Antitumor effects of YM155, a novel survivin suppressant, against human aggressive non-Hodgkin lymphoma

YM155, a novel small-molecule that down-regulates survivin, exhibits broad, potent antitumor activity against a range of human tumors. We evaluated the activity of YM155 in aggressive non-Hodgkin lymphoma. In a number of diffuse large B-cell lymphoma lines, YM155 exhibited 50% growth inhibition with values between 0.23 and 3.9 nM. Within in vivo xenograft models, continuous infusion of YM155 eradicated large, established subcutaneous WSU-DLCL-2 and Ramos tumors, with sustained efficacy observed through 4 cycles of YM155 therapy. YM155 increased survival significantly versus rituximab in disseminated Ramos models. This study suggests that YM155 may represent an effective treatment for aggressive lymphomas.     

Hypoglycemic agent YM440 suppresses hepatic glucose output via gluconeogenesis by reducing glucose-6-phosphatase activity in obese Zucker rats

Using a glucose clamp, we had shown that YM440, (Z)-1,4-bis{4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}but-2-ene, reduced the increased hepatic glucose output in obese Zucker rats. We further examined effects of YM440 on ¹⁴C-incorporation from [¹⁴C]bicarbonate into blood glucose via gluconeogenesis, and on gluconeogenic enzymatic activities. Fed obese Zucker rats showed a 4-fold increase of ¹⁴C-incorporation into blood glucose compared to that in lean rats. Glucose-6-phosphatase and fructose-1,6-bisphosphatase activities in obese rats were increased 1.4-fold and 1.6-fold compared with lean rats. YM440 (300 mg/kg for 2 weeks) decreased ¹⁴C-incorporation into blood glucose by 29% in obese rats. Glucose-6-phosphatase but not fructose-1,6-bisphosphatase activity was reduced by YM440 and closely correlated with ¹⁴C-incorporation into blood glucose, indicating a key role for glucose-6-phosphatase in hepatic glucose output. These results suggest that the increased gluconeogenesis in obese rats is mainly due to the increased activities of glucose-6-phosphatase and fructose-1,6-bisphosphatase and that YM440 suppresses hepatic glucose output by reducing glucose-6-phosphatase activity.     

Multiple doses of the antimuscarinic agent solifenacin do not affect the pharmacodynamics or pharmacokinetics of warfarin or the steady-state pharmacokinetics of digoxin in healthy subjects

AIMS: Solifenacin succinate is used for the treatment of overactive bladder (OAB). The potential for pharmacokinetic and/or pharmacodynamic interactions between solifenacin and warfarin or digoxin was investigated. METHODS: The solifenacin-warfarin study was a two-period crossover trial conducted in healthy males. Subjects received warfarin on the 10th day of 16 days of dosing with either solifenacin or placebo. The solifenacin-digoxin study was an one-sequence crossover trial conducted in healthy males and females. Following a phase-in period for digoxin, solifenacin was administered concomitantly with the drug on days 9-18. RESULTS: The AUC(PT; 0-168 h) following a single dose of warfarin was unchanged in the presence of solifenacin [point estimate = 1.005; 90% confidence interval (CI) 0.98, 1.02)]. The AUC(0-infinity) values for both warfarin enantiomers were also unchanged. A small increase in the C(max) of digoxin was observed during treatment with solifenacin, but for AUC(ss,tau) and C(max) the 90% CI fell within the prespecified interval of 0.80-1.25. Combined administration of solifenacin and warfarin or digoxin was well tolerated. CONCLUSIONS: Since the pharmacokinetics and pharmacodynamics of a single dose of warfarin and the steady-state pharmacokinetics of digoxin were not affected by coadministration of solifenacin in healthy subjects, the need for dosing adjustments for digoxin and/or warfarin does not seem warranted.     

TRH类似物YM14673对缺血神经元c-fos表达的影响

为探讨促甲状腺素释放激素 (TRH)类似物YM1 4673 (YM)对脑缺血损伤保护作用的机制 ,用无损伤小动脉瘤夹夹闭Wistar大鼠大脑中动脉 (MCA)和双侧颈总动脉 (CCAs) 1h ,造成脑缺血再循环模型。大鼠脑冠状切片 (1 0μm)分别进行苏木素 伊红 (HE)染色和免疫组化染色。结果 :缺血 1h再灌 2 4h给药组 (术前 3 0min,ip ,YM 1mg/kg)与缺血组比较大脑皮质神经元降解相对减少。缺血 1h再灌 4h ,缺血组海马结构齿状回及CA4区有强的c fos蛋白样免疫反应 (CFPLI) ,而给药组在上述区域CFPLI相对较低。表明YM对缺血神经元c fos的表达有一定的抑制作用。     

A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery

BACKGROUND: YM150, a new oral direct factor Xa inhibitor is used as prophylaxis for venous thromboembolism (VTE), a well-known risk after orthopaedic surgery. OBJECTIVES: To assess the safety and efficacy of thromboprophylaxis with YM150 in a dose escalation study. PATIENTS/METHODS: Patients (174) undergoing hip replacement surgery were randomized per cohort to oral once daily YM150 or subcutaneous enoxaparin (40 mg daily) in a 4:1 ratio for 7-10 days treatment. The YM150 doses were 3, 10, 30 and 60 mg by sequential four-dose escalation cohorts. The primary endpoint was major and/or clinically relevant non-major bleeding. The incidence of VTE was defined as a composite of verified symptomatic events and/or positive findings at bilateral venography on the last treatment day. An independent adjudication committee evaluated blindly the outcomes of the open-label study. RESULTS: No major and three clinically relevant non-major bleeds were reported, 1 (2.9%; 95% CI, 0.1-15.1) in the 3 mg and 2 (5.7%; 95% CI, 1.0-18.8) in the 10 mg YM150 dose groups. Of 147 patients (84%) with an evaluable venogram, VTE was observed in 51.9% (95% CI, 31.9-71.4), 38.7% (95% CI, 22.6-57.0), 22.6% (95% CI, 9.7-39.4), and 18.5% (95% CI, 7.5-36.5) in the YM150 dose groups 3, 10, 30 and 60 mg, respectively. A significant YM150 dose-related trend in VTE incidence was found (P=0.006). VTE with enoxaparin was 38.7% (95% CI, 22.6-57.0). CONCLUSIONS: YM150, 10-60 mg daily, starting 6-10 h after primary hip replacement, was shown to be safe, well tolerated and effective.     

Marked anti-tumour activity of the combination of YM155, a novel survivin suppressant,and platinum-based drugs

Background:

Survivin, a member of the inhibitor of apoptosis protein family, is an attractive target for cancer therapy. We have now investigated the effects of the combination of YM155, a novel small-molecule inhibitor of survivin expression, and platinum compounds (cisplatin and carboplatin) on human non-small cell lung cancer (NSCLC) cell lines.

Methods:

The anti-cancer efficacy of YM155 in combination with platinum compounds was evaluated on the basis of cell death and progression of tumour xenografts. Platinum compound-induced DNA damage was evaluated by immunofluorescence analysis of histone γ-H2AX.

Results:

Immunofluorescence analysis of histone γ-H2AX showed that YM155 delayed the repair of double-strand breaks induced in nuclear DNA by platinum compounds. The combination of YM155 and platinum compounds also induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Finally, combination therapy with YM155 and platinum compounds delayed the growth of NSCLC tumour xenografts in nude mice to an extent greater than that apparent with either treatment modality alone.

Conclusion:

These results suggest that YM155 sensitises tumour cells to platinum compounds both in vitro and in vivo, and that this effect is likely attributable to the inhibition of DNA repair and consequent enhancement of apoptosis.     

Effect of ramosetron on short-circuit current response in rat colonic mucosa

We investigated the effects of ramosetron (YM060, (−)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride) on the short-circuit current (I_sc) responses to 5-HT receptor agonists in the rat distal colon, and compared its potency to that of other 5-HT₃ receptor antagonists. 5-Hydroxytryptamine (5-HT) concentration-dependently increased I_sc. The I_sc response to 5-HT was partially reduced by tetrodotoxin and ramosetron, and strongly inhibited by GR113808 ([[1-[(2-methylsulphonyl)amino]ethyl]-4-piperidin-yl]methyl 1-methyl-1H-indole-3-carboxylate). 2-Methyl-5-HT and 5-methoxytryptamine also increased I_sc. The former response was inhibited by ramosetron, and the latter was abolished by GR113808. Ramosetron, YM114 (KAE-393, (−)-(R)-5-[(1-indolinyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride) and granisetron concentration-dependently antagonized the I_sc responses to 2-methyl-5-HT with reduction in the maximal response at higher concentrations. Apparent pA₂ values for these antagonists were 10.40, 10.37 and 8.99, respectively. Ondansetron produced clear rightward shifts of the concentration-response curves to 2-methyl-5-HT, with a pA₂ value of 8.53. These results suggest that 5-HT increases I_sc through the 5-HT₃ and 5-HT₄ receptors, and that ramosetron is a potent and selective 5-HT₃ receptor antagonist in rat colonic mucosa.     

YM155对肝癌HepG2细胞增殖和凋亡的影响

目的:探讨YM155对肝癌HepG2细胞增殖和凋亡的影响及可能的机制。方法:采用CCK-8法检测细胞生长抑制率；应用流式细胞仪检测细胞凋亡率的变化；Western blot法检测细胞中蛋白表达的变化，实时定量RT-PCR检测survivin mRNA表达的变化。结果:YM155对人肝癌HepG2细胞的生长抑制作用呈现剂量和时间依赖性。流式细胞术结果显示，HepG2细胞凋亡率明显升高,呈现剂量依赖性。YM155可引起survivin mRNA及蛋白表达下降，而caspase-3、caspase-9和PARP蛋白表达上升。结论:YM155可以抑制人肝癌HepG2细胞的增殖并促进其凋亡，其机制可能是通过激活caspase凋亡途径来实现。     

Glucose uptake stimulator YM‐138552 activates gene expression and translocation of glucose transporter isotype 4

In this study, we examined the effect of YM‐138552 on the glucose uptake, gene expression, and transport activities of the insulin‐regulatable glucose transporter isotype 4 (Glut4) in skeletal muscle cells. YM‐138552 stimulated medium glucose consumption in a dose‐dependent manner (EC₅₀ = 0.07 μM) in myoblast muscle C2C12 cells under differentiation conditions with 2% horse serum supplement. The stimulatory effect of glucose consumption was verified by radiolabeled 2‐DG uptake assay. The compound showed dose‐dependent stimulation of 2‐DG uptake in G8 myoblast muscle cells up to a 1 μM concentration (EC₅₀ = 0.19 μM). To investigate the mechanism of glucose uptake stimulation by YM‐138552, the mRNA level of Glut4 was determined using real‐time quantitative RT‐PCR. The Glut4 mRNA level expressed in C2C12 cells treated with YM‐138552 increased up to at least 24 h (227% vs. control), after which it gradually decreased to the initial level at 36 h. In addition, we established that C2C12 cells stably expressed the myc‐tagged Glut4 protein (C2C12‐Glut4myc) and measured the Glut4 translocation activity. The Glut4 translocation activity was stimulated by treatment of YM‐138552 without insulin in a dose‐dependent manner (EC₅₀ = 0.62 μM), and no insulin effect (100 nM) was observed. This suggests that YM‐138552 has an insulin‐like effect. These results suggest that the stimulation of glucose uptake by YM‐138552 in muscle cells was partly due to upregulation of the Glut4 gene expression and its translocation activation. Our findings on the in vitro effects of YM‐138552 glucose uptake stimulation through the Glut4 transporter may suggest a direction for the development of new drugs for the treatment of NIDDM. Drug Dev. Res. 51:43–48, 2000. © 2000 Wiley‐Liss, Inc.