抗血管生成和肿瘤血管正常化的研究进展

实体瘤所致的残废超过肿瘤总残废的85%.实体瘤的生长和转移有赖于肿瘤血管.抗血管生成治疗(antiangiogenesis)对战胜瘤症有着很大的潜力.     

血管抑素与肿瘤的抗血管生成治疗

血管抑制是一种新发现的特异的血管内皮细胞增殖抑制剂，对肿瘤血管形成具有强烈的抑制作用，是非常有效的抗肿瘤血管形成抑制因子，可能在血管生成调控中起重要的作用。     

肿瘤抗血管生成治疗研究进展

肿瘤的生长和转移有赖于血管生成。抗血管生成治疗以血管内皮细胞为靶向,通过对抗肿瘤血管生成,切断肿瘤的供养,从而遏制肿瘤的生长和转移,其方法主要包括抑制或中和血管生成因子、应用血管生成抑制剂和针对特异性标记物应用素或抗体攻击肿瘤血管内皮细胞,它具有高效性、特异性、不易产生耐药和毒副作用小等优点。迄今,包括Ｅｎｄｏｓｔａｔｉｎ和Ａｎｇｉｏｓｔａｔｉｎ在内的多种抗血管生成药物在抗肿瘤实验研究中取得良好效果,并已开始走向临床。     

肿瘤血管生成与乳腺癌研究进展

肿瘤新生血管生成在肿瘤的生长和转移过程中起着重要作用，抗血管生成治疗可能成为肿瘤治疗的新方法。本文综述了乳腺癌的血管生成机制及乳腺癌抗血管生成治疗的研究进展。     

靶向血管生成拟态治疗肿瘤的研究进展

肿瘤微血管包括由血管内皮细胞围成的经典血管结构和由肿瘤细胞围成的血管生成拟态(Vasculogenic mimicry,VM)两种模式。近年研究提示,抗血管生成药能够显著抑制经典的微血管结构,但是不能抑制VM形成,反而促进VM形成。这是影响其临床疗效的原因之一。然而近期研究发现,中成药、基因治疗以及其它靶向VM形成机制的药在抗VM形成中具有独特的优势。本文就目前靶向VM形成治疗肿瘤的研究现状展开综述,为开发既能抗血管生成又能抗VM形成的新一代抗血管生成药提供借鉴。     

抗血管生成与肿瘤生物治疗

由于实体瘤的生长和转移有赖于新生血管的形成，抗血管生成的肿瘤治疗策略从理论上讲具有抗瘤谱广、不易产生耐药及药物易于到达靶部位等特点，因此，以抗血管生成为主的肿瘤生物治疗研究成为近十年的研究热点。     

肿瘤血管生成及抗血管生成基因治疗

肿瘤的侵袭和转移明显影响患者的预后,而肿瘤的血管生成是肿瘤生长、侵袭、转移的基本条件。因而抑制肿瘤血管生成是治疗肿瘤的关键。本文就肿瘤血管生成的调控及抗肿瘤血管生成基因治疗的研究进展作一综述。     

血管生长因子与肿瘤血管生成

血管生成对恶性肿瘤的发生、发展和预后至关重要。就血管内皮生长因子、血小板源性内皮细胞生长因子、碱性成纤维细胞生长因子等血管生成调节因子的研究进展进行综述,介绍了抗血管生存治疗肿瘤的现状和发展动向。     

Future options ofanti-angiogenic cancer therapy

In human patients, drugs that block tumor vessel growth are widely used to treat a variety of cancer types. Many rigorous phase 3 clinical trials have demonstrated signiifcant survival beneifts; however, the addition of an anti-angio-genic component to conventional therapeutic modalities has generally produced modest survival beneifts for cancer patients. Currently, it is unclear why these clinically available drugs targeting the same angiogenic pathways produce dissimilar effects in preclinical models and human patients. In this article, we discuss possible mechanisms of various anti-angiogenic drugs and the future development of optimized treatment regimens.     

晚期非小细胞肺癌血管正常化时化疗的临床观察

目的 探讨重组人血管内皮抑制素（恩度）诱导肿瘤血管正常化时联合化疗治疗晚期非小细胞肺癌（NSCLC）的疗效及安全性。方法 收集经病理组织学或细胞学确诊的Ⅲ、Ⅳ期NSCLC患者43例,随机分为恩度“窗口期”联合化疗组（A）和恩度同步化疗组（B）。A组21例,具体为：恩度15mg静滴,d1～d14;多西紫杉醇75mg／m2 静滴,d5;B组22例,恩度用法同A组,多西紫杉醇75mg／m2静滴,d1。两组均21天为1周期。按照 RECIST 1.1和NCI CTC 3.0标准分别评价近期疗效和毒副反应。用Kaplan-Meier法进行生存分析。结果A、B两组患者的有效率分别为14.2％和9.1％（P=0.63）,疾病控制率分别为57.1％和54.6％（P=0.76）,中位无进展生存期分别为3.7个月和3.5个月（P=0.19）,中位总生存期分别为10.2个月和10.5个月（P=0.77）。两组的主要不良反应表现为脱发、血液学毒性和乏力,差异无统计学意义。结论 恩度“窗口期”联合化疗与恩度同步化疗治疗NSCLC在有效率、生存期和不良反应方面未见明显差异。     

贝伐珠单抗诱导肿瘤血管正常化的时间窗及与紫杉醇联合治疗肺癌荷瘤鼠的实验研究

目的 探讨贝伐珠单抗诱导肿瘤血管正常化的时间窗及贝伐珠单抗联合紫杉醇对小鼠肺腺癌移植瘤的抑瘤效果。方法 选取成功构建的人肺腺癌A549裸鼠皮下移植瘤模型54只,实验分为两部分：第一部分荷瘤小鼠24只随机分为两组：对照组和贝伐珠单抗组各12只,分别腹腔注射生理盐水和贝伐珠单抗5 mg／kg,于给药后选取第1、3、5、8天共4个时间点,每个时间点各3只,测量瘤体体积及裸鼠体质量,采用Western blotting和免疫荧光法分别检测瘤体内血管内皮生长因子（VEGF）水平和微血管密度（MVD）。第二部分小鼠30只随机分为四组：对照组、紫杉醇单药组和贝伐珠单抗单药组各5只及联合组15只。联合组于贝伐珠单抗给药当天及给药后第3、5天各选取5只腹腔注射紫杉醇,紫杉醇和贝伐珠单抗的剂量分别为3 mg／kg和5 mg／kg,于给药后选取第3、7、10、14、17、20天共6个时间点测量瘤体体积,21天后处死裸鼠称取瘤体质量,采用Western blotting和免疫组化法分别检测瘤体VEGF水平和MVD。结果 在第一部分实验中,与对照组相比,贝伐珠单抗组给药后肿瘤的生长得到抑制,以第三天抑制效应最显著,此时瘤体的体积最小,瘤体内VEGF含量表达减少,瘤体MVD也相应减少。在第二部分实验中,与对照组相比,贝伐珠单抗不同时间点联合紫杉醇给药均可显著抑制肿瘤生长,以贝伐珠单抗联合紫杉醇第三天给药组抑制效应更为显著,且瘤体的体积、质量、VEGF含量及MVD均较其他联合给药组少。结论 贝伐珠单抗诱导的血管正常化时间窗可能在给药后第1～3天,在该时间窗内联合紫杉醇可达到最大的抗肿瘤效应。     

Blood glucose level normalization and accurate timing improves the accuracy of PET-based treatment response predictions in rectal cancer

Purpose

To quantify the influence of fluctuating blood glucose level (BGLs) and the timing of PET acquisition on PET-based predictions of the pathological treatment response in rectal cancer.

Material and methods

Thirty patients, diagnosed with locally advanced-rectal-cancer (LARC), were included in this prospective study. Sequential FDG-PET-CT investigations were performed at four time points during and after pre-operative radiochemotherapy (RCT). All PET-data were normalized for the BGL measured shortly before FDG injection. The metabolic treatment response of the tumor was correlated with the pathological treatment response.

Results

During RCT, strong intra-patient BGL-fluctuations were observed, ranging from −38.7 to 95.6%. BGL-normalization of the SUVs revealed differences ranging from −54.7 to 34.7% (p < 0.001). Also, a SUV_max time-dependency of 1.30 ± 0.66 every 10 min (range: 0.39-2.58) was found during the first 60 min of acquisition. When correlating the percent reduction of SUV_max after 2 weeks of RCT with the pathological treatment response, a significant increase (p = 0.027) in the area under the curve of ROC-curve analysis was found when normalizing the PET-data for the measured BGLs, indicating an increase of the predictive strength.

Conclusions

This study strongly underlines the necessity of BGL-normalization of PET-data and a precise time-management between FDG injection and the start of PET acquisition when using sequential FDG-PET-CT imaging for the prediction of pathological treatment response.     

Tumor progression-dependent angiogenesis in gastric cancer and its potential application

Despite improvements in the early diagnosis, prognosis and therapeutic strategies for gastric cancer (GC), human GC remains one of the most frequently diagnosed malignant tumors in the world, and the survival rate of GC patients remains very poor. Thus, a suitable therapeutic strategy for GC is important for prolonging survival. Both tumor cells themselves and the tumor microenvironment play an important role in tumorigenesis, including angiogenesis, inflammation, immunosuppression and metastasis. Importantly, these cells contribute to gastric carcinogenesis by altering the angiogenic phenotype switch. The development, relapse and spreading of tumors depend on new vessels that provide the nutrition, growth factors and oxygen required for continuous tumor growth. Therefore, a state of tumor dormancy could be induced by blocking tumor-associated angiogenesis. Recently, several antiangiogenic agents have been identified, and their potential for the clinical management of GC has been tested. Here, we provide an up-to-date summary of angiogenesis and the angiogenic factors associated with tumor progression in GC. We also review antiangiogenic agents with a focus on the anti-vascular endothelial growth factor receptor (VEGFR)-mediated pathway for endothelial cell growth and their angiogenesis ability in GC. However, most antiangiogenic agents have reported no benefit to overall survival (OS) compared to chemotherapy alone in local or advanced GC. In phase III clinical trials, only ramucirumab (anti-VEGFR blocker) and apatinib (VEGFR-TKI blocker) have reported an improved median overall response rate and prolonged OS and progression-free survival outcomes as a 2nd-line agent combined with chemotherapy treatment in advanced GC. By providing insights into the molecular mechanisms of angiogenesis associated with tumor progression in GC, this review will hopefully aid the optimization of antiangiogenesis strategies for GC therapy in combination with chemotherapy and adjuvant treatment.     

食管癌血管生成的研究进展

食管癌的高侵袭性与血管生成密切相关,并伴随微血管密度、血管内皮生长因子、血管生成相关因子及其受体表达水平的改变.研究发现,血清中高水平的血管生成相关因子与食管癌患者疗效不佳及预后不良密切相关,提示其可作为食管癌治疗的新靶点,值得进一步深入探索.     

DNA hypermethylation as a predictor of extramural vascular invasion (EMVI) in rectal cancer

Purpose: DNA hypermethylation in gene promoter regions (CpG islands) is emerging as an important pathway in colorectal cancer tumourigenesis. Whilst genetic mutations have been associated with extramural vascular invasion (EMVI) in rectal cancer, no such association has yet been made with epigenetic factors.

Methods: 100 consecutive neoadjuvant-naïve patients undergoing curative surgery for rectal were classified according to the presence or absence of EMVI on histopathological examination. DNA was extracted from tumours and subjected to bisulfite conversion and methylation-specific PCR to determine CIMP status (high, intermediate, or low; according to a validated panel of 8 genes). CIMP status was correlated with EMVI status, histopathological, clinical, and demographic variables, in addition to overall (OS) and disease free (DFS) survival.

Results: 51 patients were characterised as CIMP-low, 48 CIMP-intermediate, and one patient CIMP-high. EMVI-positivity was associated with CIMP-intermediate epigenotype (p < 0.001). Patients with EMVI-positive tumours were found to have significantly more advanced disease by pT, pN, and pAJCC categorisation (p = 0.002, p < 0.001, and = p < 0.001, respectively). EMVI-positivity was significantly associated with the requirement for adjuvant chemotherapy (p < 0.001), and worse DFS but not OS (p = 0.012 and p = 0.052).

Conclusions: Given the association between CIMP-intermediate epigenotype and EMVI-positivity, and the subsequent disadvantage in pathological stage, requirement for adjuvant therapy and worse survival, tumour epigenotyping could potentially play an important role in personalising patients’ cancer care. Further work is required to understand the mechanisms that underlie the observed effect, with the hope that they may provide novel opportunities for intervention and inform treatment decisions in rectal cancer.     

自发及诱导性过氧化氢生成增强胃肠道肿瘤细胞与血管内皮粘附作用的研究

目的探讨胃肠道肿瘤细胞内活性氧生成在肿瘤进展中的作用.方法选择三种胃癌细胞系SGC-7901、MKN-45、MKN-28及三种结肠癌细胞系LS174T、LoVo、HCT-8,以过氧化物酶-荧光法检测癌细胞自发的过氧化氢生成量,以及癌细胞在佛波酯刺激后,诱导的过氧化氢生成,同时观察癌细胞与血管内皮粘附作用的变化特点.结果胃、结肠癌细胞不同程度地自发生成过氧化氢,平均浓度为0.9 nmol@L-1@10-6细胞,在佛波酯的作用下,这种生成被诱导性增加,平均浓度为2.1nmol@L-1@10-6细胞.常规培养的肿瘤细胞与内皮细胞均有粘附作用,当以过氧化氢酶作用后,SGC-7901、MKN-45的粘附力有明显的下降(P＜0.05);癌细胞在佛波酯作用后,SGC-7901、MKN-45、LS174T及LoVo在过氧化氢生成增加的同时,与内皮细胞的粘附力均比作用前为高,并可被过氧化氢酶所抑制.结论胃、结肠癌细胞组成性及诱导性过氧化氢生成可能有利于癌细胞转移的实现.     

Cardiovascular effects of systemic cancer treatment

Many methods of systemic anticancer treatment have detrimental effects on the cardiovascular system, thus limiting the possibility of further therapy, worsening patients’ quality of life and increasing mortality. The best recognized and most clinically relevant is the cardiotoxicity of anthracyclines. Other cytotoxic drugs associated with significant risk of cardiovascular complications include alkylating agents, 5-fluorouracil and paclitaxel. Cardiovascular adverse effects are also associated with the use of targeted therapies, such as trastuzumab, bevacizumab and tyrosine kinase inhibitors, and some of the drugs used in the treatment of hematological malignancies, such as all-trans-retinoic acid and arsenic trioxide.The most serious cardiac complication of anticancer therapy is congestive heart failure, associated predominantly with the use of anthracyclines, trastuzumab and high-dose cyclophosphamide. Myocardial ischemia is mainly caused by antimetabolite and interferon alpha treatment. Other adverse effects may include hypotension, hypertension, arrhythmias and conduction disorders, edema, pericarditis and thrombo-embolic complications.The aim of this review is to summarize and critically analyze the available evidence on the cardiovascular toxicity of systemic anticancer therapies, with particular attention to the recently recognized adverse effects of targeted therapies.     

心脏大血管成形术在肺癌外科中的应用

目的 探讨心脏大血管成形术在肺癌外科中的应用价值。方法 回顾性总结山东省立医院胸外科自1988－2001年在肺癌手术中涉及心脏大血管成形术的131例病例资料。结果 131例中上腔静脉置换或部分切除17例,左无名静脉与右心耳搭桥术1例,肺动脉成形术或楔形切除术86例,左心房部分切除术27例。全组无死亡,部分病例随访结果令人满意。结论 应用心脏大血管成形术可以提高肺癌手术切除率及手术的安全性,可以最大限度地保留患者的肺功能,并有助于提高患者的术后生存率及生活质量。