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

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 (5DFUR).19 F tumor spectra were acquired for determination of rate constants of capecitabine breakdown and buildup and subsequent breakdown of intermediates, 5-deoxy-5-fluorocytidine (5DFCR) and 5DFUR. The rate constant of 5DFUR 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 5DFUR 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 5DFUR conversion. Using in vivo fluorine-19 magnetic resonance spectroscopy to measure 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.

Magnetic resonance imaging and spectroscopy of transgenic models of cancer

“…This study demonstrated the feasibility of using MRS to non-invasively monitor therapeutic transgene expression in tumors. Tumor response to capecitabine, a novel prodrug of 5-fluorouracil, strongly correlated with tumor thymidine phosphorylase expression levels in a transgenic human bladder tumor model, as monitored by using 19 F MRS of capecitabine as a surrogate marker for determining thymidine phosphorylase levels in tumor (101).…”

Multinuclear NMR Measurements and DFT Calculations for Capecitabine Tautomeric Form Assignment in a Solution

“…A detailed assignment of the 1 H/ 13 C/ 19 F and 15 N-NMR signals is presented in Table 3 . The form I of capecitabine should also be the one encountered in numerous studies on human liquids and organs [ 21 , 22 , 23 ] whose major content is water. At this stage of our studies, it should be mentioned that there is no reason to revise the notation of the capecitabine structure, as suggested previously [ 14 ].…”

Current Opportunities and Challenges of Magnetic Resonance Spectroscopy, Positron Emission Tomography, and Mass Spectrometry Imaging for Mapping Cancer MetabolismIn Vivo

“…Most in vivo studies on MR pharmacokinetic measurements of tumors employ fluorinated drugs, such as [5- 19 F]-fluorouracil (5-FU) and its prodrug, as detected by 19 F MRS [88, 89], because 19 F MRS provides relatively high sensitivity combined with low background signal. Successful image-guided delivery of a prodrug enzyme, bacterial cytosine deaminase (bCD), which converts nontoxic [5- 19 F]-fluorocytosine (5-FC) to 5-FU, was recently reported in preclinical studies [90].…”