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Exploring vascular dysfunction caused by tirapazamine.

Lynsey A Huxham¹, Alastair H Kyle, Jennifer H E Baker

¹Department of Medical Biophysics, British Columbia Cancer Research Centre, 675 West 10th Ave, Vancouver, British Columbia, Canada V5Z 1L3.

Microvascular Research

|November 21, 2007

Summary

The hypoxic cytotoxin tirapazamine induces vascular dysfunction and non-perfused tissue in tumors. Tirapazamine

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Area of Science:

Oncology
Pharmacology
Cancer Biology

Background:

Tirapazamine is a hypoxic cytotoxin known to cause vascular dysfunction in HCT-116 xenografts.
This study extends the investigation of tirapazamine's vascular effects to SiHa xenografts and SCCVII murine tumors.

Purpose of the Study:

To investigate the mechanism of tirapazamine-induced vascular dysfunction.
To explore the role of nitric oxide synthase (NOS) inhibition in tirapazamine's mechanism of action.

Main Methods:

Administration of tirapazamine to tumor-bearing mice (HCT-116, SiHa, SCCVII).
In vivo assessment of tumor vascular function and tissue perfusion.
In vitro immunohistochemical staining of endothelial cells.
Combination studies with carbogen and NOS inhibitors (L-NNA).

Main Results:

Tirapazamine treatment led to central non-perfused tissue in SiHa and SCCVII tumors within 1 day.
Carbogen breathing reduced, but did not eliminate, tirapazamine's vascular effects.
Tirapazamine's vascular effects are not mediated by microtubule disruption, unlike combretastatin-A-4-phosphate.
Preliminary data suggest NOS inhibition by tirapazamine may contribute to tumor necrosis.

Conclusions:

Tirapazamine induces vascular dysfunction and central tumor necrosis in various xenograft and murine models.
The mechanism of action differs from microtubule-disrupting agents.
Nitric oxide synthase inhibition is a potential mechanism underlying tirapazamine's vascular effects.