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


METHODS
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.
Tozer
Gillian M
GM
Cancer Research UK Tumour Microcirculation Group, Academic Unit of Surgical Oncology, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, United Kingdom. g.tozer@sheffield.ac.uk
Prise
Vivien E
VE
Lewis
Gemma
G
Xie
Shaoping
S
Wilson
Ian
I
Hill
Sally A
SA
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001783:Blood Flow Velocity / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019335:Nitroarginine / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012513:Sarcoma, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D013267:Stilbenes; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; C058728:fosbretabulin