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), originally designed as a prodrug for antibody-directed enzyme prodrug therapy (ADEPT) application, has been used for direct in vivo observation of in situ 5-FU generation in two human colon tumors heterotransplanted in nude mice. Because of the very fast elimination of glucuro-conjugated drugs, this observation required intratumoral injection. These tumors, when becoming necrotic, are rich enough in beta-glucuronidase to allow (19)F magnetic resonance spectroscopy monitoring, at the tumor level, of both prodrug elimination and 5-FU liberation without preliminary treatment by a specifically targeted enzyme conjugate. Convenient tumors have been selected by magnetic resonance imaging (MRI) on the basis of a correlative study between MRI and conventional histology. This contribution is the first report evidencing such a direct intra-tumoral conversion of a glucuro-conjugated prodrug into the expected active drug. This method, which should allow overall estimation of the beta-glucuronidase content of tumors, might also be helpful for selecting tumors as specific targets for non-toxic glucuro-conjugated prodrugs without prior treatment with a fusion protein. Copyright 2000 John Wiley & Sons, Ltd.