Magnetic resonance imaging and spectroscopy of combretastatin A(4) prodrug-induced disruption of tumour perfusion and energetic status

The effects of combretastatin A(4) prodrug on perfusion and the levels of P -31 metabolites in an implanted murine tumour were investigated for 3 h aft er drug treatment using nuclear magnetic resonance imaging (MRI) and spectr oscopy (MRS). The area of regions of low signal intensity in spin-echo imag es of tumours increased slightly after treatment with the drug. These regio ns of low signal intensity corresponded to necrosis seen in histological se ctions, whereas the expanding regions surrounding them corresponded to haem orrhage. Tumour perfusion was assessed before and 160 min after drug treatm ent using dynamic MRI measurements of gadolinium diethylenetriaminepentaace tate (GdDTPA) uptake and washout. Perfusion decreased significantly in cent ral regions of the tumour after treatment. This was attributed to disruptio n of the vasculature and was consistent with the haemorrhage seen in histol ogical sections. The mean apparent diffusion coefficient of water within th e tumour did not change, indicating that there was no expansion of necrotic regions during the 3 h after drug treatment. Localized P-31-MRS showed tha t there was decline in cellular energy status in the tumour after treatment with the drug. The concentrations of nucleoside triphosphates within the t umour fell, the inorganic phosphate concentration increased and there was a significant decrease in tumour pH for 80 min after drug treatment. The rap id, selective and extensive damage caused to these tumours by combretastati n A(4) prodrug has highlighted the potential of the agent as a novel cancer chemotherapeutic agent. We have shown that the response of tumours to trea tment with the drug may be monitored non-invasively using MRI and MRS exper iments that are appropriate for use in a clinical setting.