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.     

A new antitumor agent amrubicin induces cell growth inhibition by stabilizing topoisomerase II-DNA complex

Amrubicin is a novel, completely synthetic 9-aminoanthracycline derivative. Amrubicin and its C-13 alcohol metabolite, amrubicinol, inhibited purified human DNA topoisomerase II (topo II). Compared with doxorubicin (DXR), amrubicin and amrubicinol induced extensive DNA-protein complex formation and double-strand DNA breaks in CCRF-CEM cells and KU-2 cells. In this study, we found that ICRF-193, a topo II catalytic inhibitor, antagonized both DNA-protein complex formation and double-strand DNA breaks induced by amrubicin and amrubicinol. Coordinately, cell growth inhibition induced by amrubicin and amrubicinol, but not that induced by DXR, was antagonized by ICRF-193. Taken together, these findings indicate that the cell growth-inhibitory effects of amrubicin and amrubicinol are due to DNA-protein complex formation followed by double-strand DNA breaks, which are mediated by topo II.     

Host genes affecting survival period of chemically induced bladder cancer in mice

Treatment of C57BL/6 J (B6) and NON male mice with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) resulted in a high incidence of bladder cancer. The mean survival period, however, differed significantly by strain: 481+/-219 days in B6 (n = 31) and 203+/-119 days in NON (n = 30) (P < 0.0001). Major causes of death were renal failure due to obstruction of the urinary tract, or local invasion of tumors. The fact that the BBN-treated NON x B6 reciprocal F1 mice had survival periods as short as those of the parental NON mice suggests a genetically dominant susceptibility in NON or recessive resistance in B6. A linkage analysis of 248 back-cross mice to B6 suggested at least two quantitative trait loci determining the length of the survival period: one was mapped close to D2Mit260 (logarithm of odds, LOD, score 2.21), a microsatellite marker locus 83 cM from the centromere on chromosome 2, and another was close to D6Mit159, 7 cM from the centromere on chromosome 6 (LOD score 2.51).     

Daily wheel running activity modifies the period of free-running rhythm in rats via intergeniculate leaflet

The period of free-running rhythms (tau) in rats, as measured using a running wheel, is different from that measured using an Automex. The aim of this work was to examine the effects of lesions of the intergeniculate leaflet (IGL) on the tau of these two activity rhythms. When blind rats were transferred from a cage with a running wheel to a cage without a running wheel, the tau lengthened. The tau of the wheel-running activity was associated with the number of wheel revolutions per day. A complete lesion of the IGL lengthened the tau of the wheel-running activity, and caused a reduction in the number of wheel revolutions per day in all rats. In rats housed in cages without a running wheel, locomotor activity was reduced by IGL lesions, although the tau was unaffected. When IGL-lesioned rats were transferred from a cage with a running wheel to a cage without a running wheel, no further change was observed. These results indicate that the tau is modified by the daily activity of wheel-running, but not by general locomotor activity, and that the IGL may be involved in this modification.     

IL-12 promotes the adhesion of NK cells to endothelial selectins under flow conditions

This study examined the adhesive interactions of peripheral blood NK cells with P- and E-selectin and analyzed the effect of IL-12 on the binding of NK cells to these selectins. P-selectin glycoprotein ligand-1 (PSGL-1) is expressed on most resting and IL-12-activated NK cells. However, the percentage of resting NK cells bound to P-selectin-IgG was 15%, and that of activated NK cells bound to P-selectin-IgG was 65%. Furthermore, the number of IL-12-activated NK cells bound to P-selectin-transfected Chinese hamster ovary cells was significantly higher than that of resting NK cells under flow conditions. These interactions were abolished by the incubation of these NK cells with anti-PSGL-1 (PL-1) mAb. Thus, PSGL-1/P-selectin interaction is important in the binding of resting and activated NK cells to P-selectin. NK cells express sialyl-Lewis(x) (sLe(x)) structure recognized by anti-sLe(x) mAb (KM-93), and IL-12 activation of NK cells increased the mean fluorescence intensity of KM-93-reactive NK cells. Adhesion of IL-12-activated NK cells to E-selectin-transfected Chinese hamster ovary cells was stronger than that of resting NK cells under flow conditions. These interactions were reduced markedly by incubation with anti-sLe(x) mAb. Thus, sLe(x) is the major ligand of resting and activated NK cells for E-selectin. These findings indicate that IL-12 stimulation of NK cells promotes their adhesion activity to endothelial selectins.     

Comparative hypocholesterolemic effects of six vegetable oils in cholesterol-fed rat

The hypocholesterolemic efficacies of various polyunsaturated fatty acids were compared in rats given cholesterol-enriched diets.Oenothera biennis Linn oil (OBLO, linoleic +γ-linolenic), sunflower oil (linoleic), palm oil (PLO, oleic+linoleic), soybean oil (linoleic+α-linolenic), high-oleic safflower oil (oleic+linoleic), or mixed oil (linoleic+α-linolenic) was added to the diet at 200 g/kg (20% groups). OBLO was also added at 100 g/kg diet (10% group). The serum total and very low density lipoprotein+intermediate lipoprotein+low density lipoprotein cholesterol concentrations of the 10 and 20% OBLO groups were consistently lower than those in the other groups. The liver cholesterol concentration in the PLO group was lower in all groups. The liver cholesterol concentrations in the 10 and 20% OBLO groups were also lower than in the other groups. There were no significant differences in the fecal neutral sterol and bile acid extraction among groups.     

Kinetics and photoeffects of oxidation and reduction of hexaamminecobalt complex in alkaline media

Cyclic voltammograms of hexaamminecobalt complex have been measured in high pH solutions. The spectroscopic result suggested that hydroamminecobalt complex adsorbed on the electrode surface during cathodic polarization, and this species grew to form cobalt hydroxide after a long time of electrolysis. In the anodic process, the reaction orders for pH and NH₃ were both |1|. Based on these results, the reaction mechanism has been discussed.The effect of light on the electrode process has been studied by irradiating with ultraviolet light of the 254 nm mercury resonance line. It has been indicated that the hydroxoammine complex is decomposed to cobalt hydroxide and free ligand under light.