Characterizing the Tumor Response to Treatment With Combretastatin A4 Phosphate

Salmon, Beth A.; Siemann, Dietmar W.

doi:10.1016/j.ijrobp.2006.12.051

Cited by 46 publications

(73 citation statements)

References 27 publications

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“…The latter is in keeping with reported increased vascularity and VEGF levels in the viable rim following VDA treatment, suggesting increased angiogenic activity in those parts of the tumor that survive VDA therapy (70,162). There is also evidence that the enhanced therapeutic effects observed when VDAs and AAs are combined may be due, in part, to the ability of AAs to suppress the recruitment of endothelial progenitor cells to tumor regions that survive VDA treatment (163).…”

Section: Rationale For Combined Vttsupporting

confidence: 76%

Realizing the Potential of Vascular Targeted Therapy: The Rationale for Combining Vascular Disrupting Agents and Anti-Angiogenic Agents to Treat Cancer

Siemann

Chaplin

Horsman

2017

Cancer Investigation

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Vascular targeted therapies (VTTs) are agents that target tumor vasculature and can be classified into two categories: those that inhibit angiogenesis and those that directly interfere with established tumor vasculature. Although both the anti-angiogenic agents (AAs) and the vascular disrupting agents (VDAs) target tumor vasculature, they differ in their mechanism of action and therapeutic application. Combining these two agents may realize the full potential of VTT and produce an effective therapeutic regimen. Here, we review AAs and VDAs (monotherapy and in combination with conventional therapies). We also discuss the rationale of combined VTT and its potential to treat cancer.

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Section: Rationale For Combined Vttsupporting

confidence: 76%

Realizing the Potential of Vascular Targeted Therapy: The Rationale for Combining Vascular Disrupting Agents and Anti-Angiogenic Agents to Treat Cancer

Siemann

Chaplin

Horsman

2017

Cancer Investigation

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“…In preclinical models following CA4P administration, revascularization and continued proliferation of a viable tumor rim, due at least in part to systemic mobilization and homing of bone marrow-derived circulating endothelial progenitor cells (CEPC) was observed (7,8). In a mouse model of melanoma, disruption of the VDA-induced CEPC spike by an antiangiogenic antibody resulted in marked reductions in tumor rim size and blood flow as well as enhanced VDA antitumor activity (8).…”

Section: Introductionmentioning

confidence: 99%

Phase I Trial of Combretastatin A4 Phosphate (CA4P) in Combination with Bevacizumab in Patients with Advanced Cancer

Nathan

Zweifel

Padhani

et al. 2012

Clinical Cancer Research

157

119

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Purpose: The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) induces significant tumor necrosis as a single agent. Preclinical models have shown that the addition of an anti-VEGF antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity.Experimental Design: Patients with advanced solid malignancies received CA4P at 45, 54, or 63 mg/m 2 on day 1, day 8, and then every 14 days. Bevacizumab 10 mg/kg was given on day 8 and at subsequent cycles four hours after CA4P. Functional imaging with dynamic contrast enhanced-MRI (DCE-MRI) was conducted at baseline, after CA4P alone, and after cycle 1 CA4P þ bevacizumab.Results: A total of 63 mg/m 2 CA4P þ 10 mg/kg bevacizumab q14 is the recommended phase II dose. A total of 15 patients were enrolled. Dose-limiting toxicities were grade III asymptomatic atrial fibrillation and grade IV liver hemorrhage in a patient with a history of hemorrhage. Most common toxicities were hypertension, headache, lymphopenia, pruritus, and pyrexia. Asymptomatic electrocardiographic changes were seen in five patients. Nine of 14 patients experienced disease stabilization. A patient with ovarian cancer had a CA125 response lasting for more than a year. DCE-MRI showed statistically significant reductions in tumor perfusion/vascular permeability, which reversed after CA4P alone but which were sustained following bevacizumab. Circulating CD34 þ and CD133 þ bone marrow progenitors increased following CA4P as did VEGF and granulocyte colony-stimulating factor levels. Conclusions: CA4P in combination with bevacizumab appears safe and well tolerated in this dosing schedule. CA4P induced profound vascular changes, which were maintained by the presence of bevacizumab.

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“…However, this vascular disruption spares the outer cellular rim of the tumor mass, which seems to be supported by normal blood vessels that surround the tumor capsule and remain unaffected by VDA action (6). It is believed that this viable rim mediates recovery from the vascular damage caused by VDA treatment (6).…”

Section: Introductionmentioning

confidence: 99%

BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy

Kremmidiotis

Leske

Lavranos

et al. 2010

Molecular Cancer Therapeutics

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Vascular disruption agents (VDA) cause occlusion of tumor vasculature, resulting in hypoxia-driven tumor cell necrosis. Tumor vascular disruption is a therapeutic strategy of great potential; however, VDAs currently under development display a narrow therapeutic margin, with cardiovascular toxicity posing a dose-limiting obstacle. Discovery of new VDAs, which display a wider therapeutic margin, may allow attainment of improved clinical outcomes. To identify such compounds, we used an in vitro selectivity screening approach that exploits the fact that tumor endothelial cells are in a constant state of activation and angiogenesis and do not undergo senescence. Our effort yielded the compound BNC105. This compound acts as a tubulin polymerization inhibitor and displays 80-fold higher potency against endothelial cells that are actively proliferating or are engaged in the formation of in vitro capillaries compared with nonproliferating endothelial cells or endothelium found in stable capillaries. This selectivity was not observed with CA4, a VDA currently under evaluation in phase III clinical trials. BNC105 is more potent and offers a wider therapeutic window. CA4 produces 90% vascular disruption at its no observed adverse event level (NOAEL), whereas BNC105 causes 95% vascular disruption at 1/8th of its NOAEL. Tissue distribution analysis of BNC105 in tumor-bearing mice showed that while the drug is cleared from all tissues 24 hours after administration, it is still present at high concentrations within the solid tumor mass. Furthermore, BNC105 treatment causes tumor regressions with complete tumor clearance in 20% of treated animals. Mol Cancer Ther; 9(6); 1562-73. ©2010 AACR.

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Characterizing the Tumor Response to Treatment With Combretastatin A4 Phosphate

Cited by 46 publications

References 27 publications

Realizing the Potential of Vascular Targeted Therapy: The Rationale for Combining Vascular Disrupting Agents and Anti-Angiogenic Agents to Treat Cancer

Realizing the Potential of Vascular Targeted Therapy: The Rationale for Combining Vascular Disrupting Agents and Anti-Angiogenic Agents to Treat Cancer

Phase I Trial of Combretastatin A4 Phosphate (CA4P) in Combination with Bevacizumab in Patients with Advanced Cancer

BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy

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