Exploring vascular dysfunction caused by tirapazamine

Microvasc Res. 2008 Mar;75(2):247-55. doi: 10.1016/j.mvr.2007.09.006. Epub 2007 Oct 11.


We have previously reported that the hypoxic cytotoxin tirapazamine causes central vascular dysfunction in HCT-116 xenografts. Here we further extend this finding to SiHa xenografts and SCCVII murine tumors. Within 1 day after treatment with tirapazamine both tumor types develop areas of non-perfused tissue in central regions of tumors. To explore the mechanism by which the hypoxic cytotoxin tirapazamine causes vascular dysfunction we altered the blood oxygen content with carbogen (95% O(2) and 5% CO(2)) breathing in tumor bearing mice. Carbogen treatment was able to decrease the number of tumors responding to tirapazamine but was not able to eradicate the vascular dysfunction completely. In complementary in vitro studies, immunohistochemical staining of tirapazamine-treated endothelial cells indicated that, unlike the vascular targeting agent (VTA) combretastatin-A-4-phosphate, the vascular effects caused by tirapazamine are not due to microtubule disruption. Another possible mechanism of action for tirapazamine could involve its ability to inhibit nitric oxide synthase (NOS). Studies combining other vascular targeting agents (VTAs) such as the combretastatins have shown a potentiation of vascular disruption in tumors when combined with NOS inhibitors, possibly due to vessel constriction from decreased nitric oxide (NO) levels. We propose the theory that vascular dysfunction caused by tirapazamine may be via NOS inhibition. In support of this hypothesis preliminary experiments showed NOS inhibition with L-NNA (N-omega-nitro-L-arginine) increases tumor necrosis, 1 day after administration, in our HCT-116 tumor model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Carbon Dioxide / pharmacology
  • Cell Hypoxia
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Endothelial Cells / drug effects*
  • Endothelial Cells / enzymology
  • Endothelial Cells / pathology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiopathology
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • HCT116 Cells
  • Humans
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred NOD
  • Mice, SCID
  • Necrosis
  • Neoplasms, Experimental / blood supply
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / metabolism
  • Nitroarginine / pharmacology
  • Oxygen / metabolism
  • Oxygen / pharmacology
  • Regional Blood Flow / drug effects
  • Time Factors
  • Tirapazamine
  • Triazines / pharmacology*
  • Triazines / therapeutic use


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Triazines
  • Carbon Dioxide
  • Tirapazamine
  • Nitroarginine
  • carbogen
  • Nitric Oxide Synthase
  • Oxygen