title: Direct in vivo observation of 5-fluorouracil release from a prodrug in human tumors heterotransplanted in nude mice: a magnetic resonance study.
abstract: 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.
authors.affiliation: Institut Curie Recherche, Laboratoire Raymond Latarjet, INSERM U350, Centre Universitaire, 91405 Orsay, France.
authors.forename: J L
authors.initials: JL
authors.lastname: Guerquin-Kern
authors.forename: A
authors.initials: A
authors.lastname: Volk
authors.forename: E
authors.initials: E
authors.lastname: Chenu
authors.forename: R
authors.initials: R
authors.lastname: Lougerstay-Madec
authors.forename: C
authors.initials: C
authors.lastname: Monneret
authors.forename: J C
authors.initials: JC
authors.lastname: Florent
authors.forename: D
authors.initials: D
authors.lastname: Carrez
authors.forename: A
authors.initials: A
authors.lastname: Croisy
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D005966:Glucuronidase / Q000032:analysis; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D005966:Glucuronidase; D005472:Fluorouracil