Direct in vivo observation of 5-fluorouracil release from a prodrug in human tumors heterotransplanted in nude mice: a magnetic resonance study

A glucuro-conjugated carbamate derivative of 5-fluorouracil (5-FU), origina lly designed as a prodrug for antibody-directed enzyme prodrug therapy (ADE PT) application, has been used for direct in vivo observation of in situ 5- FU generation in two human colon tumors heterotransplanted in nude mice. Be cause of the very fast elimination of glucuro-conjugated drugs, this observ ation required intratumoral injection. These tumors, when becoming necrotic , are rich enough in beta-glucuronidase to allow F-19 magnetic resonance sp ectroscopy monitoring, at the tumor level, of both prodrug elimination and 5-FU liberation without preliminary treatment by a specifically targeted en zyme conjugate. Convenient tumors have been selected by magnetic resonance imaging (MRI) on the basis of a correlative study between MRI and conventio nal histology. This contribution is the first report evidencing such a dire ct intra-tumoral conversion of a glucuro-conjugated prodrug into the expect ed active drug. This method, which should allow overall estimation of the b eta-glucuronidase content of tumors, might also be helpful for selecting tu mors as specific targets for non-toxic glucuro-conjugated prodrugs without prior treatment with a fusion protein. Copyright (C) 2000 John Wiley & Sons , Ltd.