Combretastatin A4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging.

Abstract

PURPOSE:

Combretastatin A4 phosphate (CA4P) is a novel vascular targeting agent. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) studies were performed to examine changes in parameters related to blood flow and vascular permeability in tumor and normal tissue after CA4P treatment.

MATERIALS AND METHODS:

Changes in kinetic DCE-MRI parameters (transfer constant [Ktrans] and area under contrast medium-time curve [AUC]) over 24 hours after treatment with CA4P were measured in 18 patients in a phase I trial and compared with those obtained in the rat P22 carcinosarcoma model, using the same imaging technique. Rats were treated with 30 mg/kg of CA4P; patients received escalating doses from 5 to 114 mg/m2.

RESULTS:

A similar pattern and time course of change in tumor and normal tissue parameters was seen in rats and humans. Rat tumor Ktrans was reduced by 64% 6 hours after treatment with CA4P (30 mg/kg). No significant reductions in kidney or muscle parameters were seen. Significant reductions were seen in tumor Ktrans in six of 16 patients treated at >or= 52 mg/m2, with a significant group mean reduction of 37% and 29% at 4 and 24 hours, respectively, after treatment. The mean reduction in tumor initial area under the gadolinium-diethylenetriamine pentaacetic acid concentration-time curve (AUC) was 33% and 18%, respectively, at these times. No reduction was seen in muscle Ktrans or in kidney AUC in group analysis of the clinical data.

CONCLUSION:

CA4P acutely reduces Ktrans in human as well as rat tumors at well-tolerated doses, with no significant changes in kidney or muscle, providing proof of principle that this drug has tumor antivascular activity in rats and humans.

• Authors: Susan M Galbraith, Ross J Maxwell, Martin A Lodge, Gillian M Tozer, John Wilson, N Jane Taylor, J James Stirling, Luiza Sena, Anwar R Padhani, Gordon J S Rustin
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 21 Issue 15 Pg. 2831-42 (Aug 01 2003) ISSN: 0732-183X [Print] United States
• PMID: 12807936 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Contrast Media
• Stilbenes
• fosbretabulin
• Gadolinium DTPA

Topics

• Animals
• Antineoplastic Agents, Phytogenic (administration & dosage, pharmacokinetics, pharmacology)
• Area Under Curve
• Contrast Media
• Disease Models, Animal
• Gadolinium DTPA
• Humans
• Infusion Pumps
• Magnetic Resonance Imaging
• Male
• Neoplasms (blood supply, drug therapy)
• Neoplasms, Experimental (blood supply, drug therapy)
• Rats
• Stilbenes (administration & dosage, pharmacokinetics, pharmacology)
• Treatment Outcome