肿瘤抗血管生成疗法及相关药物的研究进展

目的 介绍肿瘤抗血管生成疗法的作用机制及近年抗血管生成药物研究进展。方法根据国内外的文献资料,进行整理归纳。结果 肿瘤血管生成主要与生长因子、溶解酶及炎症细胞特异性分子表达增加有关。研究证明许多天然或人工合成化学分子通过作用于上述血管增生反应中的特异性分子发挥抗肿瘤效应。结论 抗血管生成药物有望成为新一代抗肿瘤药。     

甲磺酸阿帕替尼在实体恶性肿瘤中的研究进展

在正常的生理条件下,新生血管的形成可以为周围组织提供能量及氧气,从而保证血流灌注。但在肿瘤患者中,血管新生出现失控,并加剧疾病进展及预后恶化。血管内皮生长因子(vascular endothelial growth factor,VEGF)及其受体(VEGFR)为诱导新生血管生成的重要调控途径。甲磺酸阿帕替尼作为国产自主研制出的抗血管生成药物,其本质为小分子的络氨酸激酶(tyrosine kinase,TK)抑制剂,其通过特异性地抑制VEGFR-2通路发挥抗血管生成作用,进而达到抗肿瘤的作用。目前国内相关指南已把其列入,特别是对于初始化疗治疗失败的晚期胃癌,其他如肺癌、乳腺癌、原发性肝细胞癌(hepatocellular carcinoma,HCC)等相关临床研究正在积极开展。     

Angiogenesis-dependent diseases and angiogenesis therapy

The discovery of the molecular mechanisms of physiological vasculogenesis and pathological angiogenesis helped to recognize two classes of diseases: one where the therapeutic angiogenesis can repair the tissue damages (arteriosclerosis, myocardial infarction, limb ischemia) and the other one where inhibition of pathological angiogenesis can cure the disease or delay its progression (retinopathies, benign and malignant angiogenic tumors, progression of malignant tumors). Although there are an exponentially growing number of new synthetic molecules characterized mainly by antiangiogenic properties, the discovery of a large battery of natural pro- and anti-angiogenic factors suggests that this may provide a more physiological approach to treat both class of angiogenesis-dependent diseases in the near future.     

醋酸甲羟孕酮对卵巢癌裸鼠移植瘤的抗血管生成作用

目的 观察醋酸甲羟孕酮(MPA)对人卵巢癌裸鼠移植瘤内血管生成及肿瘤细胞的抑制作用。方法 建立30只裸鼠人卵巢癌移植模型,并随机均分成对照组和2个MPA治疗组。2个治疗组分别每次皮下注射MPA60和120 mg/kg·b.w,2次/周,共4周。对照组注射相同体积生理盐水。测定三组抑瘤率,用Ⅷ因子多克隆抗原抗体测定肿瘤内微血管密度(MVD)并进行形态学观察。结果MPA(60 mg/kg·b.w.)组的抑瘤率为23.76％,MPA(120 mg/kg·b.w.)组抑瘤率为43.80％(P<0.05)。MPA高、低剂量组的MVD则分别为2.11±0.12、3.64±0.02,与对照组(5.14±0.74)比较,差异有显著性(P<0.01、P<0.05)。而2个MPA组间差异也极显著(P<0.01)。MPA组形态学观察可见大量的凋亡细胞和凋亡小体及变性坏死,而对照组少见。结论MPA对人卵巢癌COCI细胞裸鼠移植瘤内的肿瘤细胞及新生微血管具有明显抑制作用,并呈现剂量一效应关系;其对肿瘤细胞的作用机制,可能是抑制并破坏肿瘤区新生血管的生长,阻断血供所产生的结果,而并非直接对肿瘤细胞的作用。     

Single-Cell Transcriptomics of Endothelial Cells in Upper and Lower Human Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC) is a type of progressive and distant metastatic tumor. Targeting anti-angiogenic genes could effectively hinder ESCC development and metastasis, whereas ESCC locating on the upper or the lower esophagus showed different response to the same clinical treatment, suggesting ESCC location should be taken into account when exploring new therapeutic targets. In the current study, to find novel anti-angiogenic therapeutic targets, we identified endothelial cell subsets in upper and lower human ESCC using single-cell RNA sequencing (scRNA-seq), screened differentially expressed genes (DEGs), and performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The results showed that common DEGs shared in the upper and the lower endothelial cells mainly are involved in vessel development, angiogenesis, and cell motility of endothelial cells by regulating PI3K-AKT, Rap1, Ras, TGF-beta, and Apelin signaling pathways. The critical regulatory genes were identified as ITGB1, Col4A1, Col4A2, ITGA6, LAMA4, LAMB1, LAMC1, VWF, ITGA5, THBS1, PDGFB, PGF, RHOC, and CTNNB1. Cell metabolism-relevant genes, e.g., MGST3, PNP, UPP1, and HYAL2 might be the prospective therapeutic targets. Furthermore, we found that DEGs only in the upper endothelial cells, such as MAPK3, STAT3, RHOA, MAPK11, HIF1A, FGFR1, GNG5, GNB1, and ARHGEF12, mainly regulated cell adhesion, structure morphogenesis, and motility through Phospholipase D, Apelin, and VEGF signaling pathways. Moreover, DEGs only in the lower endothelial cells, for instance PLCG2, EFNA1, CALM1, and RALA, mainly regulated cell apoptosis and survival by targeting calcium ion transport through Rap1, Ras, cAMP, Phospholipase D, and Phosphatidylinositol signaling pathways. In addition, the upper endothelial cells showed significant functional diversity such as cytokine-responsive, migratory, and proliferative capacity, presenting a better angiogenic capacity and making it more sensitive to anti-angiogenic therapy compared with the lower endothelial cells. Our study has identified the potential targeted genes for anti-angiogenic therapy for both upper and lower ESCC, and further indicated that anti-angiogenic therapy might be more effective for upper ESCC, which still need to be further examined in the future.     

非小细胞肺癌抗血管生成治疗研究进展

非小细胞肺癌（non-small cell lung cancer,NSCLC）的增殖、浸润、转移都需要新生血管的支持,抗血管生成治疗已成为一种重要治疗手段。血管内皮生长因子（vascular endothelial growth factor,VEGF）作为关键的促血管生成因子,是目前NSCLC抗血管生成治疗药物的主要靶点。这些药物主要包括以VEGF或其受体VEGFR为靶点的单克隆抗体,及阻断VEGFR下游信号通路传导的小分子酪氨酸激酶抑制剂（VEGFR-TKI）两类。目前有两种抗血管生成单克隆抗体,贝伐单抗及雷莫卢单抗,被批准联合化疗一线或二线治疗原位进展或转移的NSCLC。多种VEGFR-TKI治疗NSCLC的临床试验均以失败告终,目前仅有安罗替尼在我国被批准用于NSCLC的三线治疗,而尼达尼布联合化疗在二线治疗中也显示了良好的生存获益。本篇综述我们将回顾总结抗血管生成药物单药或与其他抗肿瘤药物联用成功应用于NSCLC治疗的临床研究数据。     

Tumstatin对兔耳增生性瘢痕的抑制作用

目的 探讨肿瘤抑素(Tumstatin)对兔耳瘢痕组织生长情况的影响.方法 建立兔耳增生性瘢痕模型,用Tumstatin对兔耳腹侧建立的增生性瘢痕模型通过在体局部注射进行干预,随机设立Tumstatin治疗组、Tumstatin预防治疗组、曲安奈德对照组、生理盐水对照组;停止药物注射21天后各组同时于每只兔的双侧对称部位取材瘢痕组织,每一取材瘢痕组织均分成同样大小的四等份,分别进行组织形态学观察、CD34免疫组化方法测定血管密度的变化、观察血管内皮细胞与成纤维细胞凋亡的变化情况.结果 Tumstatin预防治疗组和Tumstatin治疗组中,新生毛细血管密度、内皮细胞活性以及成纤维细胞数量都较曲安奈德和生理盐水对照组明显降低,差异有统计学意义(P<0.05).结论 Tumstatin能够较曲安奈德更明显地抑制增生性瘢痕的生长,为Tumstatin用于防治增生性瘢痕的可行性提供了初步的理论依据.     

Multi-targeted tyrosine kinase inhibitor sunitinib: a novel strategy for sporadic malignant pheochromocytoma

Sporadic malignant pheochromocytoma, a rare disease with poor prognosis, is always difficult to treat due in part to lack of effective agents. We presented three patients with advanced malignant pheochromocytoma treated by sunitinib, which indicates that sunitinib is an effective agent for this malignancy.

     

92nd Annual Meeting of the American Association for Cancer Research

The 92nd Annual Meeting of the AACR comprised over 5000 abstracts, 12 plenary and award lectures and numerous talks in educational sessions, symposia and mini-symposia. Given the wealth of information presented, we narrowed our coverage to the area of prenyltransferase and protein kinase inhibitors. Many rationally designed drugs are now in clinical trials and exciting results were presented for the Bcr-Abl inhibitor STI-571. The cancer community is beginning to envision new ways to evaluate and administer these well-tolerated drugs which do not fit the traditional anticancer drug profile. There is an emphasis in developing surrogate markers for evaluating the mechanism-based effectiveness as well as identifying off-target toxicities. In addition, there is a large effort in investigating effective drug combinations and the use of these new agents as radiosensitisers. Here we present specific examples of these issues as applied to prenylation and protein kinase inhibitors.