Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1994 Apr;85(4):331–334. doi: 10.1111/j.1349-7006.1994.tb02362.x

Enhanced Vascular Permeability in Solid Tumor Is Mediated by Nitric Oxide and Inhibited by Both New Nitric Oxide Scavenger and Nitric Oxide Synthase Inhibitor

Hiroshi Maeda 1,✉, Youichiro Noguchi 1, Keizo Sato 1, Takaaki Akaike 1
PMCID: PMC5919468  PMID: 7515384

Abstract

A newly discovered nitric oxide radical scavenger, an imidazolineoxyl N‐oxide derivative, was used to investigate the role of nitric oxide radical (*NO) in the vascular permeability enhancement of solid tumor. Sarcoma‐180 solid tumor in ddY mice was used for this experiment. Electron spin resonance spectroscopy was used to quantitate the reacted and unreacted scavenger. The results showed that extensive extravasation, assessed by intravenous injection of Evans blue, could be greatly suppressed by both *NO scavenger administered orally and *NO synthase inhibitor administrated intraperitoneally. This indicates that *NO is responsible for the vascular permeability in solid tumors.

Keywords: Tumor vascular permeability, Nitric oxide, Nitric oxide scavenger, Bradykinin

Full Text

The Full Text of this article is available as a PDF (244.1 KB).

REFERENCES

  • 1. ) Akaike , T. , Yoshida , M. , Miyamoto , Y. , Sato , K. , Kohno , M. , Sasamoto , K. , Miyazaki , K. , Ueda , S. and Maeda , H.Antagonistic action of imidazolineoxyl N‐oxides against endothelium‐derived relaxing factor/⋅NO through a radical reaction . Biochemistry , 32 , 827 – 832 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Akaike , T. , Yoshida , M. , Sato , K. , Ueda , S. and Meada , H.Therapeutic effect of a new ⋅NO‐antidote, imidazolineoxyl N‐oxide on endotoxin shock in rats . Proc. 3rd Int. Meet. on Biol. Nitric Oxide ( 1994. ), in press . [DOI] [PubMed] [Google Scholar]
  • 3. ) Maeda , H. , Akaike , T. , Yoshida , M. , Sato , K. and Noguchi , Y.A new class of antidote of nitric oxide, imidazolineoxyl N‐oxide derivative: therapeutic effect of endotoxin shock and suppressive effect on vascular permeability in solid tumor . In “ The Role of Nitric Oxide in Physiology and Pathology ,” ed. Koprowski H. , Springer‐Verlag; , Berlin ( 1994. ), in press . [Google Scholar]
  • 4. ) Folkman , J.What is the evidence that tumors are angiogenesis dependent ? J. Natl. Cancer Inst. , 82 , 4 – 6 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Skinner , S. A. , Tutton , P. J. M. and O'Brein , P. E.Microvascular architecture of experimental colon tumors in the rats . Cancer Res. , 50 , 2411 – 2417 ( 1990. ). [PubMed] [Google Scholar]
  • 6. ) Suzuki , M. , Takahashi , T. and Sato , T.Medial regression and its functional significance in tumor‐supplying host arteries: a morphometric study of hepatic arteries in human liver with hepatocellular carcinoma . Cancer , 59 , 444 – 450 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Suzuki , M. , Hori , K. , Abe , I. , Saito , S. and Sato , H.A new approach to cancer chemotherapy: selective enhancement of tumor blood flow with angiotensin II . J. Natl. Cancer Inst. , 67 , 663 – 669 ( 1981. ). [PubMed] [Google Scholar]
  • 8. ) Hori , K. , Suzuki , M. , Abe , I. , Saito , S. and Sato , H.Increase in tumor vascular area due to increased blood flow by angiotensin II in rats . J. Natl. Cancer Inst. , 74 , 453 – 459 ( 1985. ). [PubMed] [Google Scholar]
  • 9. ) Matsumura , Y. and Maeda , H.A new concept for macro‐molecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs . Cancer Res. , 46 , 6387 – 6392 ( 1986. ). [PubMed] [Google Scholar]
  • 10. ) Maeda , H. and Matsumura , Y.Tumoritropic and lymphotropic principles of macromolecular drugs . Crit. Rev. Ther. Drug Carrier Syst. , 6 , 193 – 210 ( 1989. ). [PubMed] [Google Scholar]
  • 11. ) Maeda , H.SMANCS and polymer‐conjugated macro‐molecular drugs: advantages in cancer chemotherapy . Adv. Drug Delivery Rev. , 6 , 181 – 202 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Maeda , H. , Seymour , L. W. and Miyamoto , Y.Conjugates of anticancer agents and polymers: advantages of macro‐molecular therapeutics in vivo . Bioconjugate Chem. , 3 , 351 – 362 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Iwai , K. , Maeda , H. and Konno , T.Use of oily contrast medium for selective drug targeting to tumor: enhanced therapeutic effect and X‐ray image . Cancer Res. , 44 , 2115 – 2121 ( 1984. ). [PubMed] [Google Scholar]
  • 14. ) Senger , D. R. , Galli , S. J. , Dvorak , A. M. , Perruzzi , C. A. , Harrey , V. S. and Dvorak , H. F.Tumor cells secrete a vascular permeability factor that promotes accumulation of ascitic fluid . Science , 219 , 983 – 985 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Maeda , H. , Matsumura , Y. and Kato , H.Purification and identification of [hydroxyprolyl3]bradykinin in ascitic fluid from a patient with gastric cancer . J. Biol. Chem. , 263 , 16051 – 16054 ( 1988. ). [PubMed] [Google Scholar]
  • 16. ) Matsumura , Y. , Kimura , M. , Yamamoto , T. and Maeda , H.Involvement of the kinin‐generating cascade in enhanced vascular permeability in tumor tissue . Jpn. J. Cancer Res. , 79 , 1327 – 1334 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. ) Matsumura , Y. , Maruo , K. , Kimura , M. , Yamamoto , T. , Konno , T. and Maeda , H.Kinin‐generating cascade in advanced cancer patients and in vitro study . Jpn. J. Cancer Res. , 82 , 732 – 741 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. ) Ettinghausen , S. E. , Puri , R. J. and Rosenberg , S. A.Increased vascular permeability in organs mediated by the systemic administration of lymphokine‐activated killer cells and recombinant interleukin‐2 in mice . J. Natl. Cancer Inst. , 80 , 177 – 187 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Kelm , M. , Feelisch , M. , Spahr , R. , Piper , H. M. , Noack , E. and Schrader , J.Quantitative and kinetic characterization of nitric oxide and EDRF released from cultured endothelial cells . Biochem. Biophys. Res. Commun. , 154 , 236 – 244 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Tadjkarimi , S. , O'Neil , G. S. , Luu , T. N. , Allen , S. P. , Schyns , C. J. , Chester , A. H. and Yacoub , M. H.Comparison of cyclic GMP in human internal mammary artery and saphenous vein: implications for coronary artery bypass graft patency . Cardiovasc. Res. , 26 , 297 – 300 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Myers , P. R. , Guerra , R. , Jr. and Harrison , D. G.Release of multiple endothelium‐derived relaxing factors from porcine coronary arteries . J. Cardiovasc. Pharmacol. , 20 , 392 – 400 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Palmer , R. M. J. , Ferrige , A. G. and Moncada , S.Nitric oxide release accounts for the biological activity of endothelium‐derived relaxing factor . Nature , 327 , 524 – 526 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Piper , P. J. , Freemantle , C. , Mahadevan , V. , Riveros‐Moreno , V. , Buttery , L. D. K. , Springall , D. R. and Polak , J. M.Effect of dexamethasone on inducible nitric oxide synthase expression and blood flow in murine tumor . J. Endothelial Cell Res. , 1 , Suppl. 1 S. 51 , Abst. No. 201 ( 1993. ). [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES