Noninvasive Measurements of Capecitabine Metabolism in Bladder Tumors Overexpressing Thymidine Phosphorylase by Fluorine-19 Magnetic Resonance Spectroscopy

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Abstract
Purpose: Previous studies have shown that tumor response to capecitabine strongly correlates with tumor thymidine phosphorylase (TP). The aims of our study were to (a) investigate the pharmacological role of TP by measuring the pharmacokinetics (PK) of capecitabine in a human bladder tumor model that was characterized by the overexpression of TP and (b) develop the use of PK measurements for capecitabine by fluorine-19 magnetic resonance spectroscopy as a noninvasive surrogate marker for determining TP levels in tumors and for predicting tumor response to capecitabine in patients. Experimental Design: TP overexpressing (2T10) and control tumors were grown s.c. in nude mice. Mice were given a dose of capecitabine or 5′-deoxy-5-fluorouridine (5′DFUR). 19F tumor spectra were acquired for determination of rate constants of capecitabine breakdown and buildup and subsequent breakdown of intermediates, 5′-deoxy-5-fluorocytidine (5′DFCR) and 5′DFUR. The rate constant of 5′DFUR breakdown was also evaluated. Results: The rate constant of breakdown of intermediates was significantly faster in 2T10 tumors than controls (P < 0.003). No significant differences in the rate of capecitabine breakdown or intermediate buildup were observed. The rate constant of 5′DFUR breakdown in the 2T10 tumors was doubled compared with controls (P < 0.001). Conclusions: This study confirmed the expected pathway of capecitabine metabolism and showed that the level of TP was related to the rate of 5′DFUR conversion. Using in vivo fluorine-19 magnetic resonance spectroscopy to mea-sure the PK of capecitabine and its intermediate metabolites in tumors may provide a noninvasive surrogate method for determining TP levels in tumors and for predicting tumor response to capecitabine in patients.