Development of a Novel In Vitro Human Tissue-Based Angiogenesis Assay to Evaluate the Effect of Antiangiogenic Drugs

Woltering, Eugene A.; Lewis, James M.; Maxwell, Pamela; Frey, Daniel; Wang, Yi Zarn; Rothermel, J. D.; Anthony, Catherine T.; Balster, Douglas A.; O’Leary, J. Patrick; Harrison, Lynn H.

doi:10.1097/01.sla.0000072111.53797.44

Cited by 27 publications

(35 citation statements)

References 26 publications

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“…Additionally, as a tubulin-binding agent, patupilone should show antivascular effects by disrupting rapidly proliferating and immature endothelial cells, which have a particularly strong dependence on tubulin to maintain their shape (9). Support for this hypothesis was recently provided with cultured cells using low doses of patupilone (10) and on clinical tumor explants (11). Inhibition of endothelial cell function could also have a negative effect on the metastatic process.…”

mentioning

confidence: 84%

Patupilone Induced Vascular Disruption in Orthotopic Rodent Tumor Models Detected by Magnetic Resonance Imaging and Interstitial Fluid Pressure

Ferretti

Allegrini

O’Reilly

et al. 2005

Clinical Cancer Research

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Purpose: Evaluation of vascular disruptive activity in orthotopic models as potential surrogate biomarkers of tumor response to the microtubule-stabilizing agent patupilone. Experimental Design: Mice bearing metastatic B16/BL6 melanoma and rats bearing mammary BN472 tumors received vehicle or efficacious patupilone doses (4 and 0.8-1.5 mg/kg i.v., respectively). Tumor vascularity assessment by dynamic contrast-enhanced or dynamic susceptibility contrast magnetic resonance imaging and interstitial fluid pressure (IFP) occurred at baseline, 2 days (mice and rats), and 6 days (rats) after treatment and were compared with histologic measurements and correlated with tumor response.Results: In B16/BL6 metastases, patupilone (4 mg/kg) induced a 21 F 5% decrease (P < 0.001) in tumor blood volume and a 32 F 15% decrease (P = 0.02) in IFP after 2 days and reduced tumor growth and vessel density (>42%) after 2 weeks (P V 0.014). Patupilone dose-dependently inhibited BN472 tumor growth (day 6) and reduced IFP on days 2 and 6 (À21% to À70%), and the percentage change in IFP correlated (P < 0.01) with the change in tumor volume. In both models, histology and vascular casts confirmed decreases in tumor blood volume. One patupilone (0.8 mg/kg) administration decreased (P < 0.01) tumor IFP (54 F 4%), tumor blood volume (50 F 6%), and vessel diameter (40 F 11%) by day 6 but not the apparent diffusion coefficient, whereas histology showed that apoptosis was increased 2.4-fold and necrosis was unchanged.Apoptosis correlated negatively (P < 0.001) with IFP, tumor blood volume, and tumor volume, whereas tumor blood volume and IFP were correlated positively (P = 0.0005). Conclusions: Vascular disruptive effects of patupilone were detected in situ using dynamic contrast-enhanced or dynamic susceptibility contrast magnetic resonance imaging and IFP. Changes in IFP preceded and correlated with tumor response, suggesting that IFP may be a surrogate biomarker for patupilone efficacy.

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mentioning

confidence: 84%

Patupilone Induced Vascular Disruption in Orthotopic Rodent Tumor Models Detected by Magnetic Resonance Imaging and Interstitial Fluid Pressure

Ferretti

Allegrini

O’Reilly

et al. 2005

Clinical Cancer Research

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“…Epothilone B has been described to have superior potency to paclitaxel in inhibition of endothelial cell proliferation in vitro after continuous low-dose administration (9). Woltering et al (8) have reported that epothilone B inhibits in vitro angiogenesis at relatively high concentrations. Both observations do not provide insight in angiogenesis inhibition at subtoxic concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…Epothilones are structurally unrelated to taxanes but share their ability to stabilize microtubules (7). Evidence for antiangiogenic properties of epothilone B has been provided by the observation that vessel formation was inhibited in vitro (8) and by studies on frequent low-dose administration, which resulted in inhibition of proliferation of endothelial cells in culture (9). Vinca alkaloids show a different mode of action than taxanes and epothilones: they inhibit both tubulin polymerization and mitotic spindle formation.…”

Section: Introductionmentioning

confidence: 99%

Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton

Bijman¹,

Amerongen

Laurens

et al. 2006

Molecular Cancer Therapeutics

105

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Conventional anticancer agents may display antiangiogenic effects, but the underlying mechanism is poorly understood. We determined the antiangiogenic properties of cisplatin, doxorubicin, and the microtubule-targeting agents docetaxel, epothilone B, and vinblastine at concentrations not affecting cell proliferation. We also assessed tubulin and actin morphology and the activity of two key molecules in cell motility, the small Rho GTPases Cdc42 and Rac1. The highest non-toxic concentration (HNTC) of each drug was defined as the concentration inhibiting a maximum of 10% human umbilical vein endothelial cell growth on a 1-hour drug exposure, being for cisplatin 10 Mmol/L, doxorubicin 100 nmol/L, docetaxel 10 nmol/L, epothilone B 1 nmol/L, and vinblastine 10 nmol/L. Comparative endothelial cell functional assays using HNTCs for an exposure time of 1 hour indicated that endothelial cell migration in the wound assay, endothelial cell invasion in a transwell invasion system, and endothelial cell formation into tubelike structures on a layer of Matrigel were significantly inhibited by docetaxel, epothilone B, and vinblastine (P < 0.05), but not by cisplatin and doxorubicin. Docetaxel was slightly more efficient in the inhibition of endothelial cell motility than epothilone B and vinblastine. Fluorescence microscopy revealed that only the microtubule-targeting agents affected the integrity of the tubulin and F-actin cytoskeleton, which showed disturbed microtubule structures, less F-actin stress fiber formation, and appearance of nuclear F-actin rings. These observations were associated with early inhibition of Rac1 and Cdc42 activity. In conclusion, HNTCs of microtubuletargeting agents efficiently reduce endothelial cell motility by interference with microtubule dynamics preventing the activation of Rac1/Cdc42 and disorganizing the actin cytoskeleton. [Mol Cancer Ther 2006;5(9):2348 -57]

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“…Curcumin and turmeric extracts were assayed for antiangiogenic activity in a human placental vein disc angiogenesis model (HPVAM) developed by Woltering et al (2003). The test compounds were dissolved in culture media and used human placental vein assay in 96-well plates based on the methods described previously (Hornick et al, 2003;Liu et al, 2005).…”

Section: In Vitro Human Tissue-based Angiogenesis Assaymentioning

confidence: 99%

Antiangiogenic Effect of Curcumin in Pure Versus in Extract Forms

Liu

Schwimer

Liu

et al. 2008

Pharmaceutical Biology

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Curcumin isolated from turmeric (Curcuma longa L., Zingaberaceae) root was found to be anti-angiogenic in a human tissue-based angiogenesis assay. As a liposoluble compound, curcumin can be extracted from turmeric root with organic solvents such as ethanol or acetone. Curcumin in its pure form has poor solubility in water, potentially limiting its medicinal use for humans when it is taken orally or injected. This study attempted to investigate the possibility of improving curcumin's low solubility using an extract as a carrier. This would maintain anti-angiogenic properties with improved water-solubility. Experiments were undertaken to determine the extraction efficiency of different solvents for curcumin. Anti-angiogenic activities of curcumin in its pure form and in extracts were compared as a general trend ethanol or acetone was more efficient in extracting curcumin than their aqueous counterparts. Using 50 and 70% aqueous ethanol as well as 70% aqueous acetone yielded significantly more turmeric extracts by weight than absolute acetone, which was the lowest. Conversely, turmeric extracts extracted with 95% ethanol and absolute acetone contained significantly higher curcumin concentrations than water extract, which was the lowest. Combining the higher extract yield and highest curcumin concentrations in the extract, 95% ethanol gave the highest yield of single entity curcumin. In the angiogenesis assay, pure curcumin at the concentration of 85 µM (in 1% ethanol v/v) in the culture medium totally suppressed angiogenic responses. In contrast, a curcumin concentration of 18.5 µM (in the form of 100 µg/ml turmeric extract) achieved the same total inhibition of angiogenesis in culture. This nearly 5 fold gap reflected the unaccounted involvement of other antiangiogenic compounds including curcumin derivatives, and/or enhancement of curcumin by Accepted: 11 February 2008 Address correspondence to: Zhijun Liu, School of Renewable Natural Resources, LSU Agricultural Center, Baton Rouge, LA 70803. E-mail: zhiliu@lsu.edu non-antiangiogenic compounds in the extract. This finding suggests that curcumin in the form of extracts be potentially more pharmacologically active than pure curcumin. Further investigations of this hypothesis and possible interactions are warranted.

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Development of a Novel In Vitro Human Tissue-Based Angiogenesis Assay to Evaluate the Effect of Antiangiogenic Drugs

Cited by 27 publications

References 26 publications

Patupilone Induced Vascular Disruption in Orthotopic Rodent Tumor Models Detected by Magnetic Resonance Imaging and Interstitial Fluid Pressure

Patupilone Induced Vascular Disruption in Orthotopic Rodent Tumor Models Detected by Magnetic Resonance Imaging and Interstitial Fluid Pressure

Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton

Antiangiogenic Effect of Curcumin in Pure Versus in Extract Forms

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