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


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.


CONCLUSIONS
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.
Galbraith
Susan M
SM
Department of Medical Oncology, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom.
Maxwell
Ross J
RJ
Lodge
Martin A
MA
Tozer
Gillian M
GM
Wilson
John
J
Taylor
N Jane
NJ
Stirling
J James
JJ
Sena
Luiza
L
Padhani
Anwar R
AR
Rustin
Gordon J S
GJ
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D003287:Contrast Media; D004195:Disease Models, Animal; D019786:Gadolinium DTPA; D006801:Humans; D007260:Infusion Pumps; D008279:Magnetic Resonance Imaging; D008297:Male; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy; D051381:Rats; D013267:Stilbenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D016896:Treatment Outcome
D000972:Antineoplastic Agents, Phytogenic; D003287:Contrast Media; D013267:Stilbenes; C058728:fosbretabulin; D019786:Gadolinium DTPA