been added to the system in order to scavenge the coproduced O₂, and, thus, to hinder the reverse reactions. In the aim of achieving carbon‐neutral photocatalytic water splitting, nonfood hydrocarbons of castor‐ and jojoba‐oils were evaluated as OSA. Moreover, various surfactants were tested as emulsifiers for W/O binary solution for promoting photocatalytic water splitting rate. Among the OSA used, the castor‐oil was found to be more suitable candidate compared to jojoba‐oil, which was attributed to its smaller carbon chain numbers of mainly 18. Without surfactants, around 20 vol %‐castor‐oil aqueous binary solution with TiO₂/Pt(0.10 wt %) provided the highest water splitting rate of about 30 mL‐H₂/(m²·h). Among tested surfactants, liquid‐detergent was the best due to its optical transparency. 40 vol %‐ or 60 vol %‐castor‐oil emulsion with a drop of liquid‐detergent resulted in a water splitting rate of 125 mL‐H₂/(m²·h), which was four times greater that the aforementioned highest value. © 2010 American Institute of Chemical Engineers AIChE J, 2011