阿帕替尼治疗肺巨细胞癌1例并文献复习

目的:探讨肺巨细胞癌的临床特征、诊断和治疗方法。方法:报道1例肺巨细胞癌患者的临床资料并对相关文献进行复习。对肺巨细胞癌的临床特征、影像学表现、病理学特征和治疗方法进行分析。结果:1例肺巨细胞癌患者因刺激性呛咳、左侧胸部闷痛3个月入院。胸部CT检查及病理穿刺活检明确诊断为肺巨细胞癌。采取多西他赛联合顺铂3周方案化疗,化疗2个周期后临床症状轻微好转且疗效评价稳定（SD）,化疗4个周期后疗效评价进展（PD）,口服阿帕替尼抗肿瘤血管生成治疗后疗效评价亦是PD。结论:肺巨细胞癌临床罕见,生存期短,预后差,目前无标准的治疗方法,化疗可能短暂延缓肿瘤进展,阿帕替尼抗肿瘤血管生成治疗效果可能欠佳。     

抗血管生成药物治疗恶性脑水肿的研究进展

抗血管生成药物通过减少血管通透性和血脑屏障破坏,能有效减轻恶性脑水肿,缓解临床症状,改善患者生命质量。目前多种抗血管生成药物在治疗恶性脑水肿方面取得了积极的疗效,因此被认为是较糖皮质激素治疗恶性脑水肿更为安全、有效的治疗手段。     

奥希替尼联合贝伐珠单抗治疗伴EGFR T790M突变肺腺癌的疗效与机制研究

  目的  通过移植瘤动物实验探讨奥希替尼联合抗VEGF单克隆抗体靶向药物贝伐珠单抗的疗效及作用机制,为进一步临床试验提供理论依据。  方法  构建EGFR T790M突变的H1975人肺腺癌细胞移植瘤动物模型。实验分组:低剂量奥希替尼组、高剂量奥希替尼组、低剂量奥希替尼联合贝伐珠单抗组、高剂量奥希替尼联合贝伐珠单抗组。每组各5只小鼠,给药  方法  奥希替尼2.5 mg/kg/d或5 mg/kg/d,采用每天灌胃处理;贝伐珠单抗5 mg/kg,每周2次腹腔注射。接种后和给药期间绘制肿瘤生长曲线,给药2周后处死裸鼠,活检整个肿瘤。免疫组织化学SP法检测肿瘤HIF-1α、VEGF和微血管密度（microvessel density,MVD）。应用Western blot法检测EGFR及其下游AKT和ERK信号通路蛋白的表达。  结果  给药2周后,高剂量奥希替尼单药组较低剂量奥希替尼单药组肿瘤体积明显缩小,HIF-1α、VEGF表达率和MVD显著降低（P < 0.05）,p-EGFR、p-AKT和p-ERK表达减少（P < 0.05）。低剂量奥希替尼联合贝伐珠单抗组肿瘤体积明显小于低剂量奥希替尼单药组（P < 0.05）,上述因子均明显降低（P < 0.05）。低剂量奥希替尼联合组与高剂量奥希替尼单药组比较,肿瘤体积差异无统计学意义（P=0.178）,p-EGFR、p-AKT、p-ERK表达差异无统计学意义（P＞0.05）。高剂量奥希替尼联合组与高剂量奥希替尼单药组体积差异无统计学意义（P=0.642）。两个联合组之间,体积差异均无统计学意义（P=0.072）,上述因子表达差异均无统计学意义（P＞0.05）。  结论  贝伐珠单抗能够显著增加奥希替尼对伴EGFR T790M突变的肺腺癌移植瘤的杀伤能力。贝伐珠单抗与奥希替尼协同作用是通过降低肿瘤中VEGF表达,改善肿瘤微环境,增强抑制EGFR下游信号通路激活而实现的。      

多基因联合作用对kallistatin活性增强的研究

 目的 加强kallistatin(Kal)这一多功能内源性抗血管生成因子抗肿瘤活性。方法 将其他多个基因与Kal联合应用,利用脂质体将带有目的基因的质粒转染入内皮细胞和肿瘤细胞,分析多基因联合治疗对细胞特性的影响。结果 Kal对肺癌细胞A549、NCI-H446、SPC-A1都具抑制作用。Kal与Trail或vasostatin(Vas)联合,可加强对SPC-A1细胞的抑制作用,但三者联合该抑制作用并未进一步加强。Kal与angiostatin(Ang)、Vas 联合应用可显著增强对血管内皮细胞EVC304生长、迁移以及小管形成的抑制作用。结论 Kal基因可与多种类型的基因联合作用,增强对肿瘤细胞和血管内皮细胞的抑制作用,为肿瘤的多基因联合治疗提供了实验基础。     

The antitumor effect of a novel angiogenesis inhibitor (an octahydronaphthalene derivative) targeting both VEGF receptor and NF-κB pathway

Development of a novel type of angiogenesis inhibitor will be essential for further improvement of therapeutics against cancer patients. We examined whether an octahydronaphthalene derivative, AMF-26, which was screened as an inhibitor of intercellular adhesion molecule-1 (ICAM-1) production stimulated by inflammatory stimuli in vascular endothelial cells, could block angiogenesis in response to vascular endothelial growth factor (VEGF) and/or inflammatory cytokines. Low dose AMF-26 effectively inhibited the tumor necrosis factor-α (TNF-α)- or the interleukin-1β (IL-1β)-induced production of ICAM-1 in human umbilical vascular endothelial cells (HUVECs). We found that the TNF-α-induced phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear translocation of p65 were impaired by AMF-26 in both endothelial cells and cancer cells. AMF-26 was found to inhibit the phosphorylation of VEGF receptor 1 (VEGFR1), VEGFR2 and the downstream signaling molecules Akt, extracellular signal-regulated kinase (ERK)1/2 stimulated by VEGF in HUVECs. Therefore, the VEGF-induced proliferation, migration and tube formation of vascular endothelial cells was highly susceptible to inhibition by AMF-26. Oral administration of AMF-26 significantly blocked VEGF- or IL-1β-induced angiogenesis in the mouse cornea, and also tumor angiogenesis and growth. Together, our results indicate that AMF-26 inhibits angiogenesis through suppression of both VEGFR1/2 and nuclear factor-κB (NF-κB) signaling pathways when stimulated by VEGF or inflammatory cytokines. AMF-26 could be a promising novel candidate drug for cancer treatments.     

The safety and efficacy of bevacizumab in the treatment of patients with recurrent or metastatic cervical cancer

Introduction: Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF). (Avastin; Genetech, Inc, San Francisco, CA) Angiogenesis is blocked by the binding of bevacizumab to VEGF, inhibiting the binding of this ligand to the VEGF receptor. On 14 August 2014 the Food and Drug Administration (FDA) approved use of bevacizumab in persistent, recurrent, or metastatic cervical cancer.

Areas covered: Herein we review pharmacodynamics and kinetics, clinical data and treatment-related toxicities of bevacizumab in the treatment of metastatic, recurrent or persistent cervical cancer. Additionally, future areas of development are reviewed.

Expert commentary: Anti-angiogenesis therapy with bevacizumab is central to metastatic, persistent, and recurrent cervical cancer treatment. Additional anti-angiogenesis drugs are in development. Future studies will need to establish if the addition of multiple anti-angiogenesis agents or anti-angiogenesis in combination with immunotherapy is more effective than bevacizumab with chemotherapy.     

疱疹性角膜基质炎的研究进展

疱疹性角膜基质炎（ｈｅｒｐｅｓｓｔｒｏｍａｌｋｅｒａｔｉｔｉｓ,ＨＳＫ）是我国重要的致盲性眼病之一。研究表明,ＨＳＫ是角膜感染单纯疱疹病毒后,自然杀伤细胞、巨噬细胞、中性粒细胞、Ｔ淋巴细胞、树突状细胞、淋巴管、血管以及众多细胞因子共同参与的免疫炎症反应。除接种病毒疫苗、抗病毒、免疫抑制外,目前还出现了免疫调节、抗淋巴管和抗血管等治疗方法。本文将对ＨＳＫ病原学、流行病学、发病机制以及治疗措施等方面的研究进展进行综述。     

灯台叶醇提物体外抗肿瘤作用研究

目的研究灯台叶醇提物对体外肿瘤细胞增殖和凋亡的影响,以及对鸡胚尿囊膜血管生成的抑制作用。方法采用MTT法检测灯台叶醇提物对体外培养肿瘤细胞(人卵巢癌细胞C200、人乳腺癌细胞MNK-7、人肝癌细胞SNU-398)的抗肿瘤作用;以PI/Annexin-V染色检测灯台叶醇提物对人乳腺癌细胞MNK-7凋亡的影响;以鸡胚尿囊膜血管生成(CAM)实验,研究灯台叶醇提物对新生血管生成的抑制作用。结果灯台叶醇提物在0.1～2.0 mg/mL对各肿瘤细胞的增殖有显著抑制作用,2.0 mg/mL灯台叶醇提物对人乳腺癌细胞增殖抑制率达到83.6%;2.0 mg/mL灯台叶醇提物作用后人乳腺癌细胞凋亡率达到62.5%;灯台叶醇提物在1～1000μg/mL对鸡胚尿囊膜血管生成有显著抑制作用,给药鸡胚的新生血管数减少,其中10μg/mL抑制率最高,一级血管抑制率为52.1%,二级血管抑制率为48.3%。结论在实验给药浓度下,灯台叶醇提物对受试肿瘤细胞的增殖具有较强抑制作用,对鸡胚尿囊膜血管生成有显著抑制作用。     

中药独活及其单体蛇床子素体外抗血管生成的实验研究

目的：探讨独活醇提物及其单体蛇床子素对体外血管生成的抑制作用及其可能的机制.方法：采用MTT法观察中药独活醇提物及蛇床子素对人脐静脉血管内皮细胞（human umbilical vein endothelial cell.HUVEC）和人肠癌LoVo细胞增殖的影响,Transwell小室趋化实验、体外小管形成实验以及流式细胞术,观察并比较独活醇提物及蛇床子素对HUVEC迁移、小管形成、凋亡及周期的影响.结果：3.75-30μg/ml的独活醇提物及蛇床子素作用48h时对HUVEC的细胞增殖抑制率分别在5.16％-10.15％和22.64％-65.56％之间,对LoVo细胞增殖抑制率分别在2.86％-7.29％和5.15％-24.39％之间.体外小管及小管迁移实验显示,3.75-30μg/ml的蛇床子素作用24h时HUVEC小管形成数目减少,且管腔不完整.3.75-30μg/ml的独活醇提物和蛇床子素处理12h对HUVEC迁移抑制率分别在-2.16％至8.00％和13.70％至63.04％之间.3.75-30μg/ml的独活醇提物和蛇床子素诱导HUVEC细胞凋亡率分别在6.1％-14.4％和18.8％-89.5％之间.独活醇提物和蛇床子素作用HUVEC 24h后,使内皮细胞周期主要阻滞在G0-G1期,蛇床子素对细胞周期影响强于独活醇提物.结论：蛇床子素在体外抑制血管生成作用强于独活醇提物,说明蛇床子素可能是独活醇提物中发挥抗血管生成作用的主要成分,其作用机制可能与抑制HUVEC增殖、迁移和小管形成,诱导HUVEC凋亡,阻滞HUVEC细胞周期有关.     

Angiogenesis,vasculogenic mimicry and vascular invasion in cutaneous malignant melanoma – implications for therapeutic strategies and targeted therapies

Angiogenesis, defined as new vessel growth from a pre-existing vessel, has been shown to be crucial for tumor survival and growth in several lineage-unrelated malignancies including melanoma. The concept of vasculogenic mimicry, a highly patterned microcirculation independent of angiogenesis, has also been described in melanoma. The prognostic value of vascular invasion, characterized by the presence of tumor cells within vascular channels, in melanoma remains controversial as in the current American Joint Committee on Cancer-staging system for melanoma vascular invasion is not included for microscopic staging purposes. This review summarizes contemporary understanding of these three processes i.e. angiogenesis, vasculogenic mimicry, and vascular invasion in an effort to uncover putative targets as therapeutic strategies in melanoma.