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

E. Ramsay Camp, Anthony Yang, Wenbiao Liu, Fan Fan, Ray Somcio, Daniel J. Hicklin, Lee M. Ellis

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Purpose: 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. 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 < 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% (P < 0.03). The combination of inhibitors decreased perfusion by 73% (P < 0.03). 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.

Original languageEnglish (US)
Pages (from-to)2628-2633
Number of pages6
JournalClinical Cancer Research
Volume12
Issue number8
DOIs
StatePublished - Apr 15 2006
Externally publishedYes

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Vascular Endothelial Growth Factor Receptor-2
Vascular Endothelial Growth Factor Receptor
Pancreatic Neoplasms
Nitric Oxide Synthase
Blood Vessels
Neoplasms
Perfusion
Vascular Endothelial Growth Factor A
Growth
Heterografts
Nude Mice
Drinking Water
Arginine
Nitric Oxide
Research Design
Therapeutics
Staining and Labeling
Injections
Antibodies

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Camp, E. Ramsay; Yang, Anthony; Liu, Wenbiao; Fan, Fan; Somcio, Ray; Hicklin, Daniel J.; Ellis, Lee M.

In: Clinical Cancer Research, Vol. 12, No. 8, 15.04.2006, p. 2628-2633.

Research output: Contribution to journalArticle

Camp, E. Ramsay ; Yang, Anthony ; Liu, Wenbiao ; Fan, Fan ; Somcio, Ray ; Hicklin, Daniel J. ; Ellis, Lee M. / 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. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 8. pp. 2628-2633.
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abstract = "Purpose: 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. 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 < 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{\%} (P < 0.03). The combination of inhibitors decreased perfusion by 73{\%} (P < 0.03). 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.",
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T1 - 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

AU - Camp, E. Ramsay

AU - Yang, Anthony

AU - Liu, Wenbiao

AU - Fan, Fan

AU - Somcio, Ray

AU - Hicklin, Daniel J.

AU - Ellis, Lee M.

PY - 2006/4/15

Y1 - 2006/4/15

N2 - Purpose: 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. 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 < 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% (P < 0.03). The combination of inhibitors decreased perfusion by 73% (P < 0.03). 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.

AB - Purpose: 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. 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 < 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% (P < 0.03). The combination of inhibitors decreased perfusion by 73% (P < 0.03). 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.

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