EFFECTS OF COMBRETASTATIN ON MURINE TUMORS MONITORED BY P-31 MRS, H-1MRS AND H-1 MRI

Purpose: Combretastatins have tubulin-binding activity and are being i nvestigated for their toxicity against tumour vasculature. We report t he 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 (100 mg/kg, i.p.) on energy metabolism and necrosis, respectively, in the C 3H murine mammary tumour, Materials and Methods: The tumours (volume c a, 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 (T R = 6 s) was performed before treatment and at 1-, 2-, 3-, and 24-h af ter injection of drug or saline via an i.p. line. H-1 MRS (PRESS; 24 m u l voxel; TR = 2 s; TE = 135 ms) and both T-1-weighted (TR = 0.2 s; T E = 0.02 s) and T-2-weighted (TR = 2 s; TE = 0.20 s) H-1 MRI were perf ormed 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 sign ificant fall in pH (by 0.11 units) was observed at 1 h, Although an in crease in the H-1 MR spectroscopy signal at about 1.32 ppm (predominan tly from lactate) was observed in some tumours following combretastati n treatment, this effect was not seen consistently, No changes in the intensity of T-3-weighted H-1 MR images or in tumour necrosis (measure d histologically) were detected within 3 h of treatment. Conclusions: The reduction in tumour energetics and pH was consistent with a reduct ion in tumour blood flow but this occurred before any significant inci dence of haemorrhagic necrosis was detected. The combretastatin dose u sed to achieve these effects was less than one tenth of the maximum to lerated dose in mice. (C) 1998 Elsevier Science Inc.