Phase I Clinical Trial of Weekly Combretastatin A4 Phosphate: Clinical and Pharmacokinetic Results

Rustin, G. J. S.; Galbraith, Susan; Anderson, Helén; Stratford, Michael R.L.; Folkes, Lisa K.; Sena, Luiza; Gumbrell, Lindsey; Price, Patricia M

doi:10.1200/jco.2003.05.185

Cited by 301 publications

(260 citation statements)

References 16 publications

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“…In the first study by Rustin et al (2003a) CA4P was given weekly for 3 weeks followed by a week gap . Thirty-four patients with advanced solid tumours received 167 infusions.…”

Section: Combretastatin A4 Phosphatementioning

confidence: 99%

Vascular disrupting agents in clinical development

2007

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Growth of human tumours depends on the supply of oxygen and nutrients via the surrounding vasculature. Therefore tumour vasculature is an attractive target for anticancer therapy. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of specific anticancer drugs has been developed. These so-called vascular disrupting agents (VDAs) target the established tumour vasculature and cause an acute and pronounced shutdown of blood vessels resulting in an almost complete stop of blood flow, ultimately leading to selective tumour necrosis. As a number of VDAs are now being tested in clinical studies, we will discuss their mechanism of action and the results obtained in preclinical studies. Also data from clinical studies will be reviewed and some considerations with regard to the future development are given.

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“…In the first study by Rustin et al (2003a) CA4P was given weekly for 3 weeks followed by a week gap . Thirty-four patients with advanced solid tumours received 167 infusions.…”

Section: Combretastatin A4 Phosphatementioning

confidence: 99%

Vascular disrupting agents in clinical development

2007

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“…Phase I human cancer clinical trials of the sodium CA4 phosphate prodrug (2; Fig. 1) have been successfully completed (12,13) and the drug is currently undergoing phase II trials.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4

Thomson

Naylor

Everett

et al. 2006

Molecular Cancer Therapeutics

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Nitrothienylprop-2-yl ether formation on the 3 ¶-phenolic position of combretastatin A-4 (1) abolishes the cytotoxicity and tubulin polymerization-inhibitory effects of the drug. 5-Nitrothiophene derivatives of 1 were synthesized following model kinetic studies with analogous coumarin derivatives, and of these, compound 13 represents a promising new lead in bioreductively targeted cytotoxic anticancer therapies. In this compound, optimized gemdimethyl A-carbon substitution enhances both the aerobic metabolic stability and the efficiency of hypoxia-mediated drug release. Only the gem-substituted derivative 13 released 1 under anoxia in either in vitro whole-cell experiments or supersomal suspensions. The rate of release of 1 from the radical anions of these prodrugs is enhanced by greater methyl substitution on the A-carbon. Cellular and supersomal studies showed that this A-substitution pattern controls the useful range of oxygen concentrations over which 1 can be effectively released by the prodrug. [Mol Cancer Ther 2006;5(11):2886 -94]

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“…Dynamic contrast enhanced (DCE) MRI based on the transport properties of the small paramagnetic contrast agent gadolinium-DTPA (Gd-DTPA) is the most commonly used imaging approach to study tumor vascular perfusion and permeability. 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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Phase I Clinical Trial of Weekly Combretastatin A4 Phosphate: Clinical and Pharmacokinetic Results

Abstract: CA4P was well tolerated in 14 of 16 patients at 52 or 68 mg/m2; these are doses at which tumor blood flow reduction has been recorded.

Cited by 301 publications

References 16 publications

Vascular disrupting agents in clinical development

Vascular disrupting agents in clinical development

Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4

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

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