Validation of a new combretastatin A-4 (CA-4) analogue in a colon cancer mouse model using PET imaging

Introduction Combretastatin A-4 and its analogues are potent inhibitors of tubulin polymerization and display antivascular properties in vivo. In addition, they exhibit potent anticancer activity in many solid tumours. A series of novel 1,4-dyaril-2-azetidinones were synthesized and the most potent compounds displayed inhibition of tubulin polymerization, activation of AMP-activated protein kinase (AMPK) and antiproliferative activity against colon cancer cells (1). Here, we in vivo evaluated 1,4-dyaril-2-azetidinone therapeutic efficacy in a mouse model of colon cancer using [18F]FDG PET imaging. Methods Previous studies revealed a MTD of 40 mg/kg. On these basis, we tested therapeutic effects of 40 mg/kg as acute and fractionated dose. Athymic nude mice (n = 18) were injected s.c. in the dorsal flank with 2*106 human colorectal adenocarcinoma cells, SW48. Once tumours reached about 140 mm3, animals were randomized into 3 groups: control (vehicle), acute dose (i.v, 40 mg/kg), fractionated dose (i.v, 8 mg/kg 5qwx1). Mice were twice a week monitored for weight and tumor volume by callipers. In parallel, [18F]FDG-PET studies were performed at 8 and 15 days from therapy beginning. For quantification, radioactivity concentration in tumours was expressed as tumor-to-background ratio. Results None mice died after drug administration but we noted an early weight loss which was recovered after 7 days. Since 7 days we observed a cytostatic effect and a significant difference volume between control and treated groups. After 11 days, treated tumours restarted to grow. In parallel, control mice tumours displayed a higher [18F]FDG uptake (T/B: 4.3 ± 1.8) compared to those of acute dose mice (1.5 ± 0.5). [18F]FDG uptake of fractionated dose treated mice was heterogeneous. After tumour relapse, all treated mice displayed [18F]FDG uptake similar to that of control mice (T/B: 4.2 ± 0.1; 6.3 ± 0.4 respectively for acute and fractionated groups). Conclusions CA-4 analogue seems to be a potential therapeutic agents against colon cancer and [18F]FDG PET allows to monitor tumour response to therapy. Further validations using CA-4 analogue- poor responsive tumour cells and other radioligands as [18F]FLT will be performed. Acknowledgment/References 1. Tripodi F et al. J Med Chem 2012 This research was supported by Sysbionet (Italian Research Infrastructures of the Italian ESFRI roadmap)