The vascular response of tumor and normal tissues in the rat to the vascular targeting agent, combretastatin A-4-phosphate, at clinically relevant doses

Prise, Vivien E.; Honess, Davina J.; Stratford, Michael R.L.; Wilson, J D; Tozer, Gillian M.

doi:10.3892/ijo.21.4.717

Cited by 52 publications

(59 citation statements)

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“…For single doses of CA4P, the MTD is estimated to be around 68 mg/m 2 in patients [46] , which gives the clinically relevant dose of about 10 mg/kg in rats [47,48] . In mice, the roughly estimated MTD is 1000-1500 mg/kg [49] .…”

Section: Dose Of Vdasmentioning

confidence: 99%

Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer

Marchal¹,

2011

WJR

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Solid malignancies have to develop their own blood supply for their aggressive growth and metastasis; a process known as tumor angiogenesis. Angiogenesis is largely involved in tumor survival, progression and spread, which are known to be significantly attributed to treatment failures. Over the past decades, efforts have been made to understand the difference between normal and tumor vessels. It has been demonstrated that tumor vasculature is structurally immature with chaotic and leaky phenotypes, which provides opportunities for developing novel anticancer strategies. Targeting tumor vasculature is not only a unique therapeutic intervention to starve neoplastic cells, but also enhances the efficacy of conventional cancer treatments. Vascular disrupting agents (VDAs) have been developed to disrupt the already existing neovasculature in actively growing tumors, cause catastrophic vascular shutdown within short time, and induce secondary tumor necrosis. VDAs are cytostatic; they can only inhibit tumor growth, but not eradicate the tumor. This novel drug mechanism has urged us to develop multiparametric imaging biomarkers to monitor early hemodynamic alterations, cellular dysfunctions and metabolic impairments before tumor dimensional changes can be detected. In this article, we review the characteristics of tumor vessels, tubulindestabilizing mechanisms of VDAs, and in vivo effects of the VDAs that have been mostly studied in preclinical studies and clinical trials. We also compare the different tumor models adopted in the preclinical studies on VDAs. Multiparametric imaging biomarkers, mainly diffusion-weighted imaging and dynamic contrast-enhanced imaging from magnetic resonance imaging, are evaluated for their potential as morphological and functional imaging biomarkers for monitoring therapeutic effects of VDAs.

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Section: Dose Of Vdasmentioning

confidence: 99%

Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer

Marchal¹,

2011

WJR

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“…DCE MRI was included as part of the Phase I clinical trials of CA4P (24,25). Results of preclinical and clinical DCE MRI studies have shown a reversible change in vascular perfusion in the tumor periphery following a single dose of VTA (26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

Antivascular effects of combretastatin A4 phosphate in breast cancer xenograft assessed using dynamic bioluminescence imaging and confirmed by MRI

et al. 2008

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Bioluminescent imaging (BLI) has found significant use in evaluating long-term cancer therapy in small animals. We have now tested the feasibility of using BLI to assess acute effects of the vascular disrupting agent Combretastatin A4 phosphate (CA4P) on luciferase expressing MDA-MB-231 human breast tumor cells growing as xenografts in mice. Following administration of luciferin substrate, there is a rapid increase in light emission reaching a maximum after about six minutes, which gradually decreases over the following 20 min. The kinetics of light emission are highly reproducible, however, following IP administration of CA4P (120 mg/kg), the detected light emission was decreased between 50 and 90 percent and time to maximum was significantly delayed. Twenty-four hours later, there was some recovery of light emission following further administration of luciferin substrate. Comparison with dynamic contrast-enhanced MRI based on the paramagnetic contrast agent Omniscan showed comparable changes in the tumors consistent with the previous literature. Histology also confirmed shutdown of tumor vascular perfusion. We believe this provides an important novel application for BLI, which could have widespread application in screening novel therapeutics expected to cause acute vascular changes in tumors.

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“…8,9 CA4P and other VDAs are highly selective for rodent and human tumors where they cause significantly greater vascular damage compared with normal tissues. [8][9][10][11][12] The mechanisms through which VDAs elicit their anti-tumor activity are conceptually different from those of classic chemotherapeutic agents that directly target the tumor cell component and kill cells by apoptosis or related mechanisms. 13 Although the precise molecular pathways that drive tumor vascular collapse are not yet fully understood, in vitro analyses have shown that VDAs act through binding to tubulin resulting in microtubule depolymerization, triggering morphological changes in endothelial cells that include increased blebbing and contraction, contributing to the disruption of cell-to-cell junctions and increased permeability.…”

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confidence: 99%

“…Mitotic-arrested cells subsequently undergo mitotic catastrophe and apoptosis through caspase-dependent and -independent mechanisms. In vivo, the plasma half-life of the active CA4 is short 11,29 and it is difficult to predict whether drug exposures are great enough for significant direct cytotoxic effects to occur under these conditions, especially as there may be a degree of drug trapping within tumor tissue, as a consequence of vascular collapse. To maximize efficacy and achieve local tumor control, it is necessary to combine vascular disrupting agents with other therapeutic approaches such as conventional chemotherapy or radiotherapy.…”

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Vascular effects dominate solid tumor response to treatment with combretastatin A‐4‐phosphate

Lunt

Akerman

Hill

et al. 2011

Intl Journal of Cancer

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Vascular‐targeted therapeutics are increasingly used in the clinic. However, less is known about the direct response of tumor cells to these agents. We have developed a combretastatin‐A‐4‐phosphate (CA4P) resistant variant of SW1222 human colorectal carcinoma cells to examine the relative importance of vascular versus tumor cell targeting in the ultimate treatment response. SW1222Res cells were generated through exposure of wild‐type cells (SW1222WT) to increasing CA4P concentrations in vitro. Increased resistance was confirmed through analyses of cell viability, apoptosis and multidrug‐resistance (MDR) protein expression. In vivo, comparative studies examined tumor cell necrosis, apoptosis, vessel morphology and functional vascular end‐points following treatment with CA4P (single 100 mg/kg dose). Tumor response to repeated CA4P dosing (50 mg/kg/day, 5 days/week for 2 weeks) was examined through growth measurement, and ultimate tumor cell survival was studied by ex vivo clonogenic assay. In vitro, SW1222Res cells showed reduced CA4P sensitivity, enhanced MDR protein expression and a reduced apoptotic index. In vivo, CA4P induced significantly lower apoptotic cell death in SW1222Res versus SW1222WT tumors indicating maintenance of resistance characteristics. However, CA4P‐induced tumor necrosis was equivalent in both lines. Similarly, rapid CA4P‐mediated vessel disruption and blood flow shut‐down were observed in both lines. Cell surviving fraction was comparable in the two tumor types following single dose CA4P and SW1222Res tumors were at least as sensitive as SW1222WT tumors to repeated dosing. Despite tumor cell resistance to CA4P, SW1222Res response in vivo was not impaired, strongly supporting the view that vascular damage dominates the therapeutic response to this agent.

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The vascular response of tumor and normal tissues in the rat to the vascular targeting agent, combretastatin A-4-phosphate, at clinically relevant doses

Cited by 52 publications

References 0 publications

Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer

Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer

Antivascular effects of combretastatin A4 phosphate in breast cancer xenograft assessed using dynamic bioluminescence imaging and confirmed by MRI

Vascular effects dominate solid tumor response to treatment with combretastatin A‐4‐phosphate

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