Enhancement of vascular targeting by inhibitors of nitric oxide synthase.
OBJECTIVE
This study investigates the enhancement of the vascular targeting activity of the tubulin-binding agent combretastatin A4 phosphate (CA4P) by various inhibitors of nitric oxide synthases.


METHODS
The syngeneic tumors CaNT and SaS growing in CBA mice were used for this study. Reduction in perfused vascular volume was measured by injection of Hoechst 33342 24 h after drug administration. Necrosis (hematoxylin and eosin stain) was assessed also at 24 h after treatment. Combretastatin A4 phosphate was synthesized by a modification of the published procedure and the nitric oxide synthase inhibitors L-NNA, L-NMMA, L-NIO, L-NIL, S-MTC, S-EIT, AMP, AMT, and L-TC, obtained from commercial sources.


RESULTS
A statistically significant augmentation of the reduction in perfused vascular volume by CA4P in the CaNT tumor was observed with L-NNA, AMP, and AMT. An increase in CA4P-induced necrosis in the same tumor achieved significance with L-NNA, L-NMMA, L-NIL, and AMT. CA4P induced little necrosis in the SaS tumor, but combination with the inhibitors L-NNA, L-NMMA, L-NIO, S-EIT, and L-TC was effective.


CONCLUSIONS
Augmentation of CA4P activity by nitric oxide synthase inhibitors of different structural classes supports a nitric oxide-related mechanism for this effect. L-NNA was the most effective inhibitor studied.
Davis
Peter D
PD
Angiogene Pharmaceuticals Ltd., England, Oxford, UK. pdd@angiogene.co.uk
Tozer
Gillian M
GM
Naylor
Matthew A
MA
Thomson
Peter
P
Lewis
Gemma
G
Hill
Sally A
SA
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005456:Fluorescent Dyes / Q000494:pharmacology; D051379:Mice; D008808:Mice, Inbred CBA; D008956:Models, Chemical; D009336:Necrosis; D009389:Neovascularization, Pathologic; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D013267:Stilbenes / Q000627:therapeutic use*; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D013267:Stilbenes; D014404:Tubulin; D019001:Nitric Oxide Synthase; C058728:fosbretabulin; C017807:bisbenzimide ethoxide trihydrochloride