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Are we systematically under-dosing patients with fluorouracil?

Introduction Fluorouracil (FU) analogs are widely used but incompletely effective for cancer treatment. Drug treatment failure may be unnecessarily high as a result of suboptimal dosing, yet finding the correct dose is difficult. Individualized dose calculation using blood monitoring was reported to achieve a target plasma level, overcoming variable plasma FU levels among patients. It might be yet more informative to assay the end effects on tissues, but this had not been done in patients. Thymidylate synthase (TS) is covalently modified after FU, inhibiting its function. This adducted TS (TS-F) protein manifests as a slower species in protein gels or as a neoepitope recognized by a specific antibody (FTS; EMD Millipore, Billerica, MA). TS is detectable by immunoblotting from human tumors and proliferative normal tissues such as duodenal mucosa. TS-F is stable, being observed in cultured cells, xenografts, and normal tissues even weeks after a single short exposure of FU. The ratio of TS-F to TS and dose relationships were explored in FU-treated cells, murine tissues, and xenografts. We present here the clinical quantitative detection of FU activity (the ratio) in tissues from two patients receiving the FU analog capecitabine by neoadjuvant dosing.