The discovery that angiogenesis is a key condition for the growth of a tumor beyond a millimeter or two, brings about a new approach in the treatment of tumors using drugs able to inhibit the formation of new blood vessels. Also, it has been realized that antiangiogenic drugs can be useful in the treatment of other pathological processes, now classified as angiogenesis-dependent diseases. Initially, cartilage was considered as a possible natural source of antiangiogenic compounds due to its known avascular nature. To date, a number of in vitro and in vivo studies have suggested the existence of antiangiogenic and antitumor compounds in bovine and shark cartilage. However, the potential usefulness of shark cartilage in the treatment of cancer and other angiogenesis-dependent diseases have not been totally accepted due to (i) unsatisfactory patient outcome in clinical trials that have used shark cartilage in cancer patients, (ii) the lack of data that correlates bioavailability with pharmacological effects using oral shark cartilage. Thus, the objective of this review is to describe the main basic and clinical investigations reported in the literature, in which the antiangiogenic and/or antitumor properties of shark cartilage or of its extracts were evaluated. Possible explanations for conflicting results are discussed as well.

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We prepared a lysozyme mutant (Q41S/R61S) introducing Asn-type glycosylation signal sites by yeast expression system. On purification by cation exchange column at pH 7, three fractions were obtained. Peptide mapping and mass-spectrometry showed the fractions were the derivatives glycosylated at both Asn39 and Asn59, at only Asn39, and not glycosylated. It was revealed that the processing of Asn-linked oligosaccharide at Asn39 and Asn59 occurred independently in yeast cells. The denaturation temperatures of these derivatives by differential scanning calorimetry were 76.0, 68.8, and 67.5°C at pH 3, respectively. The stabilization of glycosylated lysozyme depends on the degree of glycosylation. We concluded that stabilized proteins can be constructed by glycosylation at proper sites. Thermodynamic stabilization by the artificial double glycosylations on a protein has not yet been reported.

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Collected human intestinal flora (whole bacteria) was incubated with glycyrrhizin (GL), glycyrrhetic acid (GA), glycyrrhetic acid monoglucuronide (GAMG) and a combination of the three for 10 min at 37°C under pH 5.6 and 7.0. The effect of these components on GL β-D-glucuronidase activity, GAMG β-D-glucuronidase activity and metabolite production in whole bacteria was examined. GL and GA were not metabolized at pH 5.6 and 7.0 by whole bacteria, while the level of GAMG changed at both pH 5.6 and 7.0. However, preincubated whole bacteria converted GA and a combination containing GA to other metabolites removed 3α-hydroxyglycyrrhetic acid and 3-oxoglycyrrhetic acid. The level of GL β-D-glucuronidase activity remaining in whole bacteria after exposure to both GA and GAMG was above its initial level at pH 5.6 and 7.0, and the level of GAMG β-D-glucuronidase activity remaining after exposure to GL, GA and GAMG was suppressed against control at pH 5.6 and 7.0. It is found that intestinal bacteria had similar action against GL, GA and GAMG at between pH 5.6 and 7.0.

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A sensitive and specific ELISA for an antiarrhythmic drug, pilsicainide, was developed, which is capable of measuring as low as 1.6 ng/ml. Anti-pilsicainide antibody was obtained by immunizing rabbits with pilsicainide conjugated with bovine serum albumin using diazotized N-(3-amino-2,6-dimethylphenyl)-8-pyrrolizidinylacetamide (3-aminopilsicainide). Enzyme labeling of pilsicainide with β-D-galactosidase was similarly performed using a diazotized 3-aminopilsicainide. Cross-reactivity data showed that the antibody well recognizes both the aromatic ring and the pyrrolizidine moieties, and thus specific enough to the structure of pilsicainide. The values for the pilsicainide concentrations detected using this assay were comparable with those detected using HPLC. There was a good correlation between the values determined by the two methods. Moreover, the ELISA was about 30-fold more sensitive in detecting pilsicainide at lower concentrations. Using this assay, drug levels were easily measured in the serum of rabbits after oral administration of pilsicainide at a single dose of 1 mg/kg. The ELISA should be a valuable tool in therapeutic drug monitoring (TDM) and pharmacokinetic studies of pilsicainide.

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Cytotoxic effects of six isoflavonoids, tectorigenin, glycitein, tectoridin, glycitin, 6''-O-xylosyltectoridin, and 6''-O-xylosylglycitin isolated from the flower of Pueraria thunbergiana BENTH. together with genistein, a known differentiation and apoptosis inducer, were examined. Among these isoflavonoids, tectorigenin and genistein exhibited cytotoxicity against various human cancer cells; glycitein showed only mild cytotoxicity. These results suggest that the isoflavone structure and 5-hydroxyl group are crucial for the cytotoxic properties and that glycosides are inactive. Moreover, tectorigenin induced differentiation of human promyelocytic leukemia HL-60 cells to granulocytes and monocytes/macrophages, and caused apoptotic changes of DNA in the cells, as did genistein. Tectorigenin also inhibited autophosphorylation of epidermal growth factor (EGF) receptor by EGF and decreased the expression of Bcl-2 protein, with less activity than genistein. From these results, tectorigenin may be a possible therapeutic agent for leukemia.

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The present study was conducted to clarify the effects of Dai-kenchu-to on accelerated small intestinal movement. We evaluated the effects of Dai-kenchu-to and its constituent herbs (dried ginger root, ginseng, zanthoxylum fruit, and malt sugar) on carbachol-accelerated mouse small intestinal transit, and contractions induced by low-frequency electrostimulation (ESC), KCl, or acetylcholine (ACh) using isolated guinea pig ileum. Dai-kenchu-to (10—300 mg/kg, p.o.) significantly improved carbachol-accelerated small intestinal transit in a dose-dependent manner. Using a concentration with the compounded rate for Dai-kenchu-to 300 mg/kg, carbachol-accelerated small intestinal transit was also significantly improved with a single dose of dried ginger root or ginseng. At a concentration of 3×10^-5 g/ml or less, Dai-kenchu-to, dried ginger root, and ginseng all inhibited ESC but not KCl- or ACh-induced contractions. However, at a higher concentration of Dai-kenchu-to (10^-4 g/ml) or zanthoxylum fruit (10^-5 g/ml or more) the ESC were enhanced. Both Dai-kenchu-to and dried ginger root at 10^-3 g/ml remarkably inhibited the KCl-induced contractions. These results indicate that Dai-kenchu-to improves accelerated small intestinal movement and that dried ginger root and ginseng may be involved in this effect. It is also thought that the mechanisms mainly involve the direct inhibition of smooth muscle but with a contribution from neural inhibition.

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Airway inflammation and reversible airway obstruction are hallmarks of bronchial asthma. In this study, we investigated the effects of a new antiallergic drug, 7-{3-[4-(2-quinolinylmethyl)-1-piperazinyl]-propoxy}-2,3-dihydro-4H-1,4-benzothiazin-3-one (VUF-K-8788), on histopathological changes in lung parenchyma of guinea pigs during late-phase asthmatic reaction (LAR), and on eosinophil-adhesion to human umbilical vein endothelial cells (HUVEC).
Repeated exposure to ovalbumin of sensitized guinea pigs induced inflammatory phenomena such as hyperplasia of airway epithelial cells, perivascular edema and infiltration of lung parenchyma by eosinophils. VUF-K-8788 inhibited these histopathological phenomena at 10 mg/kg p.o. Moreover, the eosinophil-adherence to HUVEC was inhibited by VUF-K-8788 at the concentration of 10—30 μM. In conclusion, this inhibitory effect of VUF-K-8788 on eosinophil-adherence might contribute to the prevention of LAR and infiltration by eosinophils in the experimental asthmatic model in guinea pigs.

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The antiinflammatory effects of 10 newly synthesized pyrazole derivatives on formaldehyde-induced rat paw edema were investigated. The most effective of them (K-3) was investigated again in dextran- and carrageenan-induced paw edema. In formaldehyde-induced paw edema, K-3 50, 100, and 200 mg/kg p.o. inhibited the edema by 48.9% (p<0.002), 68.7% (p<0.001), and 79.1% (p<0.001), respectively, 3 h after administration. In dextran-induced paw edema, the same dose of K-3 produced 27.1% (p<0.05), 46.8% (p<0.01), and 63.8% (p<0.002) inhibition, respectively. In the carrageenan-induced paw edema test, K-3 100 mg/kg decreased the inflammatory response by 52.0% after 4 h. Acute toxicity studies revealed that K-3 was nontoxic up to an oral dose of 2500 mg/kg.

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San’o-shashin-to, composed of Scutellariae Radix, Coptidis Rhizoma and Rhei Rhizoma (volume ratio=1:1:1), reduced an increase in arterial blood pressure of anesthetized rats induced by theophylline (5 mg/kg, i.v.). The hypotensive effect of San’o-shashin-to was produced in a dose dependent manner and was maximum at its 0.5 g/kg. Then the constituent herbal medicines were examined for their possible hypotensive effect. Scutellariae Radix of 0.2 g/kg slightly decreased in the blood presure. Rhei Rhizoma of 0.2 g/kg decreased in the blood pressure and the hypotensive effect was significantly produced even at the dose of 0.05 g/kg, while Coptidis Rhizoma had little effect. Among fractions of San’o-shashin-to separated by Diaion HP-20 column chromatography, the 50% methanol-eluted fraction had a large hypotensive effect. The 50% methanol-eluted fraction of Scutellariae Radix and Rhei Rhizoma were also effective and, especially, that of Rhei Rhizoma had a large hypotensive effect. In isometric tension study, Scutellariae Radix and Rhei Rhizoma (10—30 μg/ml) slightly exerted contractile and relaxant effects, respectively, on the phenylephrine-contracted endothelium-intact rat thoracic aorta. Coptidis Rhizoma (1—10 μg/ml) caused both endothelium-dependent and -independent relaxanion. These results suggest that the hypotensive effect of San’o-shashin-to is not mediated by the direct action on blood vessel but by other actions. Some components in Scutellariae Radix and Rhei Rhizoma, especially in the latter may play a main role in the hypotensive effect.

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We investigated the antihypertensive effect of Brand’s Essence of Chicken (BEC), a popular chicken extract used as a traditional remedy, using deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Animals were unilaterally nephrectomized, and then separated into a sham-operated group (sham group) and a DOCA-salt-treated group. The latter was further separated into a normal diet group and a BEC (freeze-dried powder, 0.1w/w%)-containing diet group. Systolic blood pressure of the normal diet group progressively increased in comparison with that of the sham group. The DOCA-salt-induced hypertension was markedly suppressed by feeding a BEC-containing diet. Systolic blood pressure after 5 weeks was 128±2 mmHg in sham group, 181±4 mmHg in the DOCA-salt-treated normal diet group and 139±5 mmHg in the DOCA-salt-treated BEC diet group, respectively. The treatment with DOCA and salt for 5 weeks significantly increased the weights of heart and left ventricle, but these increases were significantly suppressed in the BEC group. When the degree of vascular hypertrophy of the aorta was histochemically evaluated, DOCA-salt-induced increases in wall thickness and wall area of the vessels were significantly decreased by the BEC-feeding. Histopathological renal damage of fibrinoid-like necrosis in glomeruli, thickening of small arteries and tubular dilatation were observed in the DOCA-salt-treated normal diet group, but this damage was efficiently reduced by the BEC-feeding. In addition, BEC-feeding decreased urinary excretion of protein, which was elevated by the treatment with DOCA and salt. Thus, BEC seems to be useful as a prophylactic treatment in the development of hypertension and related tissue injuries.

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We studied the effect of oxatomide, an antiallergic drug, on the resistance of K562 cells to doxorubicin. Oxatomide synergistically potentiated the cytotoxicity of doxorubicin in doxorubicin-resistant K562 cells (K562/DXR) at a concentration of 1—10 μM, but had hardly any synergistic effect on the parental cell line (K562) at the same concentration. Oxatomide inhibit P-glycoprotein pump-efflux activity and the binding of [³H]-azidopine to the cell-surface protein P-glycoprotein, in a dose-related manner. These results indicate that oxatomide reverses the multidrug-resistance phenotype through direct interaction with P-glycoprotein.

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The object of this study was to investigate the binding affinity of a newly synthesized 5-HT₂ antagonist, (N-[2-[4-(5H-dibenzo[a, d]cyclohepten-5-ylidene)-piperidino]ethyl]-1-formyl-4-piperidinecarboxamide monohydrochloride monohydrate) (AT-1015), in the rabbit platelet membrane using [³H]-ketanserin by radioligand binding assay method and to compare the results with other selective 5-HT₂ antagonists. The results showed that AT-1015 displayed high affinity to 5-HT₂ receptors in rabbit platelet membranes. The pK_i value of AT-1015 was 7.40, which is slightly lower than that of ketanserin, but higher than that of cyproheptadine. On the other hand, the displacement potency of AT-1015 for 5-HT₂ receptors in rabbit platelets was similar to those of sarpogrelate and ritanserin. This is the first report of the high affinity of AT-1015 in rabbit platelets.

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Effects of the 5-HT_1A receptor agonist 8-hydroxy-2-di-n-(propylamino)tetralin (8-OH-DPAT) on plasma glucagon levels were investigated. 8-OH-DPAT increased plasma glucose and glucagon levels in rats. Both hyperglycemia and hyperglucagonemia elicited by 8-OH-DPAT were prevented by the 5-HT_1A receptor antagonist pindolol and prior adrenodemedullation. These results suggest that increases in plasma glucagon levels induced by 8-OH-DPAT were based on the adrenaline release from the adrenal gland and its effects may contribute to its hyperglycemic effects.

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Effects of the 5-HT₂ receptor antagonist, ritanserin on hyperthermia and depletion of 5-HT induced by the 5-HT-releasing drug, p-chloroamphetamine (PCA) were investigated. Ritanserin significantly suppressed PCA-induced hyperthermia in mice. PCA elicited decreases in 5-HT levels in the mouse frontal cortex. 5-HT reduction elicited by PCA was also attenuated by pretreatment with ritanserin. Since hyperthermia facilitates neurotoxicity induced by amphetamine analogue, ritanserin may inhibit PCA-induced 5-HT neurotoxicity by inhibiting hyperthermia.

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We have shown that synthetic and natural estrogens and related compounds inhibit the polymerization of microtubule proteins. In this study, cell growth inhibition by synthetic estrogens and their related compounds was examined by the MTT method using L1210, KB, and NIH-3T3 cells transformed with oncogenes, which are typical screening systems for carcinostatics. [(−)3R]Indenestrol B, a derivative of diethylstilbestrol (DES), which strongly inhibited the polymerization of microtubule proteins, also showed marked inhibition of the growth of KB cells and various oncogene-transformed NIH-3T3 cells. On the other hand, DES and indenestrol A markedly inhibited the growth of L1210 cells, indicating that these compounds exhibit cell-specific inhibitory effects on cell growth. Although the inhibition of cell growth by these compounds was not as strong as that by colchicine, the results clearly indicate the potential of these compounds as carcinostatics.

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The success of green tea as a cancer preventive is based on evidence that green tea contains tannins and antioxidants, does not show toxicity in humans and has long traditional use in Asia. In the light of this, herbal medicines are now also attracting attention as potential sources of cancer preventive agents. Using the inhibition of TNF-α release assay, we studied Acer nikoense (Megusurino-ki in Japanese), one of the herbal medicines. The inhibitory activity of TNF-α release was found in the leaf extract rather than the bark extract, and the main active constituents were identified as geraniin and corilagin, which are present in another Japanese traditional herb, Geranium thunbergii (Genno-shoko). The IC₅₀ values of TNF-α release inhibition were 43 μM for geraniin and 76 μM for corilagin, whereas that for (−)-epigallocatechin gallate (EGCG) was 26 μM. Treatment with geraniin prior to application of okadaic acid, a tumor promoter on mouse skin initiated with 7,12-dimethylbenz(a)anthracene, reduced the percentage of tumor-bearing mice from 80.0 to 40.0% and the average numbers of tumor per mouse from 3.8 to 1.1 in week 20. Thus, geraniin has slightly weaker inhibitory activity than EGCG. Since geraniin and corilagin have been well investigated as representative tannins, we discuss here the new possibility of classical herbal medicine in the development of preventive agents for cancer and other life-style related diseases.

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Schiff bases and phenyl hydrazone of isatins were prepared by reacting isatin and the appropriate aromatic primary amine/hydrazines. A new series of the corresponding N-mannich bases were synthesized by reacting them with formaldehyde and diphenylamine. The chemical structures were confirmed by means of their ¹H-NMR, IR spectral data and elemental analysis. The compounds were screened for analgesic, antiinflammatory and antipyretic activity. 1-Diphenylaminomethyl-3-(1-naphthylimino)-1,3-dihydroindol-3-one (4), 3-(1-naphthylimino)-5-bromo-1,3-dihydroindol-2-one (2) and 1-diphenylaminomethyl-3-(4-methylphenylimino)-1,3-dihydroindol-3-one (7) were found to exhibit the highest analgesic, anti-inflammatory and antipyretic activity respectively. 1-Diphenylaminomethyl-3-(4-methylphenylimino)-1,3-dihydroindol-3-one (7) was found to be the most active compound of the series.

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The component of aqueous Tinospora tuberculata extract that inhibits nitric oxide (NO) production was examined using macrophages activated by the addition of lipopolysaccharide. The aqueous extract was partitioned with ethyl acetate. The aqueous layer was fractionated with a Diaion column. The residue of the aqueous extract was extracted with methanol, and partitioned with ethyl acetate. The ethyl acetate layer was found to be associated with a distinct decrease in the NO level and inducible NO synthase. On further fractionation, the subfraction of E-3 showed high anti-NO activity. N-trans-Feruloyltyramine isolated from E-3 was identified as exhibiting strong anti-NO activity. This compound is the most active component of Tinospora tuberculata with respect to the suppression of NO production.

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Ginsenosides separated by silica gel TLC blotted to a polyvinylidene difluoride (PVDF) membrane was treated with a NaIO₄ solution followed by bovine serum albumin (BSA), resulting in a ginsenoside-BSA conjugate on a PVDF membrane. The blotted bands were stained with anti-ginsenoside Rg1 and Rb1 monoclonal antibodies (MAbs). The newly established double staining with the Western blotting methods was applied for the determination of ginsenosides possessing protopanaxadiol or protopanaxatriol and the number of sugar depending on the stained color and their Rf values in the Panax plants.

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A method for semi-micro high-performance liquid chromatography (HPLC) has been established for the simultaneous determination of glycyrrhizin (GL), glycyrrhetic acid (GA) and glycyrrhetic acid mono-glucuronide (GAMG) in incubation mixtures of rat feces with Shakuyaku-kanzo-to decoction (combination of licorice root and peony root). The analysis could be accomplished within 20 min with a TSKgel ODS-80TsQA (150×2.0 mm i.d.) column by linear gradient elution using a mobile phase containing aqueous phosphoric acid and acetonitrile at a flow rate of 0.2 ml·min^-1, a thermostatic oven at 25°C, and detection at 254 nm. The detection limits of these compounds were 0.1—0.85 pmol per injection (5 μl). The concentrations of GL and its metabolites in the incubation mixture after continuous consumption of Shakuyaku-kanzo-to were significantly different compared with those of untreated control. GL-hydrolysis of rat feces was enhanced by pre-consumption of Shakuyaku-kanzo-to.

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We examined the inhibitory action of the extract of Oren-gedoku-to, a traditional herbal medicine known to act as an antioxidant, on enzymatic lipid peroxidation in rat liver microsomes. Simultaneous addition of a spraydried preparation of Oren-gedoku-to extract (Tsumura TJ-15) inhibited enzymatic lipid peroxidation induced by reduced β-nicotinamide adenine dinucleotide phosphate (NADPH) and ADP/Fe³⁺ complex in liver microsomes in a dose-dependent manner. When the inhibition by TJ-15 of enzymatic lipid peroxidation in liver microsomes was kinetically analyzed, this medicine showed a competitive inhibition against NADPH or ADP/Fe³⁺ complex. TJ-15 inhibited the NADPH-driven enzymatic reduction of ADP/Fe³⁺ complex or cytochrome c in liver microsomes competitively. TJ-15 enhanced NADPH consumption by liver microsomes with ADP/Fe³⁺ complex. Treatment with TJ-15 after the onset of enzymatic lipid peroxidation in liver microsomes inhibited the progression of lipid peroxidation in a dose-dependent manner. The present results indicate that Oren-gedoku-to extract inhibits enzymatic lipid peroxidation in rat liver microsomes in the initiation and propagation steps in a dose-dependent manner. These results also suggest that Oren-gedoku-to extract inhibits enzymatic lipid peroxidation in rat liver microsomes not only through its antioxidant action but also through reduction of the supply of electrons derived from NADPH to ADP/Fe³⁺ complex in liver microsomes both in a competitive manner and through stimulation of NADPH oxidation.

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We cloned the gene of the acyclic sesquiterpene synthase, (E)-β-farnesene synthase (CJFS) from Yuzu (Citrus junos, Rutaceae). The function of CJFS was elucidated by the preparation of recombinant protein and subsequent enzyme assay. CJFS consisted of 1867 nucleotides including 1680 bp of coding sequence encoding a protein of 560 amino acids with a molecular weight of 62 kDa. The deduced amino acid sequence possessed characteristic amino acid residues, such as the DDxxD motif, which are highly conserved among terpene synthases. This is the first report of the cloning of a terpene synthase from a Rutaceous plant. A possible reaction mechanism for terpene biosynthesis is also discussed on the basis of sequence comparison of CJFS with known sesquiterpene synthase genes.

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The inhibitory collagenolytic activity (47—64% inhibition in 0.22—0.24 μM) of fukinolic acid and cimicifugic acids A, B, and C, which are esters of fukiic acid (3',4'-dihydroxybenzyl tartaric acid) was more potent than that (20—37% inhibition in 0.23—0.24 μM) of cimicifugic acids D, E, F, which are esters of pscidic acid (4'-hydroxybenzyl tartaric acid). Since fukiic acid showed weaker inhibition, and caffeic acid, ferulic acid, isoferulic acid, and p-coumaric acid showed far weaker activities, the entire structures of fukinolic acid and cimicifugic acids A, B, and C proved to be responsible for the inhibitory activities. Trypsin and pronase E hydrolyzed collagen nonselectively alone or in addition to collagenase. These collagenolytic activities were also inhibited by fukinolic acid. These results show that fukinolic acid may inhibit either the collagenolytic activities specific to collagenase or nonspecific to other emzymes. The present studies suggest the potential effect of fukinolic acid and cimicifugic acids of Cimicifuga rhizomes in preventing collagen degradation by collagenases or collagenolytic enzymes under pathological conditions, wound healing, or inflammation.

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A reactive oxygen species has been implicated in a range of human pathological diseases such as atherosclerosis and certain cancers. Flavonoids are reported to exhibit various biological activities, including antioxidative and free radical scavenging activities. Several flavonoids obtained from barley leaves, soybean and some medicinal plants, Silybum marianum, Sophorae Flos, Cinnamon, Ephedrae Herba and Scutellariae Radix, were tested for their DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity. The structure-activity relationships suggested that not only the numbers of hydroxy group but also the position of hydroxy group might be important for mediating potent activity.

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Perilla frutescens BRITTON (perilla, Labiatae) is a medicinal herb prescribed in Saiboku-to, which is a Kampo formula effective for allergic diseases such as bronchial asthma. The present study was conducted to evaluate the anti-allergic effect of orally administered perilla decoction and to identify the active constituents using mice ear-passive cutaneous anaphylaxis (PCA)-reaction, which is one of the animal models for type I allergy. Perilla decoction significantly suppressed PCA-reaction, and the inhibition % at the dose of 500 mg/kg was 43%. The perilla decoction contains 5.3% of luteolin 7-O-[β-glucuronosyl(2→1)β-glucuronide], 1.6% of apigenin 7-O-[β-glucuronosyl(2→1)β-glucuronide], 0.49% of scutellarin, and 2.5% of rosmarinic acid (weight of compound/dried weight of perilla decoction %), respectively. When these constituents were orally administered to mice at the dose equivalent to 500 mg/kg of perilla decoction, rosmarinic acid and apigenin 7-O-[β-glucuronosyl(2→1)β-glucuronide] significantly suppressed PCA-reaction, and their inhibition % was 41% (p<0.01) and 32% (p<0.05), respectively. Since the inhibition % or perilla decoction and rosmarinic acid were nearly equal, the anti-allergic effect of perilla decoction depends primarily on rosmarinic acid. The standard Saiboku-to decoction contained 0.013% of rosmarinic acid, which was too low to exhibit anti-allergic activity in a daily dose of Saiboku-to in adults, suggesting that perilla would be prescribed in Saiboku-to to exhibit other pharmacological effects than its anti-allergic activity, such as a sedative.

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Panax ginseng is widely used as a Chinese medicine, but it takes a long time to reach harvest and to establish its qualified strains. In the course of searching high quality Panax ginseng, we found a useful random amplified polymorphic DNA (RAPD) primer, which showed a 725 base pair band for a selected elite strain Aizu K-111 (now called Kaishusan) including its cultured tissues, while the other strains did not necessarily show this band. We sequenced the DNA fragment amplified and designed primers to improve electrophoretic profiles, based on the sequence.

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Sulfapyridine (SP) is metabolized by polymorphic N-acetyltransferase 2 (NAT2) [EC 2.3.1.5]. In this study, the correlation between the NAT2 genotype and the pharmacokinetics of SP after multiple oral dosing of sulfasalazine (SASP) was examined to elucidate the effect of multiple dosing on the predictability of the phenotype by NAT2 genotyping. Seven healthy subjects were classified into two groups; the homozygotes for the wild-type allele, NAT2^*4/^*4 (Group I) and the compound heterozygotes for the mutant allele (NAT2^*4/^*6A or NAT2^*4/^*7B) (Group II). All received once-daily 1 g of SASP (Salazopyrin^®) orally for 8 d. Plasma concentrations and urinary recoveries of SASP, SP and N-acetylsulfapyridine (AcSP) were monitored for 8 d. At 24 h on Day 1, the plasma concentration of SASP was lower and those of SP and AcSP were higher in Group II compared with Group I, but there was no significant difference. The plasma concentration ratio of AcSP to SP (AcSP/SP) tended to be lower in Group II. Urinary recoveries of SP and AcSP were increased in Group II, and their ratio was slightly reduced in Group II. Multiple dosing for 8 d resulted in an increase in the plasma concentrations of SASP, SP and AcSP. The difference between Group I and II was marked compared with single dosing, resulting in a significant difference in the plasma concentration of SP and the ratio of AcSP/SP. The simple input-output pharmacokinetic model applied for the analysis of plasma concentrations and urinary recoveries of SP and AcSP suggested the acetylation of SP into AcSP was 2.7-fold reduced in Group II (p=0.064).

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In this study, we have examined the antitumor effect of combined administrations of indomethacin (IND) with chemotherapeutic drugs on tumor growth. Colon 26 clone 20 (C20) cells and monocyte chemotactant protein-1 (MCP-1) transfected C20 cells (C20βA-2-1) were used and these cells were inoculated into the footpad of BALB/c mice. At day 1 after tumor inoculation, treatment with 0.001% IND via the drinking water was commenced. At days 4, 6, and 8, adriamycin or cisplatin was administered intravenously at a dose of 5 mg/kg or intraperitoneally at a dose of 2 mg/kg, respectively. Although IND, adriamycin and cisplatin only partially reduced the growth of the C20 tumors after treatment with each drug on its own, a marked synergistic effect was observed when they were given in combination. A synergistic effect between IND and cisplatin on C20βA-2-1 was also observed. However, IND itself showed no suppression of C20βA-2-1 tumor growth. These results suggest that combination of indomethacin with chemotherapeutic drugs could be an effective form of cancer chemotherapy. The observed effects may be dependent on the expression of MCP-1.

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