以抗血管生成为基础的节律化疗研究进展

除增殖的肿瘤细胞和其它多种正常细胞外,传统细胞毒性化疗药物也影响肿瘤血管内皮细胞的生长。当给予节律化疗,即频繁或持续给予低剂量化疗药物且不伴较长间歇期时,化疗的抗血管生成作用最强,尤其是与特异性抗血管生成药物合用时。现就其抗血管生成作用及其机制、联合用药及临床试验现状作一综述。     

抗血管生成化疗的研究进展

肿瘤血管生成是肿瘤生长和转移的关键步骤,抑制肿瘤血管生成能有效达到抗肿瘤的目的。近年来,抗血管生成分子靶向治疗是研究热点。除此之外,传统细胞毒化疗药物以低剂量、频繁或持续、短间歇的方式给药亦可产生抗血管生成作用,此时,药物的靶点是肿瘤血管内皮细胞而非肿瘤细胞,这种治疗模式称为“抗血管生成化疗”。本文就近年来抗血管生成化疗的研究进展作一综述。     

小分子抗血管生成药物在非小细胞肺癌中的研究进展

肺癌的发病率和死亡率均是全球恶性肿瘤之最,目前对于晚期非小细胞肺癌的主要治疗方法有化疗、靶向治疗、免疫治疗、抗血管生成治疗及放疗。新生血管形成不仅可以促进肿瘤生长,还可协助转移、侵袭,因此目前抗血管生成药物治疗成为晚期肺癌的研究热点。VEGFR是诱导血管形成的关键因子,在包括肺癌的多种肿瘤中过度表达,抑制VEGFR不仅可以使肿瘤血管正常化还可以抑制新生血管形成,从而更好的发挥作用。VEGF抑制剂包括:抗VEGF抗体,可溶性VEGFR,抗VEGF受体抗体,小分子酪氨酸激酶抑制剂（TKIs）。目前主要用于晚期非小细胞肺癌研究的小分子药物有安罗替尼、阿帕替尼、呋喹替尼、尼达尼布、法米替尼,而且有研究表明抗血管生成药物与化疗、靶向药物、免疫抑制剂等药物联用可以增强治疗效果。因此本文主要对抗血管生成药物的作用机制,与其他药物联用的理论基础及小分子抗血管生成药物在晚期非小细胞肺癌中的研究进展进行综述。     

长春瑞滨节拍化疗在晚期非小细胞肺癌患者中的应用

传统化疗依靠常规剂量静脉给药,毒性较大,肿瘤易复发和耐药,而节拍化疗低剂量、频繁、短间歇给予细胞毒性药物的治疗方式在一定程度上减少了化疗不良反应,延缓了肿瘤的复发、耐药;节拍化疗通过抗血管生成、免疫调节、抑制肿瘤干细胞并诱导肿瘤细胞休眠抑制肿瘤生长。口服长春瑞滨节拍化疗在晚期非小细胞肺癌患者治疗中有多种应用方案,包括单药化疗、双药化疗、联合抗血管生成药、联合靶向治疗、联合放疗、联合免疫治疗等多种治疗方案。     

肿瘤抗血管生成生物化疗的研究进展

传统的化疗通过杀伤肿瘤细胞抑制肿瘤的生长和侵袭,在对细胞毒化疗药物研究的同时发现,绝大多数药物在低剂量、高频率的给药方式下对肿瘤血管内皮细胞有持续抑制和杀伤作用,即后来所提出的抗血管生成的生物化疗。这种以肿瘤血管内皮细胞为作用靶点的化疗,其理论依据主要是肿瘤的生长和侵袭离不开新生血管的生成。目前认识到,许多化疗药物及一些抗肿瘤中药的有效成分在体外实验或体内实验中通过不同的作用机制发挥抗血管生成作用。     

恩度联合化疗治疗消化系统晚期癌症的临床研究进展

异常血管生成是各种实体瘤生长、转移共同的病理过程,抗血管生成已成为目前治疗肿瘤的重要途径.重组人血管内皮抑制素恩度是一种多靶点抗血管生成药物,试验表明其与传统化疗药物联合应用可以产生协同增效的作用,现已获得中国食品药品监督管理局批准将化疗药物联合恩度用于治疗晚期非小细胞肺癌.近年来,一些临床研究发现恩度与传统化疗药物联合在消化道恶性肿瘤的治疗中表现出稳定的有效性和安全性,可能具有良好的应用前景.本文从有效性和安全性两个方面概述恩度联合传统化疗药物治疗消化系统常见恶性肿瘤的临床研究进展,以期为后续研究和临床实践提供思路和依据.     

肿瘤血管生成抑制药物研究现状及展望

自从人们认识到实体瘤的生长依赖血管生成后,各种血管生成抑制剂应运而生,为肿瘤治疗开创了新视角.抗血管生成药物的优势在于:(1)作用的靶是具有遗传稳定性的血管内皮细胞,不易产生耐药性;(2)药物易于到达靶细胞,与化疗药物合用,可以增加其在肿瘤组织内的聚集浓度;(3)有效抑制肿瘤转移、复发等.目前已有二十余种抗血管生成药物进入临床实验阶段.本文就血管生成抑制剂的研究现状,根据其作用原理,将其分为细胞内作用和细胞外作用两类.分述如下:     

节律化疗抗血管生成效应的研究进展

目的:总结国内外关于节律化疗在抗血管生成效应方面的研究现状。方法:应用Medline和CNKI期刊全文数据库系统,以"节律化疗、肿瘤、血管生成"等为关键词,检索2000-01-2010-10有关节律化疗方面的文献。纳入标准:1)关于节律化疗抗血管生成作用机制的研究。2)关于节律化疗抗血管生成方面的临床前试验。3)关于节律化疗抗血管生成方面的临床试验。根据纳入标准,纳入分析31篇文献。结果:持续低剂量节律化疗可以通过多种机制来抑制肿瘤血管的生成。节律化疗药物与抗血管生成类药物联合或节律化疗药物之间联合应用可以有效提高治疗效果。这种新的策略在临床前模型和临床试验上是有效的,而且可能帮助解决常规高剂量化疗引起的毒副反应和耐药性的难题。结论:节律化疗的抗血管生成疗法为肿瘤治疗提供了新的途径,在实验室中已取得较满意的结果,但具体的临床应用还有许多问题需要解决。     

外周T细胞淋巴瘤抗血管生成研究进展

 外周T细胞淋巴瘤（PTCL）对传统的化疗方案不敏感,与B细胞淋巴瘤相比预后差,目前缺乏有效的治疗方案。血管生成在恶性肿瘤的生长过程中具有重要的作用,研究显示血管内皮生长因子（VEGF）的表达与PTCL的临床特征及预后相关。同时,具有抗血管生成作用的药物在PTCL的初步临床研究中显示出了疗效。     

晚期非小细胞肺癌抗血管生成药物治疗中国专家共识(2020版)

非小细胞肺癌(NSCLC)是肺癌中最常见的组织学类型, 在肺癌中占比超过80%, 以铂类为基础的双药化疗方案是治疗晚期NSCLC的传统标准方案, 但患者的5年生存率依然很低, 不足5%。新生血管的生成在多种实体肿瘤的生长、增殖和转移中发挥着关键作用。抗血管生成药物可作用于肿瘤微环境, 使现有肿瘤血管退化, 同时抑制肿瘤新生血管生成。随着我国抗血管生成药物的不断发展和药物可及性的不断提高, 抗血管生成药物成为晚期NSCLC患者不可或缺的治疗手段之一。共识在《晚期非小细胞肺癌抗血管生成药物治疗中国专家共识(2019年版)》的基础上, 由共识编写组根据近一年来发表的临床研究证据, 并结合临床实践, 整理而成共识更新版, 以指导我国肺癌治疗相关的临床科室合理使用抗血管生成药物, 进一步提高我国肺癌规范化诊疗水平。     

Novel antivascular efficacy of metronomic docetaxel therapy in prostate cancer: hnRNP K as a player

Tumor growth requires a competent vascular supply and angiogenesis is now considered a potential target for cancer treatment. Chemotherapeutic drugs, and docetaxel in particular, chronically administered using a frequent schedule at low dose (metronomic dosing), can cause potent antiangiogenic effects by targeting the endothelial cells of newly growing blood vessels. Because the exposure to cytotoxic drugs could target both endothelial and tumor cells, we investigated the effects of “metronomic docetaxel” on hormone refractory prostate carcinoma cells. In vitro, metronomic therapy lowered tumor cell viability, inducing apoptosis and reducing the invasive potential at 10‐ to100‐fold lower concentrations as compared with the maximum tolerated dose. Metronomic regimens resulted in a significant reduction of vascular endothelial cell growth factor expression and up‐regulation of endogenous angiogenesis inhibitors. Our studies suggest that heterogeneous nuclear ribonucleoprotein K is a mediator of the effects we observed. Targeting heterogeneous nuclear ribonucleoprotein K may serve as a specific antimetastasis and antiangiogenic therapy and could be a potential predictive marker to determine the optimal dose and schedule for metronomic chemotherapy regimens. These findings highlight the multiple effects that may characterize antiangiogenic metronomic chemotherapy and suggest that docetaxel might act as antitumor compound by affecting both cancer and endothelial cells at the same drug concentration. Careful optimization of drug scheduling and dosages will be required to maximize antitumor responses with metronomic approaches. © 2009 UICC     

Metronomic therapy for breast cancer

Conventional cytotoxic chemotherapeutic drugs treat cancer either by direct killing or by inhibition of growth of cycling tumor cells. In addition, evidence suggests that cytotoxic agents may inhibit tumor growth through an antiangiogenic mechanism. "Metronomic" or frequent continuous administration of the same chemotherapeutic agents at lower doses may optimize their antiangiogenic properties. The effectiveness of metronomic chemotherapy regimens can be improved significantly by concurrent administration of antiangiogenic, endothelial-specific drugs. Preclinical studies have shown that integrating chemotherapy with antiangiogenic drugs can improve efficacy and circumvent the toxicity and drug resistance associated with standard or high-dose chemotherapy. Preliminary clinical studies have shown similar results. Further confirmation of this concept is required with randomized, controlled clinical trials.     

Metronomic therapy for breast cancer

Conventional cytotoxic chemotherapeutic drugs treat cancer either by direct killing or by inhibition of growth of cycling tumor cells. In addition, evidence suggests that cytotoxic agents may inhibit tumor growth through an antiangiogenic mechanism. "Metronomic" or frequent continuous administration of the same chemotherapeutic agents at lower doses may optimize their antiangiogenic properties. The effectiveness of metronomic chemotherapy regimens can be improved significantly by concurrent administration of antiangiogenic, endothelial-specific drugs. Preclinical studies have shown that integrating chemotherapy with antiangiogenic drugs can improve efficacy and circumvent the toxicity and drug resistance associated with standard or high-dose chemotherapy. Preliminary clinical studies have shown similar results. Further confirmation of this concept is required with randomized, controlled clinical trials.     

A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer.

PURPOSE: A transgenic mouse model has revealed parameters of the angiogenic switch during multistep tumorigenesis of pancreatic islets, and demonstrated efficacy of antiangiogenic therapies. Pericytes have been revealed as functionally important for tumor neovasculature, using kinase inhibitors targeting their platelet-derived growth factor receptors (PDGFRs). Additionally, vascular endothelial growth factor receptor (VEGFR) inhibitors and metronomic chemotherapy show modest benefit against early- but not late-stage disease. MATERIALS AND METHODS: Seeking to improve efficacy against otherwise intractable end-stage pancreatic islet tumors, two receptor tyrosine kinase inhibitors, imatinib and SU11248, were used to disrupt PDGFR-mediated pericyte support of tumor endothelial cells in concert with maximum-tolerated dose (MTD) or metronomic chemotherapy and/or VEGFR inhibition. RESULTS: Imatinib, despite equivocal efficacy as monotherapy, reduced pericyte coverage of tumor vessels and enhanced efficacy in combination with metronomic chemotherapy or VEGFR inhibition. A regimen involving all three was even better. MTD using cyclophosphamide caused transitory regression, but then rapid regrowth, in contrast to metronomic cyclophosphamide plus imatinib, which produced stable disease. The MTD regimen elicited apoptosis of tumor cells but not endothelial cells, whereas the other regimens increased endothelial cell apoptosis concordant with efficacy. A "chemo-switch" protocol, involving sequential MTD and then metronomic chemotherapy, overlaid with multitargeted inhibition of PDGFR and VEGFR, gave complete responses and unprecedented survival advantage in this model. CONCLUSION: This study demonstrates a potentially tractable clinical strategy in a stringent preclinical model, wherein standard-of-care chemotherapy is followed by a novel maintenance regimen: PDFGR is targeted to disrupt pericyte support, while metronomic chemotherapy and/or VEGFR inhibitors target consequently sensitized endothelial cells, collectively destabilizing pre-existing tumor vasculature and inhibiting ongoing angiogenesis.     

Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. Currently, most models consist of subcutaneous human tumor transplants in immunodeficient mice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfected with the gene encoding secretable β-subunit human choriogonadotropin (β-hCG), which was used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID) mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX), UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti-vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic chemotherapy regimens such as UFT + CTX with DC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment.     

Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors

Vascular endothelial cells have been identified as a critical component of the neural stem cell niche, raising the possibility that brain tumor stem-like cells (TSLC) may also rely on signaling interactions with nearby tumor vasculature to maintain their stem-like state. The disruption of such a TSLC vascular niche by an antiangiogenic therapy could result in loss of stemness characteristics associated with intrinsic drug resistance and, thus, preferentially sensitize TSLC to the effects of chemotherapy. Considering these possibilities, we investigated the impact of antiangiogenic anticancer therapy on the TSLC fraction of glioma tumors. Athymic nude mice bearing s.c. tumor xenografts of the C6 rat glioma cell line were treated with either a targeted antiangiogenic agent, antiangiogenic schedules of low-dose metronomic chemotherapy, combination therapies of antiangiogenic agents and chemotherapy, or, for the purpose of comparison, a conventional cytotoxic schedule of maximum tolerated dose chemotherapy using cyclophosphamide. Targeted antiangiogenic therapy or cytotoxic chemotherapy did not reduce the fraction of tumor sphere-forming units (SFU) in the tumor, whereas all treatment groups that combined both antiangiogenic and cytotoxic drug effects caused a significant reduction in SFU. This work highlights the possibility that selective eradication of TSLC may be achieved by targeting the tumor microenvironment (and potentially a supportive TSLC niche) rather than the TSLC directly. Furthermore, this work suggests a possible novel effect of antiangiogenic therapy, namely, as a chemosensitizer of TSLC, and thus represents a possible new mechanism to explain the ability of antiangiogenic therapy to enhance the efficacy of chemotherapy.     

Metronomic dosing of BH3 mimetic small molecule yields robust antiangiogenic and antitumor effects

Bcl-2 is an antiapoptotic protein that has also been found to function as a proangiogenic signaling molecule. Improvements in antiangiogenic therapy can be engendered by metronomic dosing. Thus, we hypothesized that BH3-mimetic drugs that antagonize Bcl-2 family proteins may exert a greater efficacy when dosed metronomically. To examine this hypothesis, we employed AT101, an orally available and well-tolerated BH3-mimetic drug that has been established as effective. In a mouse xenograft model of human squamous cell carcinomas (SCC) that includes a humanized vasculature, we explored the effects of docetaxel in combination with either daily (metronomic) or weekly (bolus) doses of AT101. In addition, we explored the effect of single or combination therapy on angiogenesis and survival of endothelial or SCC cells in vitro. Metronomic AT101 therapy increased mouse survival, decreased tumor mitotic index, and decreased tumor microvessel density, compared with bolus therapy. Therapeutic potentiation was achieved by similar overall drug exposure and without altering systemic toxicities. Combinations of AT101 and docetaxel produced additive toxicity in both endothelial and SCC tumor cells. Notably, subapoptotic concentrations of AT101 potently inhibited the angiogenic potential of endothelial cells. Taken together, our findings unveil the efficacious benefits that can be achieved by metronomic delivery of BH3-mimetic drugs, in particular suggesting that SCC patients with might benefit from low-dose continuous administration of these drugs.     

La chimiothérapie métronomique du cancer du sein métastatique: à propos d’un cas

The efficacy of metronomic chemotherapy — the continuous administration of cytotoxic agents at low doses — might largely be mediated by its antiangiogenic activity. A cytotoxic effect on endothelial cells might be involved in this process. We report herein the major efficacy and excellent tolerance of low-dose cyclophosphamide and methotrexate in a 51-year-old metastatic breast cancer patient presenting with diffuse liver involvement and icterus. Given as first- or second-line treatment in metastatic breast cancer, metronomic chemotherapy has demonstrated clinical activity and represents an alternative in patients when conventional regimens are contraindicated.     

Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas

Glioblastoma is a highly angiogenic tumor with a dismal prognosis. Temozolomide (TMZ), a methylating agent is one of the most effective chemotherapeutic agents against glioblastoma. To overcome the problem that most of these tumors become resistant to chemotherapeutic regimens within a year, we investigated the antitumor efficacy of metronomic administration of low-dose TMZ in in vitro cell proliferation/cytotoxicity assay and in vivo rat and nude mouse orthotopic glioma model. By in vitro assay, we elucidated that C6/LacZ rat glioma cells were more resistant to metronomic treatment of TMZ than U-87MG human glioblastoma cells and bEnd.3 mouse brain endothelial cells. Compared with the conventional chemotherapeutic regimen of TMZ, we found that frequent administration of TMZ at a low dose (metronomic treatment) markedly inhibited angiogenesis as well as tumor growth in a TMZ-resistant C6/LacZ rat glioma model. In addition, metronomic treatment of TMZ significantly augmented apoptosis of tumor cells in this model. For the TMZ-sensitive U-87MG cells, even with a very low dose of TMZ, which is not effective to reduce tumor mass, the metronomic treatment of TMZ reduced the microvessel density, i.e. angiogenesis, in a nude mouse orthotopic model. In conclusion, for both models, the metronomic treatment of TMZ decreased angiogenesis. Especially, in TMZ-resistant glioma cells, this regimen increased apoptosis of tumor cells and decreased tumor growth. The metronomic treatment of TMZ in orthotopic glioma models demonstrated a successful antiangiogenic effect which can overcome the chemoresistance in conventional TMZ chemotherapy.