Nitric oxide synthase inhibition enhances the tumor vascular-damaging effects of combretastatin a-4 3-o-phosphate at clinically relevant doses.

Journal article

PURPOSE: The therapeutic potential of combining the prototype tumor vascular-disrupting agent combretastatin A-4 3-O-phosphate (CA-4-P) with systemic nitric oxide synthase (NOS) inhibition was investigated preclinically. EXPERIMENTAL DESIGN: Vascular response (uptake of (125)I-labeled iodoantipyrine; laser Doppler flowmetry) and tumor response (histologic necrosis; cytotoxicity and growth delay) were determined. RESULTS: Inducible NOS selective inhibitors had no effect on blood flow in the P22 rat sarcoma. In contrast, the non-isoform-specific NOS inhibitor N(omega)-nitro- l-arginine (l-NNA; 1 and 10 mg/kg i.v. or chronic 0.1 or 0.3 mg/mL in drinking water) decreased the P22 blood flow rate selectively down to 36% of control at 1 hour but did not induce tumor necrosis at 24 hours. CA-4-P, at clinically relevant doses, decreased the P22 blood flow rate down to 6% of control at 1 hour for 3 mg/kg but with no necrosis induction. However, l-NNA administration enhanced both CA-4-P-induced tumor vascular resistance at 1 hour (chronic l-NNA administration) and necrosis at 24 hours, with 45% or 80% necrosis for 3 and 10 mg/kg CA-4-P, respectively. Bolus l-NNA given 3 hours after CA-4-P was the most effective cytotoxic schedule in the CaNT mouse mammary carcinoma, implicating a particular enhancement by l-NNA of the downstream consequences of CA-4-P treatment. Repeated dosing of l-NNA with CA-4-P produced enhanced growth delay over either treatment alone in P22, CaNT, and spontaneous T138 mouse mammary tumors, which represented a true therapeutic enhancement. CONCLUSIONS: The combination of NOS inhibition with CA-4-P is a promising approach for targeting tumor vasculature, with relevance for similar vascular-disrupting agents in development.

Authors: Tozer, G; Prise, V; Lewis, G; Xie, S; Wilson, I

• Publication status: Published
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research
• Volume: 15
• Issue: 11
• Pages: 3781-3790
• Publication date: 2009-06-01
• DOI: 10.1158/1078-0432.ccr-08-2906
• EISSN: 1557-3265
• ISSN: 1078-0432
• Language: English
• Keywords: Blood Vessels; Dose-Response Relationship, Drug; Stilbenes; Tumor Burden; Sarcoma, Experimental; Drug Synergism; Antineoplastic Agents, Phytogenic; Enzyme Inhibitors; Male; Time Factors; Nitroarginine; Rats; Blood Flow Velocity; Cell Survival; Rats, Inbred Strains; Antineoplastic Combined Chemotherapy Protocols; Nitric Oxide Synthase; Animals