Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models

PURPOSE: The purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small cell lung cancer (SCLC) xenograft models. EXPERIMENTAL DESIGN: A panel of 11 SCLC xenograft models was established to evaluate the efficacy of ABT-263. Single agent activity was examined on a continuous dosing schedule in each of these models. The H146 model was used to further evaluate dose and schedule, comparison to standard cytotoxic agents, and induction of apoptosis. RESULTS: ABT-263 exhibited a range of antitumor activity, leading to complete tumor regression in several models. Significant regressions of tumors as large as 1 cc were also observed. The efficacy of ABT-263 was also quite durable; in several cases, minimal tumor regrowth was noted several weeks after the cessation of treatment. Antitumor effects were equal or superior to that of several clinically approved cytotoxic agents. Regression of large established tumors was observed through several cycles of therapy and efficacy was retained in a Pgp-1 overexpressing line. Significant efficacy was observed on several dose and therapeutic schedules and was associated with significant induction of apoptosis. CONCLUSIONS: ABT-263 is a potent, orally bioavailable inhibitor of Bcl-2 family proteins that has recently entered clinical trials. The efficacy data reported here suggest that SCLC is a promising area of clinical investigation with this agent.     

维A酸衍生物ECPIRM对皮肤T细胞淋巴瘤HH细胞增殖、凋亡的影响及其机制初探

【摘要】 目的 探讨维A酸衍生物ECPIRM对人皮肤T细胞淋巴瘤HH细胞的增殖抑制作用及潜在机制。方法 以0（对照组）、5、10、20 μmol/L ECPIRM处理HH细胞72 h,采用CCK8法检测ECPIRM对HH细胞增殖活力的影响,采用流式细胞仪检测ECPIRM对HH细胞凋亡的影响。以10 μmol/L ECPIRM处理HH细胞72 h,采用转录组学测序分析ECPIRM对HH细胞基因表达的调控作用,结合KEGG通路分析和GO功能富集分析比较ECPIRM诱导的差异表达的相关基因。采用反转录qPCR验证相关通路中关键基因的表达变化。组间差异采用单因素方差分析,采用LSD-t检验进行两两比较。结果 CCK8结果显示,ECPIRM对HH细胞IC50为（4.91 ± 2.48） μmol/L,对照组与5、10、20 μmol/L ECPIRM组HH细胞活力分别为100.00% ± 2.87%、49.58% ± 4.53%、48.36% ± 2.88%、31.44% ± 2.46%,4组细胞活力差异有统计学意义（F = 162.86,P < 0.001）,5、10、20 μmol/L组细胞活力均低于对照组（t值分别为15.36、15.73和20.89,均P < 0.001）。流式细胞仪检测结果显示,4组细胞凋亡率差异有统计学意义（11.51% ± 1.84%、23.83% ± 5.72%、36.19% ± 8.33%、49.75% ± 4.10%,F = 17.62,P < 0.001）,10、20 μmol/L组细胞凋亡率均高于对照组（t值分别为4.46、6.92,均P < 0.01）。转录组学分析发现,ECPIRM诱导的增殖抑制作用可能与类固醇的代谢调控有关。反转录qPCR验证发现,10 μmol/L ECPIRM组L-氨基酸氧化酶（IL4I1）、乙酰辅酶A乙酰转移酶2（ACAT2）、3-羟基-3-甲基戊二酰辅酶A合酶1（HMGCS1）、甲羟戊酸二磷酸脱羧酶（MVD）、3-β-羟基类固醇-8,7-异构酶（EBP）、极低密度脂蛋白受体（VLDLR）、3-羟基3-甲基戊二酰辅酶A还原酶（HMGCR）mRNA相对表达与对照组比较明显受到抑制（均P < 0.05）。结论 维A酸衍生物ECPIRM对HH细胞可发挥显著的抗增殖及凋亡诱导作用,其机制可能与类固醇代谢关键基因的表达抑制有关。     

A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo

Inhibition of the prosurvival members of the Bcl-2 family of proteins represents an attractive strategy for the treatment of cancer. We have previously reported the activity of ABT-737, a potent inhibitor of Bcl-2, Bcl-X(L), and Bcl-w, which exhibits monotherapy efficacy in xenograft models of small-cell lung cancer and lymphoma and potentiates the activity of numerous cytotoxic agents. Here we describe the biological activity of A-385358, a small molecule with relative selectivity for binding to Bcl-X(L) versus Bcl-2 (K(i)'s of 0.80 and 67 nmol/L for Bcl-X(L) and Bcl-2, respectively). This compound efficiently enters cells and co-localizes with the mitochondrial membrane. Although A-385358 shows relatively modest single-agent cytotoxic activity against most tumor cell lines, it has an EC(50) of <500 nmol/L in cells dependent on Bcl-X(L) for survival. In addition, A-385358 enhances the in vitro cytotoxic activity of numerous chemotherapeutic agents (paclitaxel, etoposide, cisplatin, and doxorubicin) in several tumor cell lines. In A549 non-small-cell lung cancer cells, A-385358 potentiates the activity of paclitaxel by as much as 25-fold. Importantly, A-385358 also potentiated the activity of paclitaxel in vivo. Significant inhibition of tumor growth was observed when A-385358 was added to maximally tolerated or half maximally tolerated doses of paclitaxel in the A549 xenograft model. In tumors, the combination therapy also resulted in a significant increase in mitotic arrest followed by apoptosis relative to paclitaxel monotherapy.     

32例新生儿肺透明膜病临床和X线分析

目的探讨分析新生儿肺透明膜病（HMD）临床和X线特征,提高对本病的认识和X线的早期诊断.方法对32例经临床和X线确诊为HMD进行回顾性分析.结果7例表现为两肺内、中带有细小颗粒状或网结状影;28例两肺野肺透亮度明显减低,呈毛玻璃样状改变,伴两肺内、中带有细小颗粒状或网结状影10例,以两下肺较明显;23例出现支气管充气征,多见于右下肺内带及左心影后,这是HMD典型的X线特征性表现;4例呈“白肺”改变;纵隔、心影及横膈轮廓模糊,但膈面位置正常.主要并发症为肺炎18例,肺出血7例,气胸2例,肺动脉高压3例.结论床边摄片是诊断HMD的主要方法;支气管充气征是HMD典型的X线特征性表现.     

石花炮制工艺优化研究

目的：根据石花的蒙医炮制目的,优化石花炮制工艺。方法：在老蒙医大夫的指导下,以药材的脆性为指标,通过水分含量的监控,优化传统炮制方法的最佳工艺条件,同时借鉴最佳传统炮制品,确立石花炮制烘干法。结果：石花微炒炮制方法的适宜条件为110℃﹑3min。在此条件下其水分含量均在4.14%～4.63%之间,重复性较好。水洗处理后石花炮制品的总灰分虽然没有明显改变,但酸不溶性灰分有明显下降,下降率可达到5%。烘法的最佳条件为60℃、3h。结论：建议蒙药石花炮制前水洗处理,微炒的适宜条件为110℃﹑3min;烘法的最佳条件为60℃和3h;炮制品水分应控制在4.1%～5.0%之间。第二种方法方便易行,工时短,有利于规模化生产。     

蒙成药孟根乌苏-18 味丸的急性毒性和长期毒性研究

目的：观察孟根乌苏-18味丸的急性毒性和长期毒性反应,为临床安全用药提供参考依据。方法：以最大允许浓度（0.4 g·mL-1）在6 h内灌胃给予小鼠孟根乌苏-18味丸混悬液两次（0.2 mL/10 g）,观察14天,考察其急性毒性反应;大鼠每天分别灌胃给予孟根乌苏-18味丸高、中、低剂量（3.67 g·kg-1、1.84 g·kg-1、0.92 g·kg-1）1次,连续给药180天,停药观察60天。结果：孟根乌苏-18味丸最大耐受量>16 g·kg-1（相当临床用量的436.36倍）。给药180天后,与对照组相比,孟根乌苏-18味丸高剂量组ALB、UREA、AST、TBIL、CHOL有显著性或非常显著性差异（P<0.05或P<0.01）,中剂量ALB、UREA有显著性差异（P<0.05）,低剂量组无显著性差异;高剂量组出现蛋白管型伴近曲小管上皮细胞不同程度变性坏死。停药60天后,与对照组比较,各组动物的一般状况、体质量、血液学指标、血清生化学指标、脏器系数等无显著性差异,高剂量组肾脏器质性病变出现了恢复趋势。结论：孟根乌苏-18味丸大鼠灌胃给药的基本安全剂量为0.92 g·kg-1（相当于临床拟用剂量的25倍）。     

肺癌干细胞Wnt信号通路的研究进展

Wnt信号通路在维持肺癌干细胞的增殖和克隆形成方面发挥着重要作用,可通过影响其关键蛋白质抑制肺癌干细胞增殖,为肺癌的治疗提供新的路径.本文旨在通过总结2005年-2010年肺癌干细胞及Wnt通路的研究现状,探讨Wnt通路与肺癌干细胞的关系.     

ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo

ABT-263 is a potent, orally bioavailable inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-x(L), and Bcl-w, which is currently in phase I clinical trials. Previous work has shown that this compound has low nanomolar cell-killing activity in a variety of lymphoma and leukemia cell lines, many of which overexpress Bcl-2 through a variety of mechanisms. Rapamycin is a macrolide antibiotic that inhibits the mammalian target of rapamycin complex, leading to cell cycle arrest and inhibition of protein translation. Rapamycin (and its analogues) has shown activity in a variety of tumor cell lines primarily through induction of cell cycle arrest. Activity has also been shown clinically in mantle cell lymphoma and advanced renal cell carcinoma. Here, we show that treatment of the follicular lymphoma lines DoHH-2 and SuDHL-4 with 100 nmol/L rapamycin induces substantial G(0)-G(1) arrest. Addition of as little as 39 nmol/L ABT-263 to the rapamycin regimen induced a 3-fold increase in sub-G(0) cells. Combination of these agents also led to a significant increase in Annexin V staining over ABT-263 alone. In xenograft models of these tumors, rapamycin induced a largely cytostatic response in the DoHH-2 and SuDHL-4 models. Coadministration with ABT-263 induced significant tumor regression, with DoHH-2 and SuDHL-4 tumors showing 100% overall response rates. Apoptosis in these tumors was significantly enhanced by combination therapy as measured by staining with an antibody specific for cleaved caspase-3. These data suggest that combination of ABT-263 and rapamycin or its analogues represents a promising therapeutic strategy for the treatment of lymphoma.     

血液净化对脓毒症多脏器功能衰竭患者血清中降钙素原、C反应蛋白及免疫功能的影响

目的探讨血液净化对脓毒症多脏器功能衰竭患者血清中降钙素原、C反应蛋白及免疫功能的影响。方法选取2016年7月～2018年11月在我院进行治疗的脓毒症多脏器功能衰竭患者76例为研究对象,随机分为研究组和对照组,研究组采取血液净化进行治疗,对照组采取常规方式进行治疗。比较两组患者的PCT(血清中降钙素原)、CRP(C反应蛋白)、免疫功能各项指标和存活率。结果研究组患者体内PCT和CRP指标低于对照组(P0.05);对照组的CD8~+、CD4~+/CD8~+和CD4~+指标水平低于研究组(P0.05);研究组的存活率高于对照组(P0.05)。结论在对脓毒症多脏器功能衰竭患者应用血液净化治疗中,取得较为理想的治疗效果,能够净化患者血浆中存在的炎症因子,使血流动力学恢复平稳,改善患者体内血清中降钙素原、C反应蛋白指标水平,提高患者的免疫功能,有利于患者疾病的康复,值得在各大医院临床上进行推广。