Effect of cimetidine on intratumoral cytokine expression in an experimental tumor

To evaluate the immunomodulatory effects of histamine in vivo, we analyzed an experimental syngenic tumor model using a colon adenocarcinoma cell line, CT-26, in Balb/c mice. In this model, distinct tumor growth was observed around 6 days after inoculation. Daily administration of cimetidine (0.12 mg/kg/day) significantly suppressed the increases in tumor volume and weight. On day 6 and day 7, histidine decarboxylase (HDC) activity was markedly increased. To examine the alterations in the local immune system, the cytokine expressions in the tumor tissue were measured by ribonuclease protection assay. The cytokine expression levels such as lymphotoxin-beta, tumor necrosis factor-alpha, interferon-gamma, interleukin-10, and interleukin-15 were considerably lower in tissues on day 14 than those on day 6. These decreased expressions were all restored by cimetidine. These results indicated that the effects of cimetidine on tumor growth in this model might be mediated by restoration of the decreased local cytokine expression, which exerts antitumoral effects.     

Mitomycin C pharmacokinetics in patients with recurrent or metastatic colorectal carcinoma

The pharmacokinetics of mitomycin C as a single agent have been determined in 25 treatment courses given to 18 patients with recurrent or metastatic colorectal carcinoma using a high performance liquid chromatography (HPLC) assay to analyze plasma and urine samples. The plasma pharmacokinetics conformed to a two-compartment linear model in 21 of 25 courses monitored with a mean t1/2 lambda 1 of 9.8 +/- 1.2 (SEM) min and mean t1/2 lambda z of 64.1 +/- 8.9 (SEM) min. The large variation observed in t1/2 lambda z was not related to dose or treatment, but an interaction of these two factors approached significance (p = 0.057). Renal excretion in the 12 courses in which it was determined averaged only 2.3% of the total administered dose during the first 4 h monitored and no mitomycin C metabolites were detected in plasma or urine by the HPLC technique used. The most common toxicity, thrombocytopenia, did not correlate with t1/2 lambda z or the area under the curve. This may be due to a failure to monitor active metabolites of mitomycin C; other factors besides plasma drug concentrations that mediate toxicity towards marrow elements; or the small number of courses associated with thrombocytopenia (less than 100,000/mm3). Our study indicates that an interaction of drug dose and treatment course may be associated with increasing t1/2 lambda z; the renal clearance contributes a small component of mitomycin C elimination; metabolites of mitomycin C cannot be detected by the present HPLC technique; and routine monitoring of mitomycin C using present methods cannot be recommended for clinical use to predict toxicity.     

Effect of beta-endorphin on G-cells in rats with experimental duodenal ulcer

Immunohistochemistry was used to study the changes in the number of G cells in the antral part of the stomach of rats (40 animals) with cystamine-induced duodenal ulcer treated with beta-endorphine. In the stomach of rats with cystamine-induced ulcer the number of G cells was discovered to be significantly increased, which was removed by an opioid peptide. Naloxone did not block the action of beta-endorphine. Thus, beta-endorphine changes the number of G cells, the drug action being not associated with opiate receptors.     

艾迪联合化疗对大肠癌免疫及肠道菌群的影响

目的 研究艾迪注射液联合FOLFOX4方案化疗对进展期结直肠癌患者肠道菌群及免疫功能的影响.方法 将60例选择病例随机分两组,A组(试验组):应用FOLFOX4方案化疗同时加用艾迪注射液50 ml每日1次静滴,共10 d;B组(对照组):单纯FOLFOX4方案化疗.分别观察两组化疗前后肠道常驻菌(肠杆菌、肠球菌、双歧杆菌、乳杆菌)指标及机体免疫状态(CD3 、CD4 、CD8 、CD4 /CD8 )的变化.结果 A组与B组比较双歧杆菌及乳杆菌明显增多, 差异有非常显著性(P<0.01);A组CD8 明显下降, CD4 /CD8 比值上升,与B组比较,差异有非常显著性(P<0.01).结论 艾迪注射液具有扶植肠道正常菌群生长的作用;艾迪注射液可降低化疗对进展期结直肠癌患者细胞免疫功能的影响,改善生活质量.     

Mechanism of antitumor effect on mouse hepatocellular carcinoma by intratumoral injection of OK-432, a streptococcal preparation

Intratumoral (i.t.) injection of OK-432, a streptococcal preparation, into implanted tumors of mouse hepatocellular carcinoma (MIH-2) showed antitumor effect including tumor eradication. Intraperitoneal administration of same dose OK-432 did not exhibit tumor suppressive effect. In vitro cytotoxic test suggested that direct cytotoxic effect of OK-432 was not associated with antitumor activity by i.t.-OK-432 treatment. It was also found that Toll-like receptor 4 signaling was not involved in i.t.-OK-432 treatment. Three mice out of five, which had shown tumor eradication by i.t.-OK-432 treatment did not reject re-challenge of MIH-2 cells. Splenocytes from i.t.-OK-432 treated mice did not produce IFN-gamma by stimulation with MIH-2 cells in vitro, but produced abundant IFN-gamma by stimulation with OK-432. Immunofluorescence microscopy demonstrated that CD4+T cells, but not CD8+T cells, infiltrated to i.t.-OK-432 treated tumor tissue produced IFN-gamma. Tumor-infiltrating CD4+T cells from i.t.-OK-432 treated tumor tissue produced IFN-gamma by in vitro stimulation with OK-432 higher than those from untreated tumor tissue. IFN-gamma directly induced apoptosis of MIH-2 cells in vitro. Collectively, i.t.-OK-432 treatment induced priming of CD4+T cells to antigenecity of OK-432, and repetitive i.t.-OK-432 treatment induced IFN-gamma production from OK-432-sensitized CD4+T cells in tumor site, leading to apoptosis of MIH-2 cells susceptible to IFN-gamma.     

Effect of berberine on catecholamine levels in rats with experimental cardiac hypertrophy

The aim of this study is to investigate the effect of berberine on catecholamine level (adrenaline and noradrenaline) in rats with experimental cardiac hypertrophy. Cardiac hypertrophy(CH) was induced by suprarenal abdominal aorta constriction, and the drugs were administered for 8 weeks starting from 4 weeks after surgery. The degree of cardiac hypertrophy was determined by heart and left ventricular weight. The level of adrenaline(AD) and noradrenaline(NA) was detected by HPLC. The data showed that in the CH model rats, the level of plasma and left ventricular tissue AD, and the level of NA in plasma were higher than that of the age-matched controls(indicating increased "total" sympathetic activity). The level of NA in left ventricular tissue of CH model rats was however lower than the age-matched controls. Berberine and captopril showed significant effect on inhibiting the development of cardiac hypertrophy. Berberine decreased plasma NA level and the AD level both in plasma and left ventricular tissue, but had no effect on improving the cardiac NA depletion. Captopril showed significant effect on increasing the depleted cardiac NA and in reducing the elevated plasma NA level. These findings show the efficacy of berberine on modulating the sympathetic nervous activity of rats with experimental cardiac hypertrophy, and reflect the therapeutic potentials of berberine in patients with cardiac hypertrophy and chronic heart failure.     

Effectiveness of carboplatin and paclitaxel as first- and second-line treatment in 61 patients with metastatic melanoma

Background

Patients with metastatic melanoma have a very unfavorable prognosis with few therapeutic options. Based on previous promising experiences within a clinical trial involving carboplatin and paclitaxel a series of advanced metastatic melanoma patients were treated with this combination.

Methods

Data of all patients with cutaneous metastatic melanoma treated with carboplatin and paclitaxel (CP) at our institution between October 2005 and December 2007 were retrospectively evaluated. For all patients a once-every-3-weeks dose-intensified regimen was used. Overall and progression free survival were calculated using the method of Kaplan and Meier. Tumour response was evaluated according to RECIST criteria.

Results

61 patients with cutaneous metastatic melanoma were treated with CP. 20 patients (85% M1c) received CP as first-line treatment, 41 patients (90.2% M1c) had received at least one prior systemic therapy for metastatic disease. Main toxicities were myelosuppression, fatigue and peripheral neuropathy. Partial responses were noted in 4.9% of patients, stable disease in 23% of patients. No complete response was observed. Median progression free survival was 10 weeks. Median overall survival was 31 weeks. Response, progression-free and overall survival were equivalent in first- and second-line patients. 60 patients of 61 died after a median follow up of 7 months. Median overall survival differed for patients with controlled disease (PR+SD) (49 weeks) compared to patients with progressive disease (18 weeks).

Conclusions

Among patients with metastatic melanoma a subgroup achieved disease control under CP therapy which may be associated with a survival benefit. This potential advantage has to be weighed against considerable toxicity. Since response rates and survival were not improved in previously untreated patients compared to pretreated patients, CP should thus not be applied as first-line treatment.     

Dynamic of myocarditis development in rats after injection of cardiac myosine combined with IFA

Myocarditis development was investigated after immunization rats with single subcutaneous injection of cardiac myosin (800 microg/kg) with incomplete Freund's adjuvant (IFA) (M + IFA group). Control group received equal volume of IFA alone or nothing (intact group). On days 4, 14, and 21 after injection, light and electron microscopy of heart sections, morphometric analysis, estimation of proinflammatory cytokines (IL-1p, IL-6, VEGF, TNFa and iNOS) expression were used to evaluate inflammatory response in myocardium. In addition, we estimated cardiac myosin antibody levels in blood serum and nitrite and nitrate levels in blood serum. Our data showed that immunization with cardiac myosin combined with IFA led to inflammatory response in the rat myocardium. Acute inflammation (i.e. lymphocyte infiltration of myocardium and increase of proinflammatory cytokines level) in M + IFA group occurred on 21 days after immunization.     

Effect of substance P on the reproduction of memory engrams and on the amino acid composition of brain structures in rats with experimental neurosis

Formation of experimental neurosis in rats was accompanied in 64% of animals by development of amnesia of conditioned reaction of passive avoidance. Disturbance of mnestic processes was manifested by a change in free amino acids pool including the acids with neurotransmitter properties (GABA, glutamate, glycine). An increase of GABA and glycine content was found in the frontal cortex and an increase of glutamate and GABA--in the hippocampus and striate body. Substance P (125 mkg/kg) administered intraperitoneally against the background of a developed neurosis, produced in 80% of cases an antiamnestic action, accompanied by a statistically significant decrease of GABA content in the frontal cortex, hippocampus and midbrain, and an increase of glutamate in the midbrain. The level of taurine decreased in the frontal cortex, hippocampus and striate body, and increased in the midbrain. Threonine content increased in the striate body and midbrain; there was an increase of taurine, serine and glycine in the midbrain and of glycine in the striate body.     

Periodic acid-Schiff reaction combined with quantitative autoradiography of 3H-thymidine- or 85S-sulfate-Labeled epithelial cells of colon

Summary The influence of periodic acid-Schiff staining on grain counts was examined using autoradiography of guinea pig colon labeled with either ³H-thymidine or ³⁵S-sulfate. Prestaining decreased the grain count, an effect due to the Schiff reagent but not to periodic acid. Poststaining altered the grains which were partly or completely lost, an effect due to periodic acid but not to the Schiff reagent. The suggested procedure is to pretreat the sections with periodic acid, process for autoradiography, and poststain with the Schiff reagent. No silver grain is then lost.