Roles of Nitric Oxide Synthase Inhibition and Vascular Endothelial Growth Factor Receptor-2 Inhibition on Vascular Morphology and Function in an In vivo Model of Pancreatic Cancer

Purpose: Both nitric oxide (NO) and vascular endothelial growth factor (VEGF) mediate tumor vascular function. Because these molecules regulate one another9s expression, we hypothesized that NO synthase (NOS) inhibition produces effects comparable to those of anti-VEGF therapy on human pancreatic cancer xenografts. Experimental Design: L3.6pl human pancreatic cancer cells were s.c. implanted in nude mice. On day 6, mice were randomized to receive ( a ) PBS (control), ( b ) DC101 [VEGF receptor 2 (VEGFR-2) antibody] by i.p. injection, ( c ) N -nitro-l-arginine (NNLA; NOS inhibitor) in the drinking water, or ( d ) both DC101 and NNLA. Mice were killed on day 20. Results: DC101 and NNLA as single agents inhibited tumor growth by ∼50% to 60% ( P P P P P P P P Conclusions: Although VEGFR-2 can mediate NOS activity, the combination of VEGFR-2 and NOS inhibition significantly increased the antivascular effect over single agent therapy. The addition of NOS inhibition led to an even further alteration of tumor vessel morphology and vascular perfusion compared with VEGFR-2 blockade, suggesting that NO and VEGFR-2 have distinct but complementary effects on the tumor vasculature.