Статті в журналах: "Activité antivasculaire"

1

Brenner, A. J., Y. Cohen, E. Breitbart, J. Rogge, and F. J. Giles. "Antivascular activity of VB111 in glioblastoma xenografts." Journal of Clinical Oncology 28, no. 15_suppl (2010): e13652-e13652. http://dx.doi.org/10.1200/jco.2010.28.15_suppl.e13652.

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2

Garkavtsev, I., V. P. Chauhan, H. K. Wong, et al. "Dehydro- -lapachone, a plant product with antivascular activity." Proceedings of the National Academy of Sciences 108, no. 28 (2011): 11596–601. http://dx.doi.org/10.1073/pnas.1104225108.

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3

Korodi, Andrei Dan, Cristian Furau, Gheorghe Furau, et al. "Tipurile de vase asociate tumorilor GIST influenteaza eficienta terapiei antivasculare cu inhibitori de receptor tirozin-kinazic." Revista de Chimie 70, no. 9 (2019): 3250–53. http://dx.doi.org/10.37358/rc.19.9.7528.

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Gastrointestinal stromal tumors (GIST�sare the most common mesenchymal neoplasms of the alimentary tract. Angiogenesis is an essential condition in the growth and development of tumors, especially in the case of GISTs due to their particular behavior. The aggressive behavior depends on the size and site of the tumor in close relationship with the intratumoral vascular development. The purpose of this study is to investigate, using immunohistochemical stainings, the types of intratumoral vessels in GIST�s, knowing the interrelation between the tumor angiogenesis and the response to the targeted antivascular therapy, influencing directly the prognosis. In our research, in all 37 cases the most numerous vessels were the immature and intermediate ones, signaling an increased angiogenic activity. The perivascular cell free vessels are the most sensitive at antivascular therapy with tyrosine kinase receptor inhibitors, providing a good response and prognosis to the treatment. Immature vessels evaluation especially, could be a an important sign in assessment of the effectiveness of antivascular therapy in GIST.

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4

Liang, Pingping, Xiaoyu Huang, Ya Wang, et al. "Tumor-Microenvironment-Responsive Nanoconjugate for Synergistic Antivascular Activity and Phototherapy." ACS Nano 12, no. 11 (2018): 11446–57. http://dx.doi.org/10.1021/acsnano.8b06478.

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5

Lee, Hsueh-Yun, Chih-Yi Chang, Mei-Jung Lai, et al. "Antimitotic and antivascular activity of heteroaroyl-2-hydroxy-3,4,5-trimethoxybenzenes." Bioorganic & Medicinal Chemistry 23, no. 15 (2015): 4230–36. http://dx.doi.org/10.1016/j.bmc.2015.06.043.

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6

Aribi, Fallia, Charlene Vey, Derya Topkaya, et al. "Phthalocyanine-chalcone conjugates." Journal of Porphyrins and Phthalocyanines 20, no. 01n04 (2016): 497–504. http://dx.doi.org/10.1142/s1088424616500310.

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A phthalocyanine-chalcone conjugate was previously reported to retain the full photodynamic activity of the phthalocyanine and a slightly lowered antivascular effect of the chalcone. Assuming that it was due to an insufficient release of the chalcone, we described here several grafting modes applied to the preparation of phthalocyanine-chalcone conjugates.

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7

Beale, Thomas M., Rebecca M. Myers, James W. Shearman, et al. "Antivascular and anticancer activity of dihalogenated A-ring analogues of combretastatin A-4." MedChemComm 1, no. 3 (2010): 202. http://dx.doi.org/10.1039/c0md00095g.

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8

Ferl, G. Z., and R. E. Port. "Quantification of Antiangiogenic and Antivascular Drug Activity by Kinetic Analysis of DCE-MRI Data." Clinical Pharmacology & Therapeutics 92, no. 1 (2012): 118–24. http://dx.doi.org/10.1038/clpt.2012.63.

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9

Tuncel, Sinem, Aurélien Trivella, Devrim Atilla, et al. "Assessing the Dual Activity of a Chalcone–Phthalocyanine Conjugate: Design, Synthesis, and Antivascular and Photodynamic Properties." Molecular Pharmaceutics 10, no. 10 (2013): 3706–16. http://dx.doi.org/10.1021/mp400207v.

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10

Salimi, F., J. Hamedi, E. Motevaseli, and F. Mohammadipanah. "Isolation and screening of rareActinobacteria, a new insight for finding natural products with antivascular calcification activity." Journal of Applied Microbiology 124, no. 1 (2017): 254–66. http://dx.doi.org/10.1111/jam.13605.

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11

Wang, Fang, Zhuang Yang, Yibin Liu, et al. "Synthesis and biological evaluation of diarylthiazole derivatives as antimitotic and antivascular agents with potent antitumor activity." Bioorganic & Medicinal Chemistry 23, no. 13 (2015): 3337–50. http://dx.doi.org/10.1016/j.bmc.2015.04.055.

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12

Romagnoli, Romeo, Pier Giovanni Baraldi, Maria Kimatrai Salvador, et al. "Synthesis, Antimitotic and Antivascular Activity of 1-(3′,4′,5′-Trimethoxybenzoyl)-3-arylamino-5-amino-1,2,4-triazoles." Journal of Medicinal Chemistry 57, no. 15 (2014): 6795–808. http://dx.doi.org/10.1021/jm5008193.

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13

Ducki, Sylvie, David Rennison, Meiko Woo, et al. "Combretastatin-like chalcones as inhibitors of microtubule polymerization. Part 1: Synthesis and biological evaluation of antivascular activity." Bioorganic & Medicinal Chemistry 17, no. 22 (2009): 7698–710. http://dx.doi.org/10.1016/j.bmc.2009.09.039.

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14

Aikins, Anastasia R., MiJung Kim, Bernardo Raymundo, and Chan-Wha Kim. "Featured Article: Downregulation of transgelin blocks interleukin-8 utilization and suppresses vasculogenic mimicry in breast cancer cells." Experimental Biology and Medicine 242, no. 6 (2017): 573–83. http://dx.doi.org/10.1177/1535370216685435.

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Vasculogenic mimicry (VM) is a non-classical mechanism recently described in many tumors, whereby cancer cells, rather than endothelial cells, form blood vessels. Transgelin is an actin-binding protein that has been implicated in multiple stages of cancer development. In this study, we investigated the role of transgelin in VM and assessed its effect on the expression of endothelial and angiogenesis-related genes during VM in MDA-MB-231 breast cancer cells. We confirmed the ability of MDA-MB-231 cells to undergo VM through a tube formation assay. Flow cytometry analysis revealed an increase in the expression of the endothelial-related markers VE-cadherin and CD34 in cells that underwent VM, compared with those growing in a monolayer, which was confirmed by immunocytochemistry. We employed siRNA to silence transgelin, and knockdown efficiency was determined by western blot analyses. Downregulation of transgelin suppressed cell proliferation and tube formation, but increased IL-8 levels in Matrigel cultures. RT-PCR analyses revealed that the expression of IL-8, VE-cadherin, and CD34 was unaffected by transgelin knockdown, indicating that increased IL-8 expression was not due to enhanced transcriptional activity. More importantly, the inhibition of IL-8/CXCR2 signaling also resulted in suppression of VM with increased IL-8 levels, confirming that increased IL-8 levels after transgelin knockdown was due to inhibition of IL-8 uptake. Our findings indicate that transgelin regulates VM by enhancing IL uptake. These observations are relevant to the future development of efficient antivascular agents. Impact statement Vasculogenic mimicry (VM) is an angiogenic-independent mechanism of blood vessel formation whereby aggressive tumor cells undergo formation of capillary-like structures. Thus, interventions aimed at angiogenesis might not target the entire tumor vasculature. A more holistic approach is therefore needed in the development of improved antivascular agents. Transgelin, an actin-binding protein, has been associated with multiple stages of cancer development such as proliferation, migration and invasion, but little is known about its role in vasculogenic mimicry. We present here, an additional mechanism by which transgelin promotes malignancy by way of its association with the occurrence of VM. Although transgelin knockdown did not affect the transcript levels of most of the angiogenesis-related genes in this study, it was associated with the inhibition of the uptake of IL-8, accompanied by suppressed VM, indicating that transgelin is required for VM. These observations are relevant to the future development of efficient antivascular agents.

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15

Galbraith, Susan M., Ross J. Maxwell, Martin A. Lodge, et al. "Combretastatin A4 Phosphate Has Tumor Antivascular Activity in Rat and Man as Demonstrated by Dynamic Magnetic Resonance Imaging." Journal of Clinical Oncology 21, no. 15 (2003): 2831–42. http://dx.doi.org/10.1200/jco.2003.05.187.

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Purpose: Combretastatin A4 phosphate (CA4P) is a novel vascular targeting agent. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) studies were performed to examine changes in parameters related to blood flow and vascular permeability in tumor and normal tissue after CA4P treatment. Materials and Methods: Changes in kinetic DCE-MRI parameters (transfer constant [Ktrans] and area under contrast medium-time curve [AUC]) over 24 hours after treatment with CA4P were measured in 18 patients in a phase I trial and compared with those obtained in the rat P22 carcinosarcoma model, using the same imaging technique. Rats were treated with 30 mg/kg of CA4P; patients received escalating doses from 5 to 114 mg/m2. Results: A similar pattern and time course of change in tumor and normal tissue parameters was seen in rats and humans. Rat tumor Ktrans was reduced by 64% 6 hours after treatment with CA4P (30 mg/kg). No significant reductions in kidney or muscle parameters were seen. Significant reductions were seen in tumor Ktrans in six of 16 patients treated at ≥ 52 mg/m2, with a significant group mean reduction of 37% and 29% at 4 and 24 hours, respectively, after treatment. The mean reduction in tumor initial area under the gadolinium–diethylenetriamine pentaacetic acid concentration-time curve (AUC) was 33% and 18%, respectively, at these times. No reduction was seen in muscle Ktrans or in kidney AUC in group analysis of the clinical data. Conclusion: CA4P acutely reduces Ktrans in human as well as rat tumors at well-tolerated doses, with no significant changes in kidney or muscle, providing proof of principle that this drug has tumor antivascular activity in rats and humans.

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16

Tuncel, Sinem, Aurélien Trivella, Devrim Atilla, et al. "Correction to “Assessing the Dual Activity of a Chalcone–Phthalocyanine Conjugate: Design, Synthesis, and Antivascular and Photodynamic Properties”." Molecular Pharmaceutics 12, no. 2 (2015): 663. http://dx.doi.org/10.1021/mp5008426.

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17

Siim, Bronwyn, Alan Lee, Sahar Shalal-Zwain, Frederik Pruijn, Mark McKeage, and William Wilson. "Marked potentiation of the antitumour activity of chemotherapeutic drugs by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA)." Cancer Chemotherapy and Pharmacology 51, no. 1 (2003): 43–52. http://dx.doi.org/10.1007/s00280-002-0529-0.

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18

Cecic, Ivana, Denise A. Chan, Patrick D. Sutphin, et al. "Oxygen Sensitivity of Reporter Genes: Implications for Preclinical Imaging of Tumor Hypoxia." Molecular Imaging 6, no. 4 (2007): 7290.2007.00017. http://dx.doi.org/10.2310/7290.2007.00017.

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Reporter gene techniques have been applied toward studying the physiologic phenomena associated with tumor hypoxia, a negative prognostic indicator. The purpose of this study was to assess the potential adverse effects of hypoxic conditions on the effectiveness of four commonly used reporter genes: Renilla luciferase, monomeric red fluorescent protein, thymidine kinase, and lacZ. Tumor-forming A375 cells expressing a trifusion reporter consisting of Renilla luciferase, monomeric red fluorescent protein, and thymidine kinase were subjected to decreasing oxygen tensions and assayed for reporter expression and activity. A375 cells expressing β-galactosidase were similarly exposed to hypoxia, with activity of the reporter monitored by cleavage of the fluorescent substrate 7-hydroxy-9 H-(1, 3-dichloro-9, 9-dimethylacridin-2-one)-β-galactoside (DDAOG). Generation of signal in in vivo tumor models expressing bioluminescent or β-galactosidase reporters were also examined over the course of hypoxic stresses, either by tumor clamping or the antivascular agent 5, 6-dimethylxanthenone-4-acetic acid (DMXAA). Our findings indicate that bioluminescent and fluorescent reporter activity are decreased under hypoxia despite minimal variations in protein production, whereas β-galactosidase reporter activity per unit protein was unchanged. These results demonstrate that combining β-galactosidase with the DDAOG optical probe may be a robust reporter system for the in vivo study of tumor hypoxia.

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19

Xia, Lin-Ying, Ya-Liang Zhang, Rong Yang, et al. "Tubulin Inhibitors Binding to Colchicine-Site: A Review from 2015 to 2019." Current Medicinal Chemistry 27, no. 40 (2020): 6787–814. http://dx.doi.org/10.2174/0929867326666191003154051.

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Due to the three domains of the colchicine-site which is conducive to the combination with small molecule compounds, colchicine-site on the tubulin has become a common target for antitumor drug development, and accordingly, a large number of tubulin inhibitors binding to the colchicine-site have been reported and evaluated over the past years. In this study, tubulin inhibitors targeting the colchicine-site and their application as antitumor agents were reviewed based on the literature from 2015 to 2019. Tubulin inhibitors were classified into ten categories according to the structural features, including colchicine derivatives, CA-4 analogs, chalcone analogs, coumarin analogs, indole hybrids, quinoline and quinazoline analogs, lignan and podophyllotoxin derivatives, phenothiazine analogs, N-heterocycle hybrids and others. Most of them displayed potent antitumor activity, including antiproliferative effects against Multi-Drug-Resistant (MDR) cell lines and antivascular properties, both in vitro and in vivo. In this review, the design, synthesis and the analysis of the structure-activity relationship of tubulin inhibitors targeting the colchicine-site were described in detail. In addition, multi-target inhibitors, anti-MDR compounds, and inhibitors bearing antitumor activity in vivo are further listed in tables to present a clear picture of potent tubulin inhibitors, which could be beneficial for medicinal chemistry researchers.

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20

Chan, C. K., and S. G. Lin. "Retinal Pigment Epithelial Tear after Ranibizumab Therapy for Subfoveal Fibrovascular Pigment Epithelial Detachment." European Journal of Ophthalmology 17, no. 4 (2007): 674–76. http://dx.doi.org/10.1177/112067210701700432.

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Purpose To describe the unusual complication of retinal pigment epithelial (RPE) tear after intravitreal ranibizumab (Lucentis®) for subfoveal fibrovascular pigment epithelial detachment (PED) and its effective management. Methods Chart review for case report of RPE tear after ranibizumab. Results An inferior RPE tear was documented by fluorescein angiography, fundus photography, and optical coherence tomography (OCT) 1 month after receiving repeat ranibizumab injection in the right eye of a patient with bilateral subfoveal fibrovascular PED. He had undergone multiple bevacizumab followed by ranibizumab injections for neovascular age-related macular degeneration (AMD) in both eyes, starting 6 months previously. Subsequent antivascular endothelial growth factor (VEGF) therapy improved vision of right eye from 20/200 to 20/40, despite RPE tear. Conclusions RPE tear may form after anti-VEGF therapy, including ranibizumab injection. Further anti-VEGF therapy may preserve or improve vision. To the authors' knowledge, this is first case report of effective suppression of neovascular activity with bevacizumab after an RPE tear following ranibizumab therapy.

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21

Lavazza, Cristiana, Carmelo Carlo-Stella, Arianna Giacomini, et al. "Human CD34+ cells engineered to express membrane-bound tumor necrosis factor–related apoptosis-inducing ligand target both tumor cells and tumor vasculature." Blood 115, no. 11 (2010): 2231–40. http://dx.doi.org/10.1182/blood-2009-08-239632.

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Abstract Adenovirus-transduced CD34+ cells expressing membrane-bound tumor necrosis factor–related apoptosis-inducing ligand (CD34-TRAIL+ cells) exert potent antitumor activity. To further investigate the mechanism(s) of action of CD34-TRAIL+ cells, we analyzed their homing properties as well as antitumor and antivascular effects using a subcutaneous myeloma model in immunodeficient mice. After intravenous injection, transduced cells homed in the tumor peaking at 48 hours when 188 plus or minus 25 CD45+ cells per 105 tumor cells were detected. Inhibition experiments showed that tumor homing of CD34-TRAIL+ cells was largely mediated by vascular cell adhesion molecule-1 and stromal cell–derived factor-1. Both CD34-TRAIL+ cells and soluble (s)TRAIL significantly reduced tumor volume by 40% and 29%, respectively. Computer-aided analysis of TdT-mediated dUTP nick end-labeling–stained tumor sections demonstrated significantly greater effectiveness for CD34-TRAIL+ cells in increasing tumor cell apoptosis and necrosis over sTRAIL. Proteome array analysis indicated that CD34-TRAIL+ cells and sTRAIL activate similar apoptotic machinery. In vivo staining of tumor vasculature with sulfosuccinimidyl-6-(biotinamido) hexanoate-biotin revealed that CD34-TRAIL+ cells but not sTRAIL significantly damaged tumor vasculature, as shown by TdT-mediated dUTP nick end-labeling+ endothelial cells, appearance of hemorrhagic areas, and marked reduction of endothelial area. These results demonstrate that tumor homing of CD34-TRAIL+ cells induces early vascular disruption, resulting in hemorrhagic necrosis and tumor destruction.

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Pohlmann, Dominika, Uwe Pleyer, Antonia M. Joussen, and Sibylle Winterhalter. "Immunosuppressants and/or antivascular endothelial growth factor inhibitors in punctate inner choroidopathy? Follow-up results with optical coherence tomography angiography." British Journal of Ophthalmology 103, no. 8 (2018): 1152–57. http://dx.doi.org/10.1136/bjophthalmol-2018-312455.

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PurposeTo report the effectiveness of treatment with antivascular endothelial growth factor (VEGF)-inhibitor and/or immunosuppressants in punctate inner choroidopathy (PIC) using standard imaging modalities and optical coherence tomography angiography (OCTA) over a time period of 16 months.MethodsIn this prospective, unmasked, single-centre study, 23 individuals with PIC underwent imaging with spectral domain OCT, fluorescein angiography, indocyanine green angiography and OCTA. Two groups were formed based on systemic treatment. In case of choroidal neovascularisation (CNV) activity, intravitreal anti-VEGF injections were carried out in both groups.ResultsGroup I included 12 patients (24 eyes) with 18 affected eyes (75%) who did not receive any systemic therapy at baseline. Group II contained 11 patients (22 eyes) who started systemic immunosuppressive therapy on average 2 years before baseline. All eyes with recurrence of CNV or residual fluid (group I: seven eyes; group II: six eyes) received anti-VEGF agents. Group I showed a significant reduction of CNV size (p=0.0078), as well as a decrease of fluid retention (p=0.0078) on OCTA after anti-VEGF injection. Group II did not demonstrate any significant reduction of CNV size, vessel shape or fluid retention post injection. But overall, fluid accumulation was significantly lower in group II (median=0.03 mm2) than in group I (median=0.32 mm2) (p=0.0028).ConclusionImmunosuppressants in addition to anti-VEGF agents showed a significant reduction of fluid accumulation, that is, reduced disease activity. We conclude that there is a benefit and effectiveness of immunosuppressants to control inflammatory secondary CNV in PIC.

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23

Fanale, Daniele, Giuseppe Bronte, Francesco Passiglia, et al. "Stabilizing versus Destabilizing the Microtubules: A Double-Edge Sword for an Effective Cancer Treatment Option?" Analytical Cellular Pathology 2015 (2015): 1–19. http://dx.doi.org/10.1155/2015/690916.

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Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy.

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Shaib, Walid, Scott Kono, and Nabil Saba. "Antiepidermal Growth Factor Receptor Therapy in Squamous Cell Carcinoma of the Head and Neck." Journal of Oncology 2012 (2012): 1–11. http://dx.doi.org/10.1155/2012/521215.

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Squamous cell carcinoma of head and neck (SCCHN) is the most common neoplasm of the upper aerodigestive tract. In this paper, we attempt to summarize the role and applications of the epidermal growth factor receptor (EGFR) inhibitors monoclonal antibodies (moAbs) and tyrosine kinase inhibitors (TKIs) locally advanced as well as metastatic SCCHN. Targeted therapy in SCCHN is now incorporated in the first-line regimes for advanced disease. Novel targeted agents, including the EGFR antibody, cetuximab, have been approved for use as single agents or in combination with radiation therapy or chemotherapy in treatment of recurrent metastatic or locally advanced SCCHN. Refractory mechanisms that bypass the pathway of EGFR inhibitors activity are identified explaining resistance to targeted therapy. Strategies of cotargeting EGFR and other pathways are under investigation. Examples of targeted therapy being used include mammalian target of rapamycin (mtor) inhibitors, antivascular endothelial growth factor (VEGF) moAb, and other inhibitors. We will be focusing our paper on the preclinical and clinical aspects of EGFR inhibition in SCCHN and touch upon other targeted therapies in application.

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Corti, Angelo, Monica Giovannini, Carmen Belli, and Eugenio Villa. "Immunomodulatory Agents with Antivascular Activity in the Treatment of Non-Small Cell Lung Cancer: Focus on TLR9 Agonists, IMiDs and NGR-TNF." Journal of Oncology 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/732680.

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Standard treatments for nonsmall cell lung cancer (NSCLC), such as surgery, chemotherapy, and radiotherapy, often lead to disappointing results. Unfortunately, also the various immunotherapeutic approaches so far tested have not produced satisfactory results to be widely applied in the clinical practice. However, the recent development of new immunomodulatory agents may open promising therapeutic options. This paper focuses on PF3512676, lenalidomide, and NGR-TNF, that is, drugs belonging to three different classes of immunomodulatory agents, that are also capable to affect tumor blood vessels with different mechanisms, and discusses the potential role of such agents in NSCLC treatment strategy.

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Patel, Vijay K., and Harish Rajak. "Development of Structure Activity Correlation Model on Aroylindole Derivatives as Anticancer Agents." Letters in Drug Design & Discovery 15, no. 2 (2018): 143–53. http://dx.doi.org/10.2174/1570180814666170823161751.

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Background: Aroylindole derivatives, the structural analogs of Combretastatin A-4 has been found to possess potent growth inhibitory activity on several cancer cell lines due to its excellent antitumor and antivascular activities. The aim of present research work is to identify lead and establish structure activity correlation of trimethoxyaroylindole derivatives, using integrated ligand and structure based computational approaches. Materials and Methods: A correlation between structure and biological activity was established using computational approaches i.e., structure activity correlation by pharmacophore and atom based 3D QSAR, molecular docking and energetic based pharmacophore mapping studies of trimethoxyaroylindole derivatives. Results and Discussion: The 3D-QSAR on trimethoxyaroylindole derivatives generated and showed best statistical result for CPHs AAARR.182 was validated by Q2 (0.6929), R2 (0.82). The Comp. 1 of the training set was employed as template for hydrogen bond donor, hydrophobic and hydrogen bond acceptor field prediction features and visualization of the 3D-QSAR model provides details of relationship between structure and biological activity of trimethoxyaroylindole derivatives. Pharmacophore model was developed by Phase and e-pharmacophore on comp. 1, the trimethoxy group with ring A, keto group, N-H group with ring B and ring C are pharmacophoric group important for the lead generation and coincide with various chemical features that may facilitate non-covalent binding between the ligand and its target receptor. Molecular docking studies showed critical interactions between Cys241, Val318 and meta, para-methoxy group at ring A while and Thr179 and NH of indole (distance 3.5 Å). The para position of trimethoxyphenyl ring bind to SH group of CYS 241 receptor molecule via hydrogen bond. Conclusion: The lead identification and establish structure activity correlation of trimethoxyaroylindole derivatives, were performed using integrated ligand and structure based computational approaches i.e., atom based 3D QSAR and pharmacophore study, molecular docking, energetic based pharmacophore mapping studies showed promising results. The outcomes of present studies could be utilized for the design of novel aroylindole derivatives including its lead optimization as potential anticancer agent.

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Yan, Wei, Tao Yang, Jianhong Yang, et al. "SKLB060 Reversibly Binds to Colchicine Site of Tubulin and Possesses Efficacy in Multidrug-Resistant Cell Lines." Cellular Physiology and Biochemistry 47, no. 2 (2018): 489–504. http://dx.doi.org/10.1159/000489983.

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Background/Aims: Many tubulin inhibitors are in clinical use as anti-cancer drugs. In our previous study, a novel series of 4-substituted coumarins derivatives were identified as novel tubulin inhibitors. Here, we report the anti-cancer activity and underlying mechanism of one of the 4-substituted coumarins derivatives (SKLB060). Methods: The anti-cancer activity of SKLB060 was tested on 13 different cancer cell lines and four xenograft cancer models. Immunofluorescence staining, cell cycle analysis, and tubulin polymerization assay were employed to study the inhibition of tubulin. N, N ′-Ethylenebis(iodoacetamide) assay was used to measure binding to the colchicine site. Wound-healing migration and tube formation assays were performed on human umbilical vascular endothelial cells to study anti-vascular activity (the ability to inhibit blood vessel growth). Mitotic block reversibility and structural biology assays were used to investigate the SKLB060-tubulin bound model. Results: SKLB060 inhibited tubulin polymerization and subsequently induced G2/M cell cycle arrest and apoptosis in cancer cells. SKLB060 bound to the colchicine site of β-tubulin and showed antivascular activity in vitro. Moreover, SKLB060 induced reversible cell cycle arrest and reversible inhibition of tubulin polymerization. A mitotic block reversibility assay showed that the effects of SKLB060 have greater reversibility than those of colcemid (a reversible tubulin inhibitor), indicating that SKLB060 binds to tubulin in a totally reversible manner. The crystal structures of SKLB060-tubulin complexes confirmed that SKLB060 binds to the colchicine site, and the natural coumarin ring in SKLB060 enables reversible binding. Conclusions: These results reveal that SKLB060 is a powerful and reversible microtubule inhibitor that binds to the colchicine site and is effective in multidrug-resistant cell lines.

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Zhang, Xinyuan, and Timothy Y. Y. Lai. "Baseline Predictors of Visual Acuity Outcome in Patients with Wet Age-Related Macular Degeneration." BioMed Research International 2018 (2018): 1–10. http://dx.doi.org/10.1155/2018/9640131.

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Age-related macular degeneration (AMD) is one of the leading causes of severe vision loss in people over 60 years. Wet AMD (wAMD) causes more severe visual acuity (VA) loss compared with the dry form due to formation of choroidal neovascularization (CNV). Antivascular endothelial growth factor (anti-VEGF) agents such as ranibizumab and aflibercept are now the standard of care treatment for wAMD. Unfortunately, up to a quarter of anti-VEGF-treated wAMD patients might not fully benefit from intravitreal injections and CNV activity may not respond to the treatment and these patients are called anti-VEGF nonresponders. This article aims to discuss the baseline factors associated with VA outcome such as age, initial VA, lesion types, disease duration, optical coherence tomography (OCT) features, fundus autofluorescence findings, and the presence of particular genotype risk alleles in patients with wAMD. Recommendations are provided regarding when to consider discontinuation of therapy because of either success or futility. Understanding the predictive factors associated with VA outcome and treatment frequency response to anti-VEGF therapy may help retina specialists to manage patients’ expectations and guide treatment decisions from the beginning of treatment on the basis of “personalized medicine.”

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Parasramka, Mansi, David A. Proia, and Richard Wayne Joseph. "Preclinical activity of the heat shock protein 90 inhibitor ganetespib in clear cell renal cell carcinoma." Journal of Clinical Oncology 32, no. 4_suppl (2014): 478. http://dx.doi.org/10.1200/jco.2014.32.4_suppl.478.

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478 Background: Resistance invariably develops in all patients with metastatic ccRCC treated with mTOR inhibitors. Previously we demonstrated that dual inhibition of Hsp90 and the mTOR pathway in lung cancer models leads to synergistic reductions in tumor growth. Herein, we tested the efficacy of ganetespib as a single agent and in combination with mTOR inhibition using in vitro and in vivoccRCC models. Methods: For the in vitro work we utilized the following seven ccRCC cell lines: Caki-1, Caki-2, A-498, A-704, 769-P, 786-O, ACHN. For the in vivo work we used A498 xenografts. In vitro, we determined the single agent EC50 of everolimus and ganetespib at 72 hours by assessing percent viability of A498 cells compared to vehicle using the MTS assay. We then performed combinations of ganetespib and everolimus at EC20, EC30, and EC50 in A498 cells. Translating these studies in vivo, we compared the combinatorial activity of ganetespib and temsirolimus to monotherapy in mice bearing A498 tumor xenografts. Results: As a single agent, all ccRCC cell lines tested were sensitive to ganetespib at nanomolar concentration (EC50 15 – 75 nm) and to everolimus at micromolar concentrations (EC50 4 – 54 mm). In vitro, the combination of ganetespib and everolimus also decreased cell viability in an additive fashion. In vivo, ganetespib and temsirolimus demonstrated comparable single agent activity at sub-MTD doses (T/C = 63 and 60, respectively). Combining ganetespib with temsirolimus improved tumor growth suppression by ~30% (T/C = 43). Conclusions: Given the broad in vitro sensitivity of ccRCC cell lines to single agent ganetespib as well as the in vivo activity of the combination of ganetespib and temsirolimus, we believe ganetespib warrants further study in ccRCC. Updated results will be presented at the conference including the in vivo activity of the combination of ganetespib and antivascular endothelial growth factor agents.

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Heo, J., D. H. Kirn, C. Breitbach, et al. "Evaluating antivascular effects and antitumoral activity in patients with hepatocellular carcinoma treated with JX-594, a targeted multimechanistic oncolytic poxvirus, prior to sorafenib therapy." Journal of Clinical Oncology 28, no. 15_suppl (2010): e14564-e14564. http://dx.doi.org/10.1200/jco.2010.28.15_suppl.e14564.

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Schmitt, Florian, Kate Donnelly, Julienne K. Muenzner, et al. "Effects of histidin-2-ylidene vs. imidazol-2-ylidene ligands on the anticancer and antivascular activity of complexes of ruthenium, iridium, platinum, and gold." Journal of Inorganic Biochemistry 163 (October 2016): 221–28. http://dx.doi.org/10.1016/j.jinorgbio.2016.07.021.

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Faatz, Henrik, Marie-Louise Farecki, Kai Rothaus, Matthias Gutfleisch, Daniel Pauleikhoff, and Albrecht Lommatzsch. "Changes in the OCT angiographic appearance of type 1 and type 2 CNV in exudative AMD during anti-VEGF treatment." BMJ Open Ophthalmology 4, no. 1 (2019): e000369. http://dx.doi.org/10.1136/bmjophth-2019-000369.

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ObjectiveOptical coherence tomography angiography (OCT-A) enables detailed visualisation of the vascular structure of choroidal neovascularisation (CNV). The aim of this study was to determine whether mathematically ascertained OCT-A vascular parameters of type 1 and type 2 CNV in exudative age-related macular degeneration (AMD) change during antivascular endothelial growth factor (anti-VEGF) treatment. The OCT-A vascular parameters were also compared with previously obtained activity parameters (fluid distribution on spectral domain OCT (SD-OCT)) to establish whether they could potentially be used as further ‘activity parameters’ for assessment of anti-VEGF treatment.Methods and AnalysisWe evaluated 27 eyes of 27 patients (mean follow-up 9.8 months) with type 1, type 2 or mixed CNV who had received anti-VEGF treatment (IVAN scheme). The parameters analysed were area (aCNV), total length of all vessels (tlCNV), overall number of vascular segments (nsCNV) and fractal dimension (FD) of the CNV. The changes in each of these parameters were correlated with the central foveal thickness (CFT).ResultsRegression and renewed perfusion of the CNV corresponded with the decrease or increase, respectively, of macular fluid distribution on SD-OCT. The increase and decrease of CFT during anti-VEGF treatment were highly significantly correlated with changes in FD (p<0.00001), aCNV (p<0.00001), tlCNV (p<0.00001) and nsCNV (p<0.00001).ConclusionOCT-A enables detailed analysis of AMD with regard to FD, aCNV, tlCNV and nsCNV. As the changes in these parameters correlate closely with changes on SD-OCT, they can be used as new activity parameters, alongside fluid distribution, for assessment of treatment effect and as parameters of stabilisation or the need for repeated treatment.

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Antonelli, Alessandro, Guido Bocci, Concettina La Motta, et al. "Novel Pyrazolopyrimidine Derivatives as Tyrosine Kinase Inhibitors with Antitumoral Activity in Vitro and in Vivo in Papillary Dedifferentiated Thyroid Cancer." Endocrinology 152, no. 1 (2011): 334. http://dx.doi.org/10.1210/endo.152.1.9995.

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Aim: We have studied the antitumoral activity of two new pyrazolo[3,4-d]pyrimidine compounds (CLM3 and CLM29) in primary papillary dedifferentiated thyroid cancer cells (DePTC cells). Methods: The antiproliferative effect was tested in DePTC cells obtained at reoperation from patients with recurrence of the tumor. The concentrations of CLM3 and CLM29 used in the in vitro experiments were 1, 10, 30, and 50 μm. Results: Proliferation assays in DePTC cells showed a significant reduction of proliferation by CLM3 and CLM29, which was by 12% with CLM3 (the most potent compound) 10 μm, 43% with CLM3 30 μm, and 60% with CLM3 50 μm. CLM3 and CLM29 increased the percentage of apoptotic cells in DePTC cells dose dependently (P &lt; 0.001) and inhibited migration (P &lt; 0.001). A DePTC cell line (AL) was injected sc in CD nu/nu mice, and tumor masses became detectable 10 d after xenotransplantation. CLM3 (40 mg/kg·die) significantly inhibited tumor growth and weight, and the therapeutic effect was significant starting on the 19th day after cell implantation (4 d after the beginning of treatment). The CLM3-treated group of animals did not show any appreciable toxicity. CLM3 and CLM29 increased thrombospondin-1 expression in the AL cell line. A significant reduction of microvessels and in the percentage of antivascular endothelial growth factor antibody immunoreactivity was observed in the CLM3 treated tumors, with a simultaneous increase of the percentage of necrosis. Conclusion: The antitumoral activity of two new pyrazolo[3,4-d]pyrimidine compounds (CLM3, CLM29) in vitro and CLM3 in vivo in DePTC has been shown, opening the way to a future clinical evaluation.

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Robbins, Cason B., Henry L. Feng, and Sharon Fekrat. "Quiescent Neovascular Age-Related Macular Degeneration After Endophthalmitis." Journal of VitreoRetinal Diseases 4, no. 4 (2020): 300–305. http://dx.doi.org/10.1177/2474126420914282.

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Purpose: This article describes eyes that achieved extended remission of neovascular age-related macular degeneration (NVAMD) following acute endophthalmitis. Methods: Adults who presented to the Duke Eye Center with acute endophthalmitis over a 9-year period and had at least 3 months of follow-up were identified. A retrospective review of medical records was performed to collect clinical data including demographic information, examination findings, etiology, treatment, and outcomes. Results: A total of 133 eyes of 130 patients with endophthalmitis were identified. Of these, 15 eyes of 14 patients (11.3%) were receiving intravitreal antivascular endothelial growth factor (anti-VEGF) injections for NVAMD. Six of these 15 eyes (40%) did not require an anti-VEGF injection after endophthalmitis for a mean of 36.2 months. Endophthalmitis was injection-related in 5 of 6 eyes (83%) and Baerveldt glaucoma drainage device–related in 1 of 6 eyes (17%). Two of the 6 (33%) had culture-proven infectious endophthalmitis, whereas 4 of 6 (67%) had culture-negative endophthalmitis. Five of 6 eyes have required no anti-VEGF therapy to date; the remaining eye restarted intravitreal aflibercept therapy 9.3 months after endophthalmitis. Conclusions: Acute endophthalmitis may be associated with reduced activity of choroidal neovascularization in a subset of eyes with NVAMD.

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Gasparini, Giampietro, Raffaele Longo, Massimo Fanelli, and Beverly A. Teicher. "Combination of Antiangiogenic Therapy With Other Anticancer Therapies: Results, Challenges, and Open Questions." Journal of Clinical Oncology 23, no. 6 (2005): 1295–311. http://dx.doi.org/10.1200/jco.2005.10.022.

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Angiogenesis is necessary for tumor growth. Drug discovery efforts have identified several potential therapeutic targets on endothelial cells and selective inhibitors capable of slowing tumor growth or producing tumor regression by blocking angiogenesis in in vivo tumor models. Certain antiangiogenic therapeutics increase the activity of cytotoxic anticancer treatments in preclinical models. More than 75 antiangiogenic compounds have entered clinical trials. Most of the early clinical testing was conducted in patients with advanced disease resistant to standard therapies. Several phase III trials have been undertaken to compare the efficacy of standard chemotherapy versus the same in combination with an experimental angiogenesis inhibitor. Preliminary results of the clinical studies suggest that single-agent antiangiogenic therapy is poorly active in advanced tumors. Although some of the results of combination trials are controversial, recent positive outcomes with an antivascular endothelial growth factor antibody combined with chemotherapy as front-line therapy of metastatic colorectal cancer have renewed enthusiasm for this therapeutic strategy. This article presents an overview of experimental and clinical studies of combined therapy with antiangiogenic agents and highlights the challenges related to the appropriate strategies for selection of the patients, study design, and choice of proper end points for preclinical and clinical studies using these agents.

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Ghinea, Nicolae. "Anti-Angiogenic Therapy: Albumin-Binding Proteins Could Mediate Mechanisms Underlying the Accumulation of Small Molecule Receptor Tyrosine Kinase Inhibitors in Normal Tissues with Potential Harmful Effects on Health." Diseases 9, no. 2 (2021): 28. http://dx.doi.org/10.3390/diseases9020028.

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Anti-angiogenics currently used in cancer therapy target angiogenesis by two major mechanisms: (i) neutralizing angiogenic factors or their receptors by using macromolecule anti-angiogenic drugs (e.g., therapeutic antibodies), and (ii) blocking intracellularly the activity of receptor tyrosine kinases with small molecule (Mr < 1 kDa) inhibitors. Anti-angiogenics halt the growth and spread of cancer, and significantly prolong the disease-free survival of the patients. However, resistance to treatment, insufficient efficacy, and toxicity limit the success of this antivascular therapy. Published evidence suggests that four albumin-binding proteins (ABPs) (gp18, gp30, gp60/albondin, and secreted protein acidic and cysteine-rich (SPARC)) could be responsible for the accumulation of small molecule receptor tyrosine kinase inhibitors (RTKIs) in normal organs and tissues and therefore responsible for the side effects and toxicity associated with this type of cancer therapy. Drawing attention to these studies, this review discusses the possible negative role of albumin as a drug carrier and the rationale for a new strategy for cancer therapy based on follicle-stimulating hormone receptor (FSHR) expressed on the luminal endothelial cell surface of peritumoral blood vessels associated with the major human cancers. This review should be relevant to the audience and the field of cancer therapeutics and angiogenesis/microvascular modulation-based interventions.

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Baselga, José, and Carlos L. Arteaga. "Critical Update and Emerging Trends in Epidermal Growth Factor Receptor Targeting in Cancer." Journal of Clinical Oncology 23, no. 11 (2005): 2445–59. http://dx.doi.org/10.1200/jco.2005.11.890.

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The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB receptor family that is abnormally activated in many epithelial tumors. The aberrant activation of the EGFR leads to enhanced proliferation and other tumor-promoting activities, which provide a strong rationale to target this receptor family. There are two classes of anti-EGFR agents: monoclonal antibodies (MAbs) directed at the extracellular domain of the receptor and small molecule, adenosine triphosphate–competitive inhibitors of the receptor's tyrosine kinase. Anti-EGFR MAbs have shown antitumor activity in advanced colorectal carcinoma, squamous cell carcinomas of the head and neck, non–small-cell lung cancer (NSCLC) and renal cell carcinomas. The tyrosine kinase inhibitors (TKIs) have a partially different activity profile. They are active against NSCLC, and a specific EGFR inhibitor has shown improvement in survival. Recently, mutations and amplifications of the EGFR gene have been identified in NSCLC and predict for enhanced sensitivity to anti-EGFR TKIs. In addition to specific anti-EGFR TKIs, there are broader acting inhibitors such as dual EGFR HER-2 inhibitors and combined anti-pan-ErbB and antivascular endothelial growth factor receptor inhibitors. Current research efforts are directed at selecting the optimal dose and schedule and identifying predictive factors of response and resistance beyond EGFR gene mutations and/or amplifications. Finally, there is a need for improved strategies to integrate anti-EGFR agents with conventional therapies and to explore combinations with other molecular targeted approaches including other antireceptor therapies, receptor-downstream signaling transduction inhibitors, and targeted approaches interfering with other essential drivers of cancer, such as angiogenesis.

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Ty, Nancy, Grégory Dupeyre, Guy G. Chabot, et al. "Structure–activity relationships of indole compounds derived from combretastatin A4: Synthesis and biological screening of 5-phenylpyrrolo[3,4-a]carbazole-1,3-diones as potential antivascular agents." European Journal of Medicinal Chemistry 45, no. 9 (2010): 3726–39. http://dx.doi.org/10.1016/j.ejmech.2010.05.022.

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Gallo-Stampino, C., G. Rizzardi, S. Toma, et al. "Safety and anticancer activity of low dose regimen of NGRhTNF, a new vascular targeting agent, in solid advanced malignancies (NGR002 phase I trial)." Journal of Clinical Oncology 25, no. 18_suppl (2007): 3540. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.3540.

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3540 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding angiogenic vessels in solid tumours where NGRhTNF specific binding relies on dynamic interactions with TNF-receptors and aminopeptidase N (CD13). NGRhTNF combines activity on tumour vascular permeability and direct anticancer activity. Consistently, mouse preclinical data indicate significant synergy between low dose NGRhTNF and cytotoxic agents. Methods: 4 dose levels of NGRhTNF (0.2 up to 1.6 mcg/sqm) have been administered q 3 w in 16 patients. Main end-points included safety, anticancer activity and pharmacokinetic.Measurement of circulating tumor and endothelial cells (CTC and CEC), sTNFRI and s TNFRII, along with plasma cyto-chemokine profile have been performed. Results: 16 patients were enrolled (6F/10M);median age 60,range 43–73). Toxicity was limited to constitutional symptoms, and chills were the most frequent event (40%). Over a median follow-up of 15 weeks, stable disease was achieved in 44% of patients, with long lasting disease control in 2 cases (27 and 75 weeks, with establishment of indication to radical surgery after 75 weeks, presently tumor free after removal of the residual tumor mass). In these 2 patients, VEGF, MMP-9, CA125, significantly decreased over time. DCE-MRI indicates that NGRhTNF increases vascular permeability after first drug exposure, particularly at the dose of 0.4 mcg/sqm, while following multiple infusions it exerts an antivascular effect, as demonstrated by the decrease of Ktrans values. Moreover NGRhTNF is able to elicit inflammatory and immune responses over time, as indicated by the modulation of expression of multiple cyto-chemokines. Finally, changes in CTC levels over time consistently matched the clinical outcome. Conclusions: Low dose NGRhTNF has an optimal safety profile along with anticancer activity acting on tumour vasculature and inducing relevant biological effects, thus rendering the agent suitable for a development both as monotherapy and in combination with chemotherapeutics. The phase II program is due to start in early 2007. [Table: see text]

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Moiseeva, E. V., N. R. Kuznetsova, E. V. Svirshchevskaya, et al. "Liposome formulations of combretastatin a4 and 4-arylcoumarin analog prodrugs: antitumor effect in the mouse model of breast cancer." Biomeditsinskaya Khimiya 58, no. 3 (2012): 326–38. http://dx.doi.org/10.18097/pbmc20125803326.

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The antimitotic agent combretastatin A4 (СА-4) has been suggested as an antivascular agent for anticancer therapy relatively recently. To reduce systemic toxicity by means of administration in liposome formulations, in this study new lipophilic prodrugs, oleic derivatives of СА-4 and its 4-arylcoumarin analog (СА4-Ole and ArC-Ole, respectively), have been synthesized: Liposomes of 100 nm mean diameter prepared on the basis of egg phosphatidylcholine and phosphatidylinositol from bakers yeast have been shown to include completely up to 10 mol. % of СА4-Ole, or 7 mol. % of ArC-Ole. Also, prodrug bearing liposomes decorated with tetrasaccharide selectin ligand Sialyl Lewis X (SiaLeX) have been constructed to achieve targeting to endothelium under neovascularization. The antitumor activity in vivo was studied in the model of slowly growing mouse breast cancer. Under the used dose (22 mg/kg) as well as the regimen of treatment (four injections, one per a week, starting from the appearance of palpable tumors) cytostatic CA-4 did not reveal any anticancer effect, and oppositely even stimulated tumor growth. Liposome formulations of CA4-Ole did not show such stimulation. However, to achieve pronounced antitumor effect, number of injections of liposomes should be apparently elevated. New antimitotic agent ArC revealed cytotoxic activity of only one tenth value obtained for CA-4 in vitro in the culture of human breast carcinoma cells. Nevertheless, in vivo in the mouse model of breast cancer this compound showed antitumor effect under double СА-4 equivalent dose. The results demonstrate availability of SiaLeX-liposomes loaded with ArC-Ole: this preparation began to inhibit tumor growth already after the second injection. It is necessary further to choose doses and regimens of administration both for ArC and liposome formulations bearing ArC-Ole.

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Abdelmotaal, Hazem, Walid Ibrahim, Mohamed Sharaf, and Khaled Abdelazeem. "Causes and Clinical Impact of Loss to Follow-Up in Patients with Proliferative Diabetic Retinopathy." Journal of Ophthalmology 2020 (February 8, 2020): 1–8. http://dx.doi.org/10.1155/2020/7691724.

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Purpose. This study determined the clinical impact and causes of loss to follow-up (LTFU) from the patients’ perspective in individuals with proliferative diabetic retinopathy (PDR) who received panretinal photocoagulation (PRP) and/or intravitreal injections (IVIs) of antivascular endothelial growth factor (VEGF). Methods. This prospective cohort study included 467 patients with PDR who received PRP and/or IVIs of anti-VEGF between May 2013 and June 2018. LTFU was defined as missing any follow-up visit for any interval exceeding 6 months, provided that patients eventually resumed care. Main outcome measures include rates and causes of LTFU. Results. A total of 391 patients (83.7%) were followed up, and 76 patients (16.3%) were LTFU over the study period. Rates of LTFU decreased with age (P=0.005). Questionnaire analysis conducted for patients’ LTFU showed a significant positive correlation between best corrected visual activity (BCVA) loss and patient’s lack of trust and satisfaction with treatment (rs = 0.458, P<0.001). There was also a significant positive correlation between treatment unaffordability and number of IVIs of anti-VEGF (rs = 0.55, P<0.001) and lack of social support and age (rs = 0.39, P<0.001). Conclusions. LTFU threatens vision in PDR patients receiving PRP and/or IVIs of anti-VEGF. Possibly, patient-specific LTFU causes should be addressed before treatment in order to minimize the risk of LTFU. The clinical trial is registered with NCT04018326 (trial registration: ClinicalTrials.gov Identifier: NCT04018326, 10th of July 2019 “Retrospectively registered”).

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Chhablani, Jay, Remya Mareen Paulose, Andres F. Lasave, et al. "Intravitreal bevacizumab monotherapy in myopic choroidal neovascularisation: 5-year outcomes for the PAN-American Collaborative Retina Study Group." British Journal of Ophthalmology 102, no. 4 (2017): 455–59. http://dx.doi.org/10.1136/bjophthalmol-2017-310411.

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PurposeTo report the long-term anatomical and visual outcomes of intravitreal bevacizumab (IVB) monotherapy in naive choroidal neovascularisation (CNV) caused by myopia.MethodsRetrospective analysis of naive CNV secondary to myopia that underwent antivascular endothelial growth factor monotherapy was performed. Collected data included demographic details, clinical examination details including visual acuity at presentation and follow-up with imaging and treatment details. Main outcome measures were resolution of CNV activity at the last visit. Secondary outcomes included change in visual acuity, number of injections and adverse events.ResultsThirty-three eyes of 31 subjects with a mean age of 51.48±16.4 years were included. The mean follow-up was 66.47 months. 27 eyes had type 2 CNV and the rest seven eyes had type 1 CNV. The mean number of IVB injections per eye was 4.9. Mean visual acuity at baseline reduced from 0.65±0.33 logMAR units (Snellen equivalent=20/89) to 0.73±0.50 logMAR units (20/107) at final follow-up (p=0.003). The mean central macular thickness decreased from 309.31±86 µm at baseline to 267.5±70.89 µm at the last visit (p=0.03). However, visual acuity was maintained (±1 line of baseline) in 13 eyes (39.4%), ≥2 line improvement in nine (27.3%) eyes and more than two lines worsening in 11 eyes (33.3%). Foveal atrophy was observed at baseline and last visit in 6 (12.5%) and 14 (29.1%), respectively (p=0.007). No systemic adverse events were observed.ConclusionIVB monotherapy is safe and effective for long-term treatment of CNV secondary to myopia in real life.

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Zhu, Andrew X., Dushyant V. Sahani, Dan G. Duda, et al. "Efficacy, Safety, and Potential Biomarkers of Sunitinib Monotherapy in Advanced Hepatocellular Carcinoma: A Phase II Study." Journal of Clinical Oncology 27, no. 18 (2009): 3027–35. http://dx.doi.org/10.1200/jco.2008.20.9908.

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PurposeTo assess the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) and explore biomarkers for sunitinib response.Patients and MethodsWe conducted a multidisciplinary phase II study of sunitinib, an antivascular endothelial growth factor receptor tyrosine kinase inhibitor, in advanced HCC. Patients received sunitinib 37.5 mg/d for 4 weeks followed by 2 weeks of rest per cycle. The primary end point was progression-free survival (PFS). We used functional magnetic resonance imaging to evaluate vascular changes in HCC after sunitinib treatment. Circulating molecular and cellular biomarkers were evaluated before and at six time points after sunitinib treatment.ResultsThirty-four patients were enrolled. The objective response rate was 2.9%, and 50% of patients had stable disease. Median PFS was 3.9 months (95% CI, 2.6 to 6.9 months), and overall survival was 9.8 months (95% CI, 7.4 months to not available). Grade 3 or 4 toxicities included leukopenia/neutropenia, thrombocytopenia, elevation of aminotransferases, and fatigue. Sunitinib rapidly decreased vessel leakiness, and this effect was more pronounced in patients with delayed progression. When evaluated early (at baseline and day 14) as well as over three cycles of treatment, higher levels of inflammatory molecules (eg, interleukin-6, stromal-derived factor 1α, soluble c-KIT) and circulating progenitor cells were associated with a poor outcome.ConclusionSunitinib shows evidence of modest antitumor activity in advanced HCC with manageable adverse effects. Rapid changes in tumor vascular permeability and circulating inflammatory biomarkers are potential determinants of response and resistance to sunitinib in HCC. Our study suggests that control of inflammation might be critical for improving treatment outcome in advanced HCC.

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Bulotta, Alessandra, Vanesa Gregorc, Gilda Rossoni, et al. "Relationships of peripheral blood lymphocyte counts (PBLC) with antitumor activity of NGR-hTNF given in combination with chemotherapy (CT)." Journal of Clinical Oncology 31, no. 15_suppl (2013): 3038. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3038.

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3038 Background: Antitumor effects of NGR-hTNF (N), a tumor-targeted antivascular agent, are driven at low dose by an early vessel stabilization that greatly enhances both intratumoral CT uptake and T-cell infiltration. Synergism with CT was shown in immunocompetent mice, but not in nude mice lacking functional T cells. Methods: By an individual patient pooled analysis of 396 patients (pts) from 7 ph II trials in 6 tumor types, we estimated the effects of baseline PBLC on the antitumor activity of N (with or without CT) and CT alone. Low dose N (0.8 μg/m2) was given in combination with CT in 171 pts. Control groups of 140 and 85 pts receiving N and CT alone, respectively, were also analyzed. CT was doxorubicin or a platinum-based regimen. In all trials, response to therapy was assessed every 6 weeks by RECIST. Endpoints of interest were response rate (RR, complete plus partial response), disease control rate (DCR, RR plus stable disease), duration of response (DOR) and progression-free survival (PFS). In logistic and Cox regression analyses, PBLC data were dichotomized in high or low levels by the median cutpoint (1.5/mL; 95% CI, 1.4-1.6). Multivariate models included age, sex, PS and tumor type as covariates. Results: In both N-alone and CT-alone groups, there was no statistically significant difference in treatment effect according to baseline PBLC. Conversely, high PBLC were related to better treatment outcome in the N plus CT group, compared to low PBLC. In this N plus CT group, high PBLC (vs low) were associated with higher RR (OR=2.8; 95% CI, 1.2-6.3; p=.01) and DCR (OR=2.6; 1.3-4.9; p=.004), and with longer DOR (HR=0.39; 0.16-0.96; p=.04) and PFS (HR=0.60; 0.43-0.85; p=.004). For high vs low PBLC, RR was 29% vs 14%, DCR 76% vs 57%, median DOR 8.2 vs 6.3 months, and median PFS 5.0 vs 3.0 months, respectively. On multivariate analyses, high PBLC remained an independent predictor of increased RR (OR=2.7; p=.01) and DCR (OR=2.6; p=.005), and improved DOR (HR=0.36; p=.04) and PFS (HR=0.60; p=.005). Conclusions: Consistently with preclinical data, these results highlight the potential value of PBLC in predicting tumor response to NGR-hTNF in combination with CT, which merits further clinical validation Clinical trial information: NCT00994097-NCT00484432-NCT00484276-NCT00484211-NCT00483509-NCT00483080-NCT01358071.

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Segaoula, Zacharie, Julien Leclercq, Valérie Verones, et al. "Synthesis and Biological Evaluation of N-[2-(4-Hydroxyphenylamino)-pyridin-3-yl]-4-methoxy-benzenesulfonamide (ABT-751) Tricyclic Analogues as Antimitotic and Antivascular Agents with Potent in Vivo Antitumor Activity." Journal of Medicinal Chemistry 59, no. 18 (2016): 8422–40. http://dx.doi.org/10.1021/acs.jmedchem.6b00847.

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Anderson, Pete M., Jacob Scott, Shireen Parsai, et al. "223-Radium for metastatic osteosarcoma: combination therapy with other agents and external beam radiotherapy." ESMO Open 5, no. 2 (2020): e000635. http://dx.doi.org/10.1136/esmoopen-2019-000635.

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BackgroundBone-seeking radiopharmaceuticals can deposit radiation selectively to some osteosarcoma tumours because of the bone-forming nature of this cancer.ObjectivesThis is the first report of using 223-radium, an alpha-emitting calcium analogue with a high therapeutic index, in combination therapy with other agents in 15 patients with metastatic osteoblastic osteosarcoma.MethodsCandidates for alpha-radiotherapy if 99mTc-MDP bone scan had avid bone-forming lesions and no therapy of higher priority (eg, definitive surgery). Monthly 223-radium infusions (1.49 μCi/kg or 55.13 kBq/kg) were given.ResultsThe median infusion number was three and the average time to progression was 4.3 months for this cohort receiving 223-radium+other agents. Agents provided during 223-radium included (1) drugs to reduce skeletal complications: monthly denosumab (n=13) or zolendronate (n=1); (2) agents with antivascular endothelial growth factor activity, pazopanib (n=8) or sorafenib (n=1), (3) alkylating agents: oral cyclophosphamide (n=1) or ifosfamide, given as a 14-day continuous infusion (n=1, two cycles), (4) high-dose methotrexate (n=1), pegylated liposomal doxorubicin (n=1); and (5) two other combinations: nivolumab and everolimus (n=1) and rapamycin and auranofin (n=1). Radiation therapy, including stereotactic body radiotherapy (SBRT), was also given to 11 patients concurrently with 223-radium (n=2), after 223-radium completion (n=3), or both concurrently and then sequentially for other sites (n=6). After 223-radium infusions, patients without RT had a median overall survival of 4.3 months compared with those with SBRT and/or RT, who had a median overall survival of 13.5 months.Conclusion Although only 1/15 of patients with osteoblastic osteosarcoma still remain alive after 223-radium, overall survival

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de Groot, John F., Kathleen R. Lamborn, Susan M. Chang, et al. "Phase II Study of Aflibercept in Recurrent Malignant Glioma: A North American Brain Tumor Consortium Study." Journal of Clinical Oncology 29, no. 19 (2011): 2689–95. http://dx.doi.org/10.1200/jco.2010.34.1636.

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Purpose Antivascular endothelial growth factor (anti-VEGF) therapy is a promising treatment approach for patients with recurrent glioblastoma. This single-arm phase II study evaluated the efficacy of aflibercept (VEGF Trap), a recombinantly produced fusion protein that scavenges both VEGF and placental growth factor in patients with recurrent malignant glioma. Patients and Methods Forty-two patients with glioblastoma and 16 patients with anaplastic glioma who had received concurrent radiation and temozolomide and adjuvant temozolomide were enrolled at first relapse. Aflibercept 4 mg/kg was administered intravenously on day 1 of every 2-week cycle. Results The 6-month progression-free survival rate was 7.7% for the glioblastoma cohort and 25% for patients with anaplastic glioma. Overall radiographic response rate was 24% (18% for glioblastoma and 44% for anaplastic glioma). The median progression-free survival was 24 weeks for patients with anaplastic glioma (95% CI, 5 to 31 weeks) and 12 weeks for patients with glioblastoma (95% CI, 8 to 16 weeks). A total of 14 patients (25%) were removed from the study for toxicity, on average less than 2 months from treatment initiation. The main treatment-related National Cancer Institute Common Terminology Criteria grades 3 and 4 adverse events (38 total) included fatigue, hypertension, and lymphopenia. Two grade 4 CNS ischemias and one grade 4 systemic hemorrhage were reported. Aflibercept rapidly decreases permeability on dynamic contrast enhanced magnetic resonance imaging, and molecular analysis of baseline tumor tissue identified tumor-associated markers of response and resistance. Conclusion Aflibercept monotherapy has moderate toxicity and minimal evidence of single-agent activity in unselected patients with recurrent malignant glioma.

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Choo, Su Pin, Quan Sing Ng, Wallace Jian Jun Chen, et al. "A phase I/II study of AZD6244 in combination with sorafenib in advanced hepatocellular carcinoma." Journal of Clinical Oncology 30, no. 15_suppl (2012): 4100. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4100.

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4100^ Background: Preclinical studies have shown that pharmacological inhibition of the MEK/ERK pathway by AZD6244 enhanced the anti-tumor effect of sorafenib in both orthotopic and ectopic models of HCC. We conducted this study to determine tolerability, pharmacokinetics, and pharmacodynamics of AZD6244 when combined with sorafenib in advanced HCC. Methods: Patients with biopsy-proven unresectable BCLC B/C hepatocellular carcinoma were recruited. Only those with Childs-Pugh A or B (7) liver cirrhosis and without prior systemic therapy were included. Sorafenib at 400mg bd was given 1 week before initiation of AZD6244 which was escalated in subsequent cohorts from 75mg om based on 3+3 design. PK and PD studies and QOL assessments were performed. DCE-MRI imaging was performed to assess tumor vascularity in response to treatment. Results: Fourteen patients were recruited (including 2 replaced). 11 had evaluable disease. Characteristics: all male, all Chinese, 12 were BCLC C stage. Two DLTs were seen out of 6 patients at dose level 1 (AZD6244 at 50mg bd) which were grade 3 fatigue and grade 3 abdominal pain with elevated transaminases. When an additional dose level 1A was added (ADZ6244 at 100mg om), 2 out of 3 patients had DLTs of grade 3 raised aspartate transaminase and grade 3 diarrhea. Thus, the MTD was determined to be AZD6244 at 75mg om when combined with sorafenib 400mg bd. Common toxicities were diarrhea (83%), rash (58%), fatigue (50%), hypertension (42%), anorexia/vomiting/thrombocytopenia (25%). Two patients had reversible LVEF dysfunction and there were no eye toxicities. PK of AZD6244 showed oral clearance of 11.2 + 6.8 L/h and terminal half-life of 6.0 +2.0 h.Objective responses were 3 PR, 6 SD and 2 PD.DCE-MRI measurements demonstrated significant reductions in permeability surface area product (PS, ml/100ml/min) and fractional intravascular blood volume (v1, ml/100ml) seven days after starting sorafenib. No additional antivascular activity was observed when AZD6244 was added to sorafenib. Conclusions: The recommended phase II dose for AZD6244 is 75mg om when combined with sorafenib 400mg bd for advanced HCC patients. This combination is feasible, shows activity and warrants further investigation.

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Cetnar, J. P., M. A. Rosen, D. J. Vaughn, et al. "Phase II study of sorafenib and docetaxel in men with metastatic castration resistant prostate cancer (mCRPC)." Journal of Clinical Oncology 27, no. 15_suppl (2009): e16055-e16055. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e16055.

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e16055 Background: Previous trials of the antiangiogenic kinase inhibitor sorafenib in mCRPC have reported PSA elevation accompanying radiographic response, and evidence that sorafenib may potentiate docetaxel (dxl) myelosuppression. To assess the safety, antivascular effects, and activity of sorafenib and dxl in mCRPC, a phase II trial with dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) was conducted. Methods: Eligible men had mCRPC and no prior chemotherapy. Treatment consisted of dxl 75 mg/m2(day 1) and sorafenib (days 2–19) of a 21 day cycle. Patients received 7 days of sorafenib before cycle 1. Six patients received sorafenib 200mg BID and remaining patients received sorafenib 400 mg BID if <4/6 patients had grade 4 neutropenia. DCE-MRI was performed at baseline, days 8 and 28. The primary endpoint was PSA response rate (>50% PSA decline). Secondary endpoints were vascular response rate (>20% decline in area under the gadolinium curve [AUC60]), toxicity rates, and time to progression (TTP). PSA-only progression (2 consecutive PSA rises) was confirmed by a third PSA rise or radiographic progression after a 21-day drug holiday. Sample size of 69 patients in 1 stage was designed to maximize detection of significant correlations between DCE-MRI and clinical outcomes. Results: Six of 13 enrolled patients (46%) had a PSA response. A median PSA increase of 37% was observed in 73% of patients after 1 week of sorafenib. The median TTP was 8+ months. Two patients had complete disappearance of bone lesions. Grade 3 adverse events were neutropenia (77%), hand-foot syndrome (23%), anemia (15%), nausea (8%), and rash (8%). A median AUC60 decline of 40% from baseline was observed after 7 days of sorafenib, and only a 6% decline on day 28 during a scheduled sorafenib holiday. Conclusions: Sorafenib 400 mg po bid and dxl 75 mg/m2 are tolerable in men with mCRPC. Elevated PSA values in men treated with sorafenib and dxl does not always reflect disease progression. DCE-MRI can capture sorafenib's impairment of tumor vasculature in osseous metastases and rebound angiogenesis during drug holidays. Bone responses and TTP data provide evidence of encouraging activity. No significant financial relationships to disclose.

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Zucali, Paolo A., Matteo Simonelli, Fabio De Vincenzo, Armando Santoro, Antonio Lambiase, and Claudio Bordignon. "Changes in shedding of soluble tumor necrosis factor receptors (sR1/R2) and in dynamic MRI as early predictors of outcome with NGR-hTNF." Journal of Clinical Oncology 31, no. 15_suppl (2013): e22145-e22145. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e22145.

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e22145 Background: Dose-response curve of NGR-hTNF, a selective antivascular agent, is typically biphasic with activity shown either at low dose (LD) or high dose (HD). Receptor shedding may block drug activity. Vascular effects at LD are characterized by early vessel stabilization and late vessel damage, while at HD by rapid vessel disruption. Methods: 60 pts (median age: 61; M/F: 44/16; PS 0/≥1: 25/35; median prior lines: 3) received in 2 ph I trials NGR-hTNF at LD (0.2-1.6 µg/m2; n=14) or HD (60-325 µg/m2; n=46) every 3 weeks. We tested the impact of early changes (post 1st dose) in baseline-normalized plasma receptor levels (n=60) and in DCE-MRI-assessed Ktrans (n=49) on treatment effect, including disease control (DC, rate of pts progression free at 6 weeks by RECIST criteria) and progression free survival (PFS). Results: Baseline receptor levels were not related to outcome. Post-dosing levels of sR1 (median, 4.6 ng/mL; interquartile range, 2.8-5.7) and sR2 (8.6; 4.5-10.7) increased with dose (p<.0001 for both), with median values of sR1 (0.3) and sR2 (0.5) at LD being significantly lower than those of sR1 (4.9) and sR2 (9.6) at HD (p<.0001 for both). Using as cutoff the 1st quartile, low sR1 levels (≤2.8 ng/mL) correlated with improved DC (OR=4.9; p=0.01) and PFS (HR=0.30; p=.003). In low vs high groups, median DC duration was 7.4 vs 2.9 months and 6-month PFS was 29% vs 0%, respectively. By adjusting for baseline covariates (age, sex, PS and prior lines), low sR1 levels remained independently associated with better DC (p=.02) and PFS (p=.008). Similar effects were noted for sR2. Levels of sR1 (r=-0.35; p=.01) and sR2 (r=-0.27; p=.07) inversely correlated with early fractional decreases in Ktrans, which resulted in median values unchanged after LD (4%; p=.73) and reduced after HD (-32%; p=.009). However, Ktrans significantly declined over time after both LD (-24%; p=.04) and HD (-44%; p=.001). Early changes in Ktrans did not relate with DC as defined by RECIST, but smaller decreases in Ktrans were associated with longer PFS (HR=0.56; p=.04). Conclusions: NGR-hTNF at LD is associated with better outcome than at HD likely due to early effects that involve minimal receptor shedding and vessel stabilization. Clinical trial information: NCT00878111-NCT00914628.

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