Pleiotropic Effects of Herbs Characterized with Blood-Activating and Stasis-Resolving Functions on Angiogenesis

Accumulative evidences have underpinned the nature candidates from Chinese medicine (CM), particularly CM served as blood activating and stasis resolving (BASR, Huoxue Huayu in Chinese) by targeting tumor-associated angiogenesis. However, recent experiment research on the therapeutic angiogenesis by BASR-CM attracts wide attention and discussion. This opinion review focused on the underlying link between two indications and anticipated that (1) BASR-CM might emphasize on a balanced multi-cytokines network interaction; (2) BASR-CM might address on the nature of diseases prior to differently affecting physiological and pathological angiogenesis; (3) BASR-CM might mainly act on perivascular cells, either promotes arteriogenesis by increasing arteriogenic factors in ischemic diseases, or simultaneously keep a quiescent vasculature to impede angiogenesis in tumor context.     

Generation of angiostatin-like fragments from plasminogen by prostate-specific antigen

Angiostatin, a potent inhibitor of angiogenesis, tumour growth and metastasis, is a biologically active fragment of plasminogen, containing the kringle domains 1-4. It is generated from plasminogen by limited proteolysis. We show that prostate-specific antigen (PSA), a serine proteinase secreted by human prostate and human prostate cancer cells, is able to convert Lys-plasminogen to biologically active angiostatin-like fragments, containing kringles 1-4, by limited proteolysis of peptide bond Glu439-Ala440 in vitro. In an in vitro morphogenesis assay, the purified angiostatin-like fragments inhibited proliferation and tubular formation of human umbilical vein endothelial cells with the same efficacy as angiostatin. This finding might help to understand growth characteristics of prostate cancer, which usually has low microvessel density and slow proliferation.     

阿帕替尼治疗晚期胰腺癌的疗效和安全性及疗效预测指标的探索北大核心

目的:观察甲磺酸阿帕替尼治疗晚期胰腺癌的疗效与安全性,探索血清血管内皮生长因子(vascular endothelial growth factor,VEGF)和血管内皮生长因子受体-2(vascular endothelial growth factor receptor-2,VEGFR-2)水平与阿帕替尼疗效的关系。方法:本课题选择经病理确诊一线治疗进展后无法耐受或不愿接受二线化疗的晚期胰腺癌患者,经知情同意后给予阿帕替尼500 mg po qd治疗,2周期评估一次,主要观察指标为疾病控制率(disease control rate,DCR),次要观察指标为无进展生存期(progression-free survival,PFS)和不良反应;应用ELISA法检测治疗前患者血清VEGF和VEGFR-2水平;卡方检验分析血清VEGF和VEGFR-2水平与阿帕替尼疗效的关系。结果:本课题共入组24例一线治疗进展的晚期胰腺癌患者,可评估患者共23例。其中完全缓解(complete response,CR)0例、部分缓解(partial response,PR)1例(4.35%)、疾病稳定(stable disease,SD)8例(34.78%)、疾病进展(progressive disease,PD)14例(60.87%)。DCR为39.13%,中位PFS为2个月。阿帕替尼在治疗过程中出现的不良反应按照发生频率依次为乏力(91.30%)、高血压(52.17%)、口腔黏膜炎(52.17%)、蛋白尿(47.83%)、贫血(43.48%)、腹泻(21.74%)、呕吐(17.39%)、消化道出血(4.35%)、陈旧伤口裂开(4.35%)。在SD组和PD组中血清VEGF和VEGFR-2水平并没有明显差异。结论:对于一线治疗进展并且体力状况良好的晚期胰腺癌患者,阿帕替尼可以作为一个可选的治疗策略,血清VEGF和VEGFR-2水平不能预测阿帕替尼疗效。     

Synergistic inhibition of angiogenesis and glioma cell-induced angiogenesis by the combination of temozolomide and enediyne antibiotic lidamycin

Present work mainly evaluated the inhibitory effects of lidamycin (LDM), an enediyne antibiotic, on angiogenesis or glioma-induced angiogenesis in vitro and in vivo, especially its synergistic anti-angiogenesis with temozolomide (TMZ). LDM alone efficiently inhibited proliferations and induced apoptosis of rat brain microvessel endothelial cells (rBMEC). LDM also interrupted the tube formation of rat brain microvessel endothelial cells (rBMEC) and rat aortic ring spreading. The blockade of rBMEC invasion and C6 cell-induced rBMEC migration by LDM was associated with decrease of VEGF secretion in a co-culture system. TMZ dramatically potentiated the effects of LDM on anti-proliferation, apoptosis induction, and synergistically inhibited angiogenesis events. As determined by western blot and ELISA, the interaction of tumor cells and the rBMEC was markedly interrupted by LDM plus TMZ with synergistic regulations of VEGF induced angiogenesis signal pathway, tumor cell invasion/migration, and apoptosis signal pathway. Immunofluorohistochemistry of CD31 and VEGF showed that LDM plus TMZ resulted in synergistic decrease of microvessel density (MVD) and VEGF expression in human glioma U87 cell subcutaneous xenograft. This study indicates that the high efficacy of LDM and the synergistic effects of LDM plus TMZ against glioma are mediated, at least in part, by the potentiated anti-angiogenesis.     

Transpupillary thermotherapy (TTT) for age-related macular degeneration

Purpose. To review the results of transpupillary thermotherapy (TTT) on choroidal neovascular membranes associated with age-related macular degeneration (AMD). Materials and Methods. 35 eyes of 35 patients with AMD and choroidal neovascularization and exudation were treated with TTT and had fundus photographs and fluorescein angiography (FA) before and at least six months after TTT. 28 eyes had predominantly occult lesions as seen on FA, while 7 demonstrated primarily classic lesions. All were treated with 650 mw power or less using the 810 nm diode laser (3000 micron spot, duration of 60 seconds). Visual acuity, lesion size, and amount of subretinal fluid were determined by results of examination and review of photographs and fluorescein angiograms. Results. A 50% reduction in subretinal fluid was achieved in 67% of treated eyes overall, with stabilization of vision (less than three lines of visual acuity lost) in 86%. Complications from treatment were infrequent (9%) and involved hemorrhage noted in the region of treatment upon follow-up. Conclusion. TTT promotes resolution of subretinal fluid and appears to stabilize visual acuity in patients with exudative AMD.     

DCLAK11, a multi-tyrosine kinase inhibitor,exhibits potent antitumor and antiangiogenic activity in vitro

Aim:

To investigate the molecular targets of DCLAK11, a novel compound discovered from a series of substituted pyridin-3-amine derivatives, and to characterize its anti-tumor properties in vitro.

Methods:

Kinase inhibition was measured by an ELISA assay. Cell viability was assessed with an SRB or a CCK8 assay. The alterations induced by kinase signaling proteins in cancer cells were detected by Western blot. Apoptosis was determined by an Annexin V-PI assay. The following assays were used to evaluate the impact on angiogenesis: wound-healing, Transwell, tube formation and microvessel outgrowth from rat aortic rings.

Results:

DCLAK11 was a multi-targeted kinase inhibitor that primarily inhibited the EGFR, HER2, and VEGFR2 tyrosine kinases with IC₅₀ value of 6.5, 18, and 31 nmol/L, respectively. DCLAK11 potently inhibited the proliferation of EGFR- and HER2-driven cancer cells: its IC₅₀ value was 12 and 22 nmol/L, respectively, in HCC827 and HCC4006 cells with EGFR exon deletions, and 19 and 81 nmol/L, respectively, in NCI-N87 and BT474 cells with HER2 amplification. Consistently, DCLAK11 blocked the EGFR and HER2 signaling in cancer cells with either an EGFR or a HER2 aberration. Furthermore, DCLAK11 effectively induced EGFR/HER2–driven cell apoptosis. Moreover, DCLAK11 exhibited anti-angiogenic activity, as shown by its inhibitory effect on the proliferation, migration and tube formation of human umbilical vascular endothelial cells and the microvessel outgrowth of rat aortic rings.

Conclusions:

DCLAK11 is a multi-targeted kinase inhibitor with remarkable potency against tyrosine kinases EGFR, HER2 and VEGFR2, which confirms its potent anti-cancer activity in EGFR- and HER2-addicted cancers and its anti-angiogenic activity.     

Cancer chemotherapeutics - angiogenesis agents: October 1999 - March 2000

Angiogenesis is often defined as the formation of capillary blood vessels from existing blood vessels. In the area of cancer research, approaches that seek to block angiogenesis are under intense investigation. In the past six months, a number of applications have appeared referring to small molecule inhibitors of matrix metalloproteinases (MMPs), the VEGF receptor tyrosine kinase, the integrin receptor α_vβ₃ and other defined targets. This review summarises the key features of these applications as well as other disclosures involving natural products claimed as angiogenesis inhibitors. The review also summarises angiogenesis-related disclosures involving endogenous inhibitors, novel targets and interesting technologies that have appeared in applications published between October 1999 and March 2000. If the patent activity is any indication, there is significant interest and a number of opportunities for treating cancer through inhibiting angiogenesis.     

New targeted therapies for renal cell carcinoma

Introduction: The aim of treatment in metastatic renal cell carcinoma is palliation. In the last 5 years, multiple targeted agents have been developed which have resulted in prolongation of patients' lives, but complete responses remain rare. New therapies and approaches are required to further improve the prognosis for patients with this disease.

Areas covered: This review discusses the molecular targets in renal cell carcinoma relevant to the development of new treatments and describes the progress of novel therapies. The evidence is compiled from the PubMed database and proceedings of scientific meetings, searched up to December 2010.

Expert opinion: A multitude of experimental agents are in clinical development and offer theoretical advantages over those currently in use. It is hoped that these treatments will result in better long-term control of metastatic renal cell carcinoma, with improved side effect profiles, but curative treatment in this disease remains elusive until the mechanisms underlying response and resistance to therapy are elucidated. Progress in the field has been limited by inadequate tissue collection within clinical trials; current and future clinical trial design will incorporate a larger translational component in an attempt to establish predictive biomarkers.     

The evolving role of antiangiogenic therapies in glioblastoma multiforme: current clinical significance and future potential

Introduction: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, but its prognosis remains poor despite significant advances in our understanding of its molecular biology and investigation of numerous treatment modalities. Despite conventional treatment consisting of surgical resection, radiotherapy, and temozolomide marginally prolonging survival, most GBM patients die within 2 years of initial diagnosis. Bevacizumab (Bev) is the best-studied antiangiogenic agent for GBM and currently the only FDA-approved second-line treatment.

Areas covered: Areas covered in this review include the molecular pathways of angiogenesis in glioblastoma, specifically the overexpression of vascular endothelial growth factor (VEGF) and robust formation of tumor neovasculature. In addition, this review covers pharmacological targeting of this process as a longstanding attractive clinical strategy, specifically by Bev.

Expert opinion: This review attempts to discuss the history of early studies of antiangiogenic treatment for GBM that eventually failed in subsequent studies and the evolving modern role of Bev in the course of treatment for a variety of indications, including symptom control, reduced glucocorticoid use, and improved quality of life.     

Thalidomide: a remarkable comeback

The thalidomide product is a racemic mixture of the L- and D-enantiomeric forms of a synthetic glutamic acid derivative that contains a phthalimide ring and a glutarimide ring. Initially marketed as a sedative, it was withdrawn from the world market after it was found to be associated with severe birth defects. Recently, the compound has generated renewed interest because of its immunomodulatory and anti-angiogenic properties. The nature of its immunologic effects is under active investigation. It is orally bioavailable and can be administered in once daily dosing. Its primary route of metabolism is spontaneous hydrolysis. In controlled clinical trials, thalidomide has proven effective in the treatment of erythema nodosum leprosum, oral and oesophageal aphthous ulceration associated with advanced HIV infection and oral ulceration associated with Behcet’s syndrome. Promising results have been obtained in preliminary studies of other immunologic and neoplastic disorders, but controlled clinical studies are still lacking for these entities. Adverse effects include teratogenicity peripheral neuropathy and sedation. In the US, thalidomide can be prescribed only through a restricted drug distribution program.