Effects of combretastatin on murine tumours monitored by 31P MRS, 1H MRS and 1H MRI

Purpose: Combretastatins have tubulin-binding activity and are being investigated for their toxicity against tumour vasculature. We report the use of P-31 and H-1 magnetic resonance (MR) spectroscopy and H-1 MR imaging for monitoring the effects of combretastatin A-4 prodrug (100mg/kg, i.p.) on energy metabolism and necrosis, respectively, in the C3H murine mammary tumour, Materials and Methods: The tumours (volume ca, 200mm(3)) were grown in the hind foot of mice, MR examinations were performed without anaesthesia within a 7.1 Tesla magnet. (31)p MRS (TR = 6 s) was performed before treatment and at 1-, 2-, 3-, and 24-h after injection of drug or saline via an i.p. line. H-1 MRS (PRESS; 24 mu l voxel; TR = 2 s; TE = 135 ms) and both T-1-weighted (TR = 0.2 s; TE = 0.02 s) and T-2-weighted (TR = 2 s; TE = 0.20 s) H-1 MRI were performed before treatment and 2.5 and 24 h afterwards. Results: The ratio P-nucleotide triphosphate/inorganic phosphate fell by 33% within 1 h of treatment and remained constant for a further 2 h, A small but significant fall in pH (by 0.11 units) was observed at 1 h, Although an increase in the H-1 MR spectroscopy signal at about 1.32 ppm (predominantly from lactate) was observed in some tumours following combretastatin treatment, this effect was not seen consistently, No changes in the intensity of T-3-weighted H-1 MR images or in tumour necrosis (measured histologically) were detected within 3 h of treatment. Conclusions: The reduction in tumour energetics and pH was consistent with a reduction in tumour blood flow but this occurred before any significant incidence of haemorrhagic necrosis was detected. The combretastatin dose used to achieve these effects was less than one tenth of the maximum tolerated dose in mice. (C) 1998 Elsevier Science Inc.