Tirapazamine causes vascular dysfunction in HCT-116 tumour xenografts.
OBJECTIVE
Tirapazamine is a hypoxic cytotoxin currently undergoing Phase II/III clinical evaluation in combination with radiation and chemotherapeutics for the treatment of non-hematological cancers. Tissue penetration studies using multicellular models have suggested that tirapazamine exposure may be limited to cells close to blood vessels. However, animal studies show tirapazamine enhances the anti-tumour activity of radiation and chemotherapy and clinical studies with tirapazamine, so far, are promising. To investigate this apparent paradox we examined the microregional effects of tirapazamine in vivo by mapping drug effects with respect to the position of blood vessels in tumour cryosections.


METHODS
Tirapazamine was administered i.p. to mice bearing HCT-116 tumours, which were excised at various times after treatment. Images of multiple-stained cryosections were overlaid to provide microregional information on the relative position of proliferating cells, hypoxia, perfusion and vasculature.


RESULTS
We observed extensive and permanent vascular dysfunction in a large proportion of tumours from mice treated with tirapazamine. In the affected tumours, blood flow ceased in the centrally located tumour vessels, leaving a rim of functional vessels around the periphery of the tumour. This vascular dysfunction commenced within 24 h after tirapazamine administration and the areas affected appeared to be replaced by necrosis over the following 24-48 h.


CONCLUSIONS
Because the majority of hypoxic cells are located in the center of tumours we propose that the activity of tirapazamine in vivo may be related to its effects on tumour vasculature and that its activity against hypoxic cells located distal to functional blood vessels may not be as important as previously believed.
Huxham
Lynsey A
LA
Medical Biophysics Department, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Kyle
Alastair H
AH
Baker
Jennifer H E
JH
McNicol
Krista L
KL
Minchinton
Andrew I
AI
D000818:Animals; D000963:Antimetabolites; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001808:Blood Vessels / Q000187:drug effects; D001973:Bromodeoxyuridine; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004396:Coloring Agents; D005260:Female; D045325:HCT116 Cells / Q000187:drug effects / Q000637:transplantation*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009336:Necrosis; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012039:Regional Blood Flow / Q000187:drug effects; D012878:Skin Neoplasms / Q000098:blood supply* / Q000188:drug therapy; D000077704:Tirapazamine; D014183:Transplantation, Heterologous; D014227:Triazines / Q000627:therapeutic use*
D000963:Antimetabolites; D000970:Antineoplastic Agents; D004396:Coloring Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D014227:Triazines; D000077704:Tirapazamine; D001973:Bromodeoxyuridine