Comparison of effects of anti-angiogenic agents in the zebrafish efficacy&amp;ndash;toxicity model for translational anti-angiogenic drug discovery

Chimote, Geetanjali; Sreenivasan, Jayasree; Pawar, Nilambari; Subramanian, Jyothi; Sivaramakrishnan, H.; Sharma, Somesh

doi:10.2147/dddt.s55621

Cited by 61 publications

(53 citation statements)

References 58 publications

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“…Interestingly, the hierarchy of drug effectiveness we see (Fig. 3F) matches well with data from zebrafish studies51. We have also noted enhanced angiogenic sprouting in the presence of tumor cells, as well as enhanced vascular leakage (unpublished observations).…”

Section: Discussionsupporting

confidence: 84%

3D microtumors in vitro supported by perfused vascular networks

Sobrino

Phan

Datta

et al. 2016

Sci Rep

328

349

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There is a growing interest in developing microphysiological systems that can be used to model both normal and pathological human organs in vitro. This “organs-on-chips” approach aims to capture key structural and physiological characteristics of the target tissue. Here we describe in vitro vascularized microtumors (VMTs). This “tumor-on-a-chip” platform incorporates human tumor and stromal cells that grow in a 3D extracellular matrix and that depend for survival on nutrient delivery through living, perfused microvessels. Both colorectal and breast cancer cells grow vigorously in the platform and respond to standard-of-care therapies, showing reduced growth and/or regression. Vascular-targeting agents with different mechanisms of action can also be distinguished, and we find that drugs targeting only VEGFRs (Apatinib and Vandetanib) are not effective, whereas drugs that target VEGFRs, PDGFR and Tie2 (Linifanib and Cabozantinib) do regress the vasculature. Tumors in the VMT show strong metabolic heterogeneity when imaged using NADH Fluorescent Lifetime Imaging Microscopy and, compared to their surrounding stroma, many show a higher free/bound NADH ratio consistent with their known preference for aerobic glycolysis. The VMT platform provides a unique model for studying vascularized solid tumors in vitro.

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Section: Discussionsupporting

confidence: 84%

3D microtumors in vitro supported by perfused vascular networks

Sobrino

Phan

Datta

et al. 2016

Sci Rep

328

349

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“…Anterior mesenteric artery (AMA) angiogenesis was inhibited with 0.2 M axitinib (PZ0193, Sigma) in CW with 0.002% DMSO as similarly performed by Chimote et al (8) Dechorinated embryos were axitinib treated from 24 to 60 hpf and then maintained in CW to 76 hpf. The vasculature was normal in DMSO-treated controls.…”

Section: Methodsmentioning

confidence: 99%

“…Indeed, embryonic ablation of several RAS components in rodents results in renal developmental pathologies indicating the requirement of the RAS during renal development (23,55,66,71). Axitinib, a highly selective inhibitor of VEGF receptors 1-3, inhibits angiogenesis in both mammals (26) and zebrafish (8,81). Inhibition of the formation of the AMA by angiogenesis allowed detection of ren-RFP before its formation, which otherwise forms too early for detectable transgene expression.…”

Section: Angiogenesis and Renin-expressing Cellsmentioning

confidence: 99%

Renin expression in developing zebrafish is associated with angiogenesis and requires the Notch pathway and endothelium

Rider

Mullins

Verdon

et al. 2015

American Journal of Physiology-Renal Physiology

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Rider SA, Mullins LJ, Verdon RF, MacRae CA, Mullins JJ. Renin expression in developing zebrafish is associated with angiogenesis and requires the Notch pathway and endothelium. Am J Physiol Renal Physiol 309: F531-F539, 2015. First published July 22, 2015 doi:10.1152/ajprenal.00247.2015.-Although renin is a critical regulatory enzyme of the cardiovascular system, its roles in organogenesis and the establishment of cardiovascular homeostasis remain unclear. Mammalian renin-expressing cells are widespread in embryonic kidneys but are highly restricted, specialized endocrine cells in adults. With a functional pronephros, embryonic zebrafish are ideal for delineating the developmental functions of renin-expressing cells and the mechanisms governing renin transcription. Larval zebrafish renin expression originates in the mural cells of the juxtaglomerular anterior mesenteric artery and subsequently at extrarenal sites. The role of renin was determined by assessing responses to renin-angiotensin system blockade, salinity variation, and renal perfusion ablation. Renin expression did not respond to renal flow ablation but was modulated by inhibition of angiotensin-converting enzyme and altered salinity. Our data in larval fish are consistent with conservation of renin's physiological functions. Using transgenic renin reporter fish, with mindbomb and cloche mutants, we show that Notch signaling and the endothelium are essential for developmental renin expression. After inhibition of angiogenesis, renin-expressing cells precede angiogenic sprouts. Arising from separate lineages, but relying on mutual interplay with endothelial cells, renin-expressing cells are among the earliest mural cells observed in larval fish, performing both endocrine and paracrine functions. renin; zebrafish; notch; endothelium; angiogenesis RENIN is the rate-limiting enzyme of the renin-angiotensin system (RAS). Mammalian ANG II, the effector of the RAS, is principally involved in blood pressure homeostasis by regulation of vasomotor tone and Na ϩ retention. ANG II also regulates cell proliferation and angiogenesis (12,22). Pathological activation of the RAS is associated with cardiovascular diseases, including hypertension and heart failure, and is consequently a major target of therapeutic agents (11).Renin and its cognate cells are required for normal renal development (2), including angiogenesis of the renal vascular tree (59). In mice, ablation of the renin gene or renin-expressing cells leads to renal developmental abnormalities (55,71,79). The vasculature of mammalian embryonic kidneys have a transient but extensive coverage of mural renin-expressing cells (17,31,32,47,63); however, their function is unclear. Adult renin-expressing cells are restricted to the juxtaglomerular apparatus and play a vital role in ion homeostasis by secreting activated renin enzyme via cytoplasmic granules (17,31,36,63). Upon physiological challenge by RAS inhibition or low Na ϩ , prearteriolar vascular smooth muscle cells (VSMC) reestablish their embryonic re...

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“…For instance, sunitinib was claimed to be a more potent antiangiogenic compound than sorafenib based on the zebrafish model (see online suppl. Table 4) [22], but does not target as efficiently the antiproliferative pathway as sorafenib and, differently from the expectations, the final clinical effect at the tested dosage was a more toxic drug than sorafenib, with a trend to poorer, rather than better survival (Fig. 3) [15].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Systemic Therapies for Advanced Hepatocellular Carcinoma: A Network Meta-Analysis of Phase III Trials

et al. 2017

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Aim/Background: After the introduction of sorafenib in the treatment of advanced hepatocellular carcinoma (HCC), different studies tried to evaluate whether other systemic therapies can improve survival. To provide a comprehensive indirect treatment comparison of efficacy and safety of novel drugs, a network meta-analysis (NMA) of phase III randomized controlled trials was performed. Methods: After pertinent literature search up to November 1, 2016, 6 studies were eligible for the analysis including 4,812 individual patients with advanced HCC: 2,454 received sorafenib, 577 received brivanib, 530 received sunitinib, 514 received linifanib, 358 received sorafenib + erlotinib and 379 received placebo. Frequentist NMA was used to compare treatments within a single analytical framework. Results: NMA showed that sorafenib alone, regardless of combination with erlotinib, and linifanib provide a significant survival advantage over placebo (p < 0.05) but without any significant difference between each other. Conversely, all regimens significantly ameliorate progression-free survival versus placebo (p < 0.05). The rank order of efficacy was: sorafenib ± erlotinib, linifanib, brivanib, sunitinib, and placebo. Sorafenib ± erlotinib was the regimen with the fewest number of adverse events that required discontinuation of treatment, whereas linifanib and brivanib resulted in the most adverse events. The risk-benefit summary identified one cluster of therapies with a similar balance between efficacy and safety which included sorafenib alone or in combination with erlotinib, having, at the same time, the highest efficacy and safety. Conclusions: Sorafenib remains the best systemic treatment for advanced HCC; linifanib also resulted in survival advantages over placebo but with a lower safety profile.

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Comparison of effects of anti-angiogenic agents in the zebrafish efficacy–toxicity model for translational anti-angiogenic drug discovery

Cited by 61 publications

References 58 publications

3D microtumors in vitro supported by perfused vascular networks

3D microtumors in vitro supported by perfused vascular networks

Renin expression in developing zebrafish is associated with angiogenesis and requires the Notch pathway and endothelium

Efficacy and Safety of Systemic Therapies for Advanced Hepatocellular Carcinoma: A Network Meta-Analysis of Phase III Trials

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