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

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
E Ramsay CampLee M Ellis

Abstract

Both nitric oxide (NO) and vascular endothelial growth factor (VEGF) mediate tumor vascular function. Because these molecules regulate one another's expression, we hypothesized that NO synthase (NOS) inhibition produces effects comparable to those of anti-VEGF therapy on human pancreatic cancer xenografts. 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. DC101 and NNLA as single agents inhibited tumor growth by approximately 50% to 60% (P < 0.008 for both). Furthermore, combined therapy inhibited mean tumor growth by 89% (P < 0.008). Combined inhibition of VEGFR-2 and NOS also decreased mean vessel counts by 65% (P < 0.03) and vessel area by 80% versus controls (P < 0.001). In contrast to DC101 where vessel diameter was similar to control, NNLA decreased mean vessel diameter by 42% (P < 0.001). NNLA also led to a 54% (P < 0.03) decrease in tumor uptake of the perfusion marker Hoechst 33342 versus controls whereas DC101 decreased Hoechst 33342 staining by 43% (...Continue Reading

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Citations

Jul 4, 2008·Nature Reviews. Cancer·Lee M Ellis, Daniel J Hicklin
Jan 10, 2008·Journal of the National Cancer Institute·Michael J GrayLee M Ellis
Jun 29, 2012·Cancer Research·Benjamin L LampsonChristopher M Counter
Sep 24, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Michael L MaitlandMark J Ratain
Jul 21, 2007·The Journal of Clinical Investigation·Marya F McCartyLee M Ellis
Sep 20, 2006·Expert Opinion on Therapeutic Targets·George Van BurenLee M Ellis
Dec 19, 2015·Nature Reviews. Drug Discovery·Csaba Szabo
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Oct 5, 2017·World Journal of Gastroenterology : WJG·Rafael LatorreEnrique Pérez-Cuadrado-Martínez
Aug 12, 2016·Antioxidants & Redox Signaling·Jian Wang, S Perwez Hussain
Jan 5, 2021·Chinese Medical Journal·Jin-Shou YangLei You
Dec 17, 2020·International Journal of Molecular Sciences·Faizan H KhanSharon A Glynn

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