Enhancement of vascular targeting by inhibitors of nitric oxide synthase

• Published in: International journal of radiation oncology, biology, physics Vol. 54; no. 5; pp. 1532 - 1536
• Main Authors: Davis, Peter D, Tozer, Gillian M, Naylor, Matthew A, Thomson, Peter, Lewis, Gemma, Hill, Sally A
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01.12.2002; Elsevier
• Subjects: Angiogenesis Inhibitors - therapeutic use; Animals; Antineoplastic Agents, Phytogenic - therapeutic use; Benzimidazoles - pharmacology; Biological and medical sciences; Combretastatin A4 phosphate; Enzyme Inhibitors - pharmacology; Fluorescent Dyes - pharmacology; Medical sciences; Mice; Mice, Inbred CBA; Models, Chemical; Necrosis; Neovascularization, Pathologic; Nitric oxide; Nitric Oxide Synthase - antagonists & inhibitors; Stilbenes - therapeutic use; Time Factors; Tubulin - metabolism; Tumor Cells, Cultured; Vascular targeting; Vascular volume; Vascular targeting; Vascular volume; Nitric oxide; Combretastatin A4 phosphate; Necrosis
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/S0360-3016(02)03925-1

Purpose: 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 and Materials: 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.