Preclinical evaluation of the antitumour activity of the novel vascular targeting agent Oxi 4503.
BACKGROUND
Tubulin depolymerizing drugs, which selectively disrupt tumour neovasculature, have recently been identified. The lead drug in this class, combretastatin A4 phosphate (CA4P), has just completed Phase I clinical trial. We have continued to synthesize and evaluate a number of combretastatins, with the aim of identifying novel agents that possess single agent activity. In the studies presented here we provide data on our lead preclinical compound and compare its antivascular and antitumour activity to that of CA4P in the murine breast adenocarcinoma CaNT. This compound, designated Oxi 4503, is the diphosphate prodrug form of combretastatin A1.


RESULTS
At a dose of 1 mg/kg Oxi 4503 induced a greater than 50% reduction in functional vascular volume, which increased to 80% or more following doses of 10, 25 and 50 mg/kg. In contrast, CA4P induced approximately 40% vascular shutdown at 50 mg/kg, but had no measurable effect at 10 mg/kg. In addition to these vascular effects, Oxi 4503 at doses of 100, 200 and 400 mg/kg induced significant retardation in the growth of established CaNT tumours. No significant growth retardation was obtained with single doses of up to 400 mg/kg CA4P.


CONCLUSIONS
In summary, these studies have identified Oxi 4503 as a preclinical development candidate with more potent antivascular and antitumour effects than CA4P when used as a single agent.
Hill
Sally A
SA
Gray Cancer Institute, Mount Vernon Hospital Northwood, Middlesex, UK.
Toze
Gillian M
GM
Pettit
George R
GR
Chaplin
David J
DJ
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D011756:Diphosphates / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D011355:Prodrugs / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D011756:Diphosphates; C465018:Oxi 4503; D011355:Prodrugs; D013267:Stilbenes; C063690:combretastatin A-1