Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502.

BACKGROUND: While adjuvant chemotherapy is preferable for high-risk colon cancer, treatment duration is controversial. Oral uracil and tegafur (UFT)/leucovorin (LV) is widely used as a standard adjuvant chemotherapy for colon cancer in Japan. We conducted a phase III trial to investigate the optimal duration of adjuvant chemotherapy for stage IIB/III colon cancer. PATIENTS AND METHODS: Patients with curatively resected stage IIB/III colon cancer were eligible for enrollment in this trial. Patients were registered within 6 weeks after surgery and were randomly assigned to receive UFT/LV for 28 of 35 days for 6 months in the control group or for 5 consecutive days per week for 18 months in the study group. The primary end point was the disease-free survival (DFS), and the secondary end points were overall survival (OS) and safety. RESULT: A total of 1071 patients were registered from 233 centers. A statistically significant difference in DFS was not observed between the study group and the control group; the 5-year DFS was 69% in the study group and 69% in the control group. The 5-year OS was 85% in the study group and 85% in the control group. CONCLUSION: Eighteen-month treatment with UFT/LV did not improve DFS or OS compared with 6-month UFT/LV treatment in patients with stage IIB/III colon cancer. The important finding from this study is that not 18 months but 6 months of treatment is enough for postoperative UFT/LV for stage IIB/III colon cancer. CLINICAL TRIAL NUMBER: UMIN-CTR C000000245.

NON-POLAR CONSTITUENTS FROM TARAXACUM OFFICINALE WEBER EX WIGG / Монголын эм зүй, эм судлал

The dichloromethane fraction from the ethanol extract of the aerial parts of Taraxacum offi cinale showed a good inhibitory effect on hepatocellular carcinoma cells (HCC). As a result of a series of column chromatographies and usage of nuclear magnetic resonances spectrometric methods and mass spectroscopy 9 known components as taraxasterol (1), taraxasterylacetate (2),pseudotaraxasterol (3), lupeolacetate (4), b-sitosterol (5), b-sitosterylglucopyranose (6), palmitic acid (7), monopalmitin (8) and chrysoerol (9) have been determined. Amongst them palmitic acid, monopalmitin and chrysoeriol have been determined for the fi rst time in the aerial parts of Taraxacum offi cinale. Six compounds as 1, 3, 4, 5, 6 and 7 were tested for their inhibitory activity on HCC and only palmitic acid exhibited more activity against HCC than others, suppressing cell proliferation, migration, adhesion and activated cell apoptosis.Keywords: Triterpenol and sterol derivatives; palmitic acid; hepatocellular carcinoma inhibition activity;IntroductionTaraxacum, commonly called dandelion, is a large genus of fl owering plants in the Asteraceae family. The latin name Taraxacum is from the Greek and means “disease remedy”, while the English name dandelion is originated from the French dent de leon, meaning “lion’s tooth”1. The Mongolian well-recognised name is “baaban beeben”, while in Japan it calls hokouei, respectively. Consequently, Taraxacum is widespread plant throughout the world, in particular, 19 species are found in the Mongolian fl ora2. Generally Taraxacum is considered weedy plant used as a medicinal herb and for food preparation. Traditionally, Taraxacum offi cinale Weber ex Wigg. in Mongolian and Tibetan medicine under the name “khurmong” the root has been used as the composition in a remedy for jaundice and other disorders of the liver and gallbladder, whilethe leaf is used as a diuretic and bitter digestive stimulant. Moreover, fresh dandelion stem latex is used for the warts treatment1,3-6. Taraxacum leaf is included as a medicinal drug in Herbal Pharmacopeia of several European countries. Numerous biological activity tests resulted that Taraxacum possessed an infl ammation modulating activity7-9, diuretic activity comparable to furosemide10, digestive stimulant, appetitive effect and activator for bile fl ow11-12, hypoglycemic activity13 and antitumor activity14. No side effects and carcinogenicity of T. offi cinale extracts and preparations have been noticed. Chemical constituents of T. offi cinale arewell studied. Scientists of different countries reported that whole plant T. offi cinale containedabundance of bitter principles as terpenoids and sterols, bile like terpenes and sterols, various fl avonoids and phenolic acids, large amount of polysaccharides as inulin and fructosans11,15-17.Also, dandelion is a rich in minerals such as iron, potassium and zinc18,19. In this work we are describing activity-guided isolation and the molecular structure elucidation of components from the dichloromethane fraction of the aerial parts of T. offi cinale, from the Mongolian fl ora.

Vitamin C administration attenuates overload-induced skeletal muscle hypertrophy in rats.

AIM: This study aimed to investigate the effects of vitamin C administration on skeletal muscle hypertrophy induced by mechanical overload in rats. METHODS: Male Wistar rats were randomly assigned to three groups: (i) sham-operated group (n = 8), (ii) placebo-administered group (n = 8) and (iii) vitamin C-administered group (n = 8). In the placebo-administered and vitamin C-administered groups, the gastrocnemius and soleus muscles of the right hindlimb were surgically removed to overload the plantaris muscle. Vitamin C (500 mg kg(-1)) was orally administered to the vitamin C-administered group once a day for 14 days. RESULTS: Synergist muscle ablation caused significant increases in wet weight and protein concentration of the plantaris muscle in both the placebo-administered (P < 0.01) and vitamin C-administered groups (P < 0.01) compared with the sham-operated group (SHA). However, the magnitude of plantaris muscle hypertrophy (expressed as a percentage of the contralateral plantaris muscle) was significantly smaller (P < 0.01) in the vitamin C-administered group (141%) than in the placebo-administered group (PLA) (152%). Compared with the SHA, only the PLA showed higher expressions of phosphorylated p70s6k and Erk1/2 (positive regulators of muscle protein synthesis) and a lower expression of atrogin-1 (a muscle atrophy marker). Concentrations of vitamin C and oxidative stress markers in the overloaded muscle were similar between the placebo-administered and vitamin C-administered groups. CONCLUSION: Oral vitamin C administration can attenuate overload-induced skeletal muscle hypertrophy, which may have implications for antioxidant supplementation during exercise training.

High-intensity laser for acupuncture-like stimulation.

The insertion of needles into specific parts of the body was shown to provide analgesic and therapeutic effects. In this study, we tested the analgesic effects of high-intensity infrared laser for acupuncture-like stimulation. Twelve adult Sprague-Dawley rats weighing 230 to 250 g were randomly assigned to laser, needle, or restraint groups. Stimulation was directed to the meridian point Taixi (KI 3) for 10 min. For laser stimulation, a pulsed Er:YAG system was used. The laser settings were adjusted to provide a focal raise in the skin temperature to about 45 degrees C. The anti-nociceptive effect was evaluated by the tail-flick test. Both needling and laser stimulation significantly increased the tail-flick latency. Peak needling effect was observed immediately after treatment, while laser stimulation was effective both immediately and 45 min after treatment. High-intensity laser stimulation may be used alternatively or in combination with conventional acupuncture needling for pain relief.

Characterization of dentin formed in transplanted rat molars by electron probe microanalysis.

The present study was designed to characterize dentin formed in transplanted rat molars by investigating calcium (Ca), phosphorus (P), and magnesium (Mg) concentrations using electron probe microanalysis (EPMA) as well as examining the rate of dentin matrix formation by vital staining. The unerupted immature lower right second molar in 2-week-old rats was transplanted into the upper right first molar socket. Rats were injected with oxytetracycline, calcein, and alizarin intraperitoneally at 1 day before and 1 and 2 weeks after transplantation, respectively, for vital staining. The maxillae and mandibles were fixed 3 weeks after transplantation, resected, and embedded in resin. Undemineralized sections were cut and examined by fluorescent microscopy and EPMA. The thickness of dentin formed in the first week after transplantation was significantly less than that of dentin formed in any other 1-week period in the transplanted tooth and was about one-fifth the thickness of dentin formed in control teeth. Formation of dentin recovered in the third week after transplantation. In the first week after transplantation, EPMA demonstrated a sharp increase in Mg concentration with a slight decrease in Ca concentration. Thereafter, no significant difference was identified among Ca, P, or Mg concentrations or the Ca/P ratio between transplanted and control teeth. These results suggest that disruption of the circulation and innervation by transplantation cause a temporary change in the matrix formation rate and elemental distribution of dentin, which is subsequently restored within 2 weeks after transplantation.

Mixed antagonistic effects of bilobalide at rho1 GABAC receptor.

Bilobalide was found to be a moderately potent antagonist with a weak use-dependent effect at recombinant human rho(1) GABA(C) receptors expressed in Xenopus oocytes using two-electrode voltage clamp methodology. Antagonism of bilobalide at homomeric rho(1) GABA(C) receptors appeared to be mixed. At low concentration, bilobalide (3 microM) caused a parallel right shift and surmountable GABA maximal response of the GABA dose-response curve characteristic of a competitive antagonist. At high concentrations, bilobalide (10-100 microM) caused nonparallel right shifts and reduced maximal GABA responses of GABA dose-response curves characteristic of a noncompetitive antagonist. The potency of bilobalide appears to be dependent on the concentrations of GABA and was more potent at lower GABA concentrations. The mechanism of action of bilobalide at rho(1) GABA(C) receptors appears to be similar to that of the chloride channel blocker picrotoxinin.

Restored vulnerability of cultured endothelial cells to high glucose by iron replenishment.

High glucose (HG) concentrations are toxic to various cells in vivo, but cells become insensitive to HG toxicity when they are subcultured serially in vitro. Oxidative stress is involved in HG toxicity, and metal ions, especially iron, mediate some oxidative stress. To investigate mechanisms involved in the insensitiveness of cultured cells to HG toxicity, we focused on the level of intracellular iron. Freshly prepared human umbilical vein endothelial cells contained a substantial amount of iron, whereas its level decreased rapidly during the course of culture (to less than 10%). The iron content was restored by incubation of the cells with Fe(III)/8-hydroxyquinoline, and the iron-supplemented cells were more susceptible to both oxidant- and HG-induced injury. Under the HG conditions, the iron-loaded cells were subjected to higher levels of oxidative stress. The enhanced HG toxicity by iron was attenuated by the treatment with several antioxidants including catalase, ascorbic acid, and pyruvate. These data suggested that the insensitiveness of subcultured cells to HG toxicity is, at least in part, due to rapid and dramatic loss of intracellular iron. Supplementation with iron is useful to restore the vulnerability of cultured cells to HG that is normally observed in in vivo situations.

Molecular cloning and characterization of UDP-GlcNAc:lactosylceramide beta 1,3-N-acetylglucosaminyltransferase (beta 3Gn-T5), an essential enzyme for the expression of HNK-1 and Lewis X epitopes on glycolipids.

A new member of the UDP-N-acetylglucosamine:beta-galactose beta1,3-N-acetylglucosaminyltransferase (beta3Gn-T) family having the beta3Gn-T motifs was cloned from rat and human cDNA libraries and named beta3Gn-T5 based on its position in a phylogenetic tree. We concluded that beta3Gn-T5 is the most feasible candidate for lactotriaosylceramide (Lc(3)Cer) synthase, an important enzyme which plays a key role in the synthesis of lacto- or neolacto-series carbohydrate chains on glycolipids. beta3Gn-T5 exhibited strong activity to transfer GlcNAc to glycolipid substrates, such as lactosylceramide (LacCer) and neolactotetraosylceramide (nLc(4)Cer; paragloboside), resulting in the synthesis of Lc(3)Cer and neolactopentaosylceramide (nLc(5)Cer), respectively. A marked decrease in LacCer and increase in nLc(4)Cer was detected in Namalwa cells stably expressing beta3Gn-T5. This indicated that beta3Gn-T5 exerted activity to synthesize Lc(3)Cer and decrease LacCer, followed by conversion to nLc(4)Cer via endogenous galactosylation. The following four findings further supported that beta3Gn-T5 is Lc(3)Cer synthase. 1) The beta3Gn-T5 transcript levels in various cells were consistent with the activity levels of Lc(3)Cer synthase in those cells. 2) The beta3Gn-T5 transcript was presented in various tissues and cultured cells. 3) The beta3Gn-T5 expression was up-regulated by stimulation with retinoic acid and down-regulated with 12-O-tetradecanoylphorbol-13-acetate in HL-60 cells. 4) The changes in beta3Gn-T5 transcript levels during the rat brain development were determined. Points 2, 3, and 4 were consistent with the Lc(3)Cer synthase activity reported previously.

[Method-performance studies of notified analytical method for clofentezine].

Method-performance studies were conducted for the notified revised analytical method of clofentezine. Clofentezine spiked in azuki beans, apple, orange, banana, grape, tea powder and tea extract at the level of 0.2 microgram/g (2 micrograms/g for tea) was analyzed in replicate in 6 laboratories. Mean values of recovery from 7 crops ranged from 78.4 to 85.2%. Repeatability relative standard deviation values ranged from 2.2 to 4.6% and reproducibility standard deviation values ranged from 4.8 to 10.3%. The detection limits were 0.005-0.01 microgram/g. These results show the notified analytical method has good performance.

Hyperhomocysteinemia impairs angiogenesis in response to hindlimb ischemia.

Hyperhomocysteinemia (HH) is an independent risk factor for atherosclerosis, including peripheral arterial occlusive disease (PAOD). Because angiogenesis and collateral vessel formation are important self-salvage mechanisms for ischemic PAOD, we examined whether HH modulates angiogenesis in vivo in a rat model of hindlimb ischemia. Rats were divided into 3 groups: the control group was given tap water, the HH group was given water containing L-methionine (1 g x kg(-1) x d(-1)), and the HH+L-arg group was given water containing methionine (1 g x kg(-1) x d(-1)) and l-arginine (2.25 vol%). At day 14 of the dietary modifications, the left femoral artery and vein were excised, and the extent of angiogenesis and collateral vessels in the ischemic limb were examined for 4 weeks. Plasma homocysteine levels significantly increased (P:<0.001), and plasma and tissue contents of nitrite+nitrate as well as tissue cGMP levels significantly decreased in the HH group compared with the control group (P:<0.01). Laser Doppler blood flowmetry (LDBF) revealed a significant decrease in the ischemic/normal limb LDBF ratio in the HH group at days 7, 14, 21, and 28 (P:<0.01 versus control). Angiography revealed a significant decrease in the angiographic score in the HH group at day 14 (P:<0.001 versus control). Immunohistochemistry of ischemic tissue sections showed a significant reduction in the capillary density in the HH group (P:<0. 001 versus control). Oral l-arginine supplementation in rats with HH (HH+L-arg) restored the decreased plasma and tissue nitrite+nitrate and cGMP contents (P:<0.05) as well as angiogenesis, as assessed by LDBF (P:<0.05 versus HH), angiographic score (P:<0.01 versus HH), and capillary density (P:<0.001 versus HH). In summary, HH impaired ischemia-induced angiogenesis and collateral vessel formation in a rat model of hindlimb ischemia in vivo. The mechanism of the HH-induced impairment of angiogenesis might be mediated in part by a reduced bioactivity of endogenous NO in the HH state.

Hypercholesterolemia inhibits angiogenesis in response to hindlimb ischemia: nitric oxide-dependent mechanism.

BACKGROUND: Endothelium-derived nitric oxide (EDNO) plays an important role in the regulation of angiogenesis, whereas hypercholesterolemia (HC) impairs EDNO release. We examined the hypothesis that HC may inhibit ischemia-induced angiogenesis by inhibition of EDNO in a rat model of unilateral hindlimb ischemia and that oral L-arginine supplementation, a substrate for NO synthase, may prevent HC-related impairment of angiogenesis. METHODS AND RESULTS: Male Sprague-Dawley rats were fed (A) standard diet (control), (B) 2% high-cholesterol diet (HC group), or (C) high-cholesterol diet with oral L-arginine (2.25% in drinking water) (HC+L-arg group). At 2 weeks of the dietary intervention, unilateral limb ischemia was surgically induced in all animals. Dietary HC groups (B and C) revealed elevated total and LDL cholesterol levels compared with control animals. Laser Doppler blood flow analyses showed significant decreases in the ischemic/normal limb blood flow ratio in the HC group compared with controls (P:<0.05) when followed up until 4 weeks after surgery. Selective angiography and immunohistochemical analyses in the ischemic limb at postoperative day 14 revealed significantly lower angiographic scores (P:<0.01) and capillary densities (P:<0.01) in the HC group than controls, which were associated with decreased tissue contents of NO(x) and cGMP. Oral L-arginine supplementation (HC+L-arg) significantly improved all parameters of the laser Doppler blood perfusion ratio, angiographic scores, and capillary densities (P:<0.01 versus HC group), which were accompanied by significant elevations in serum L-arginine levels and tissue NO(x) and cGMP contents. CONCLUSIONS: Collateral vessel formation and angiogenesis in response to hindlimb ischemia were significantly attenuated in rats with dietary HC. The mechanism may be related to the reduced NO bioactivity in the ischemic tissues. Augmentation of the tissue NO activity by oral L-arginine supplementation restored the impaired angiogenesis in HC.

Ascorbic acid supplementation to primary culture of chicken hepatocytes with non-serum medium.

Chicken liver is lack of ascorbic acid biosynthesis system, different from mammals and highly evoluted birds. Chicken hepatocytes cultured without ascorbate was expected to have lower ascorbate amounts than physiological levels. Intracellular was decreased as compared with intact liver by cell preparation performed with in situ collagenase perfusion. We added ascorbate to a primary culture of chicken hepatocytes in order to restore the amount of ascorbate. Serum-free Leivobitz's L-15 medium which do not contain ascorbate was used for control medium. Cells were cultured with several concentrations of ascorbate for 24 or 48 h. After ascorbate supplementation for 24 to 48 h, cellular ascorbate concentration increased depending on the dose of medium ascorbate. Medium lactate dehydrogenase activity derived from hepatocytes, an index of cell injury, decreased upon 5-100 mg/l of ascorbate supplementation for 48 h. Tyrosine aminotransferase activity, an index of liver function, increased following culture with 50 and 100 mg/l ascorbate for 48 h. The activities, however, decreased by supplementation with 1000 mg/l of ascorbate. In conclusion hepatocytes lost intracellular ascorbate during preparation by in situ collagenase perfusion. Supplementation of ascorbate restored cellular ascorbate concentration, lowered cell injury and raised tyrosine aminotransferase activitv in primary cultured chicken hepatocytes. Ascorbate treatment for 48 h at 50 mg/l was the best combination in this study for primary culture of chicken hepatpcyte with non-serum L-15 medium

High hurdle of clinical trials to demonstrate efficacy of anticataractogenic drugs.

Recently, the rapid progression of cataract surgical technique has led cataract patients in industrialized countries to ignore the possibilities of drug therapy. Globally, however, it will be impossible in the near future to treat cataract by surgery alone, mainly due to medicoeconomic reasons. Preventative measures must be sought. As one of the these measures, the development of anticataractogenic drugs has reemerged as a focus in the lens research field. Although clinical trials of newly developed drugs are absolutely necessary before they enter the market, they have been considered to be a rather easy task. However, in order to gain accurate and reproducible data from trials, the trial program must be carefully prepared. The numbers of participants to the trial, the selection criteria of the subjects, the objective judgment of cataractous changes, follow-up period, a high technical level for cataract documentation and image analysis are proposed. Although there still remain some difficulties concerning the methods for objective judgment, a scientifically acceptable examination must be conducted.

[The mechanism of alteration of monoamine metabolism in brain regions in marble burying behavior-isolated housing mice and effect of oren-gedoku-to on this alteration].

The mechanism of the alteration in marble burying behavior-isolated housing (MBB-IH) mice was investigated. The determination of hypothalamus monoamine and serum corticosterone contents indicated that MBB-IH mice readily responded to the stress stimuli in conditioned fear stress. Six drugs, such as buspirone (10 mg/kg, p.o.), zimelidine (10 mg/kg, p.o.), clomipramin (10 mg/kg, p.o.), yohimbine (5 mg/kg, p.o.), ethyl beta-carboline-3-carboxylate (beta-CCE, 5 mg/kg, p.o.) and flumazenil (15 mg/kg, p.o.) were singly and/or three times administered to MBB-IH mice. Their inhibitory activity on the MBB-IH mice was considered by the use of activity profiles consisting of spontaneous locomotor activity, marble burying behavior and hypothalamus monoamine content. Using these profiles, we calculated the activities as vector in three-dimensional space, and compared the distance from the control point (DCP). DCPDOPAC and DCP5-HIAA were shortened by single administration of beta-CCE and flumazenil. Oren-gedoku-to (30 and 300 mg/kg, p.o.) shortened the DCPDOPAC and DCP5-HIAA similarly to beta-CCE. The blended crude drugs in Oren-gedoku-to, Coptis rhizome (636.0 mg/kg, p.o.), Scutellaria root (644.4 mg/kg, p.o.) and Gardenia fruit (894.8 mg/kg, p.o.) shortened the DCPDOPAC. Coptis rhizome and Scutellaria root also shortened the DCP5-HIAA. These results suggest that GABA neuron function intensely affects the alteration of MBB-IH and Oren-gedoku-to has the intrinsic benzodiazepine-like activity.

[The anti-Candida activity of shikon].

Antifungal activity of Shikon, roots of Lithospermum erythrorhizon and Arnebia euchroma was investigated in vitro. The extracts containing the pigments of Ko-shikon or Nan-shikon showed the antifungal activities against Candida albicans. Acetylshikonin, one of these pigments, inhibited the fungal growth at MIC 15.6 micrograms/ml (RPMI24 h) or 3.9 micrograms/ml (YNB24 h).

Effects of leptin and orexin-A on food intake and feeding related hypothalamic neurons.

The lateral hypothalamic area (LHA) and the ventromedial hypothalamic nucleus (VMH) have historically been implicated in ingestive behavior, energy balance and body mass regulation. The LHA is more closely associated with the initiation of eating; whereas the VMH mediates the cessation of eating. The parvocellular part of the paraventricular nucleus (pPVN) is also included in the suppressing mechanism. Recently, two hypothalamic peptides, orexin-A and orexin-B, localized in the posterior and lateral hypothalamic perifornical region were discovered in the rat brain and they increase food intake. Leptin, a protein encoded by an obesity gene, expressed in adipose tissue and released into the blood also affects food intake. Orexin and leptin receptors have been localized in the LHA, pPVN, and VMH. The purpose of this study was to measure food intake in the rat in response to leptin and orexin-A; and to determine their electrophysiological effects on feeding related hypothalamic neurons. Results clearly show that leptin suppresses food intake whereas orexin-A increases food intake. These differences are associated with leptin and orexin-A modulatory effects on LHA, pPVN, and VMH glucose responding neurons. In the LHA, leptin inhibits a larger proportion of both glucose-sensitive neurons (GSNs) and non-GSNs. In the pPVN, leptin increases more GSNs in comparison to non-GSNs. Whereas in the VMH, leptin increases the activity of glucoreceptor neurons (GRNs) in comparison to non-GRNs. Orexin-A had opposite effects: increases activity of GSNs more than the non-GSNs in the LHA and significantly suppresses GRNs in the VMH. In the pPVN, orexin-A had no observable effects on neurons that have a low density of orexin 2 receptors. Results are discussed in terms of hypothalamic neural circuits that are sensitive to endogenous food intake inducing and reducing substances.

[Estimation of antibacterial activity of various antibiotics against Pseudomonas aeruginosa by score method].

Antibacterial activity of various antibiotics against Pseudomonas aeruginosa isolated from each hospitals depends on the variety or amount of antibiotics used in each hospital. The antibiotic, which is effective to P. aeruginosa in a certain hospital is not always effective to that in other hospital. The excellent antibiotics in antibacterial activity have low MIC and hard to progress in resistance, and such antibiotics may be effective against P. aeruginosa isolated from any hospitals. Therefore we thought that the antibiotic, which was progress to resistance, would show a great difference in MIC among hospitals, and we investigated MIC and difference of MIC of various antibiotics against P. aeruginosa isolated from six hospitals. Furthermore, we converted the data of MICs and difference of MIC among six hospitals into the score, and tried to estimate antibacterial activity of various antibiotics by using those scores. From the results of analysis in this report, we think the antibiotics actually surpass in antibacterial activity may be imipenem, cefozopran, cefsulodin and amikacin. New analytical method proposed in this report will become one of potential methods to estimate antibacterial activity of antibiotics against bacteria isolated from inpatient with bacterial infections.

Leptin effects on feeding-related hypothalamic and peripheral neuronal activities in normal and obese rats.

We investigated the effects of leptin on central and/or peripheral feeding-related neuronal networks in Wistar male rats either normal (350-450 g) or Zucker obese (500-800 g). Low doses (1-10 pg) of leptin inhibited glucose-sensitive vagal hepatic afferent discharges and facilitated sympathetic efferent discharges to brown and white adipose tissue. Most (40-75%) neurons in the arcuate nucleus were significantly inhibited by superperfusion with leptin (0.1 nM-10 pM) under in vitro conditions. In anesthetized animals, leptin was applied electrophoretically to single hypothalamic neurons. Both glucose-sensitive neurons (GSNs) and non-GSNs in the feeding center (LHA) were significantly inhibited. Most glucoreceptor neurons in the satiety center (VMH) were significantly excited. Their depolarization was confirmed by activation of Na+ and K+ channels by 10(-11) M leptin using the perforate blind patch-clamp method. Although leptin excited GSNs in the parvocellular part of the paraventricular nucleus, the effects of leptin on such neuronal activity were slight or absent in Zucker obese rats. These results suggest that the feeding-suppression effects of leptin are mediated by its effects on signal transduction through both the central and the peripheral nervous systems.

[Biochemical modulation of 5-FU--effect of low dose CDDP].

A pilot study of continuous or intermittent low dose 5-FU and cisplatin chemotherapy (low-dose FP therapy) was conducted at the Department of Surgery of Sapporo Medical University School of Medicine (Group A) and Sapporo Tsukisamu Hospital, and at the Department of Internal Medicine of the Kochi Prefectural Center Hospital (Group B). The cases with esophageal cancer, stomach cancer, pancreatic cancer, hepatocellular carcinoma or colonic cancer co-existing with their inoperable lesion(s) were considered in this chemotherapy. The rates of complete and partial response and of side effects were studied. Also, the effects of low-dose FP on the prognosis of the patients with pancreatic or colonic cancers were investigated. The procedure consisted of continuous 5-FU 320 mg/m2 i.v. with daily CDDP 2.5 mg/m2 i.v. for five days/week rescue was performed for at least four weeks as a rule. The rates of complete response and partial response were 64% (Group A) and 56% (Group B) in esophageal cancer, 62% (Group A and B) in stomach cancer, 48% (Group A) and 57% (Group B) in colonic cancer, and 8% (Group A) and 21% (Group B). The overall response rate was 57.8%. The frequencies of severe side effect(s) (grades 3 and 4) were within three to eight percent, and no death from side effect(s) was experienced. The effects of low-dose FP therapy on the prognosis of stage IV colonic cancer and stage IV b pancreatic cancer were studied retrospectively. It is suggested that this chemotherapy might contribute to the survival of patients with these two cancers. Otherwise, the chemotherapy of intermittent administration (day by day) of 5-FU 750 mg/m2 i.v. and CDDP 2.5 mg/m2 i.v. was selected in order to decrease the rate of side effects and their severity. The pilot study encountered no severe side effects, no cases with grade 4 side effect were experienced but the remission rates were mostly similar to that of sequential low-dose FP therapy. However, the side effect of low grade ones as symptoms in gastrointestinal tract were observed in more patients. We concluded that sequential or intermittent 5-FU/CDDP therapy might be fairly effective, and since the adjuvant chemotherapy of choice for advanced or recurrent gastrointestinal cancer, their FP therapy might be one of the adjuvant treatments.