19F NMR in vivo spectroscopy reflects the effectiveness of perfusion-enhancing vascular modifiers for improving gemcitabine chemotherapy

Nuclear magnetic resonance spectroscopy of fluorine-19 (F-19 NMR) has proven useful for evaluating kinetics of fluorinated chemotherapy drugs in tumors in vivo. This work investigated how three perfusion-enhancing vascular modifiers (BQ123, thalidomide, and Botulinum neurotoxin type A [BoNT-A]) would affect the chemotherapeutic efficacy of gemcitabine, a fluorinated drug widely used in human cancer treatment. Murine tumor growth experiments demonstrated that only BoNT-A showed a strong trend to enhance tumor growth inhibition by gemcitabine (1.7 days growth delay, P = 0.052, Student t-test). In accord with these results, F-19 NMR experiments showed that only BoNT-A increased significantly the uptake of gemcitabine in tumors (50% increase, P = 0.0008, Student t-test). Further experiments on gemcitabine kinetics (NMR vs time) and distribution (F-19 MRI) confirmed the uptake-enhancing properties of BoNT-A. The results of this study demonstrate that F-19 NMR can monitor modulation of the pharmacokinetics of fluorinated chemotherapy drugs in tumors. The results also show that F-19 NMR data can give a strong indication of the effectiveness of perfusion-enhancing vascular modifiers for improving gemcitabine chemotherapy in murine tumors. F-19 NMR is a promising tool for preclinical evaluation of such vascular modifiers and may ultimately be used in the clinic to monitor how these modifiers affect chemotherapy. Magn Reson Med 59:19-27, 2008. (C) 2007 Wiley-Liss, Inc.