Detecting vascular-targeting effects of the hypoxic cytotoxin tirapazamine in tumor xenografts using magnetic resonance imaging.
OBJECTIVE
To determine whether vascular-targeting effects can be detected in vivo using magnetic resonance imaging (MRI).


METHODS
MR images of HCT-116 xenograft-bearing mice were acquired at 7 Tesla before and 24 hours after intraperitoneal injections of tirapazamine. Quantitative dynamic contrast-enhanced MRI analyses were performed to evaluate changes in tumor perfusion using two biomarkers: the volume transfer constant (K(trans)) and the initial area under the concentration-time curve (IAUC). We used novel implanted fiducial markers to obtain cryosections that corresponded to MR image planes from excised tumors; quantitative immunohistochemical mapping of tumor vasculature, perfusion, and necrosis enabled correlative analysis between these and MR images.


RESULTS
Conventional histological analysis showed lower vascular perfusion or greater amounts of necrosis in the central regions of five of eight tirapazamine-treated tumors, with three treated tumors showing no vascular dysfunction response. MRI data reflected this result, and a striking decrease in both K(trans) and IAUC values was seen with the responsive tumors. Retrospective evaluation of pretreatment MRI parameters revealed that those tumors that did not respond to the vascular-targeting effects of tirapazamine had significantly higher pretreatment K(trans) and IAUC values.


CONCLUSIONS
MRI-derived parameter maps showed good agreement with histological tumor mapping. MRI was found to be an effective tool for noninvasively monitoring and predicting tirapazamine-mediated central vascular dysfunction.
Bains
Lauren J
LJ
Department of Physics and Astronomy, University of British Columbia, Vancouver, Canada.
Baker
Jennifer H E
JH
Kyle
Alastair H
AH
Minchinton
Andrew I
AI
Reinsberg
Stefan A
SA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001810:Blood Volume / Q000187:drug effects*; D001811:Blood Volume Determination / Q000379:methods; D015687:Cell Hypoxia / Q000187:drug effects; D003287:Contrast Media; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009336:Necrosis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000628:therapy; D019736:Prostheses and Implants; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D000077704:Tirapazamine; D014183:Transplantation, Heterologous; D014227:Triazines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D003287:Contrast Media; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine