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Using magnetic resonance imaging and immunohistochemistry to monitor the response of HCT-116 xenograft tumours to tirapazamine Bains, Lauren Jean

Abstract

Tirapazamine is a prodrug which is activated under hypoxic conditions and has shown promise in treating hypoxic tumours. Using MRI and histochemistry, the response of HCT116 xenograft tumours to tirapazamine was investigated and quantified. Dynamic contrast-enhanced and diffusion weighted MRI scans were acquired both before and after treatment with tirapazamine in under two hours of imaging time per session. MRI data was used to produce maps of the apparent diffusion coefficient (ADC), area-under-the-curve (IAUC), and pharmacokinetic parameters (Ktrans, ve, vv). Carbocyanine and BrdU/haematoxylin staining were used to produce histological images of perfusion and necrosis. Implanted fiducial markers were used to align MRI data before and after treatment, and to align MRI slices with histological sections. Qualitative and quantitative comparisons between MRI and histological images showed good agreement between the two. Data from both modalities showed that tirapazamine causes significant changes in diffusion and decreases in perfusion within 24 hours after treatment; widespread vascular shutdown and central necrosis were observed in treated tumours. The agreement of dynamic contrast-enhanced MRI and diffusion weighted MRI with accepted immunohistochemical methods suggests that the MRI techniques presented here are effective methods of monitoring the response of hypoxic, heterogeneous tumours to treatment with tirapazamine. This is the first MR investigation to measure the effects of tirapazamine in an in vivo tumour model. The non-invasive imaging protocol developed here has the potential for direct translation to the clinic in a potential trial. Interestingly, the response of tumours to tirapazamine is evidenced by marked vascular shutdown detected using dynamic contrast enhanced MR imaging, supporting the hypothesis that tirapazamine's mechanism of action may include vascular effects.

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