title: Comparison of two anthracycline-based prodrugs for activation by a monoclonal antibody-beta-glucuronidase conjugate in the specific treatment of cancer.
abstract: Antibody-directed enzyme prodrug therapy (ADEPT) may improve the therapeutic index of cytostatic agents. We compared two prodrugs, epirubicin-glucuronide (Epi-glu) and doxorubicin-spacer-glucuronide (Dox-sp-glu), for their cytotoxicity on activation by a monoclonal antibody-enzyme conjugate bound to tumor cells. The results showed that the prodrugs were 10 (Dox-sp-glu) and 100 (Epi-glu) times less toxic than the parent drugs against OVCAR-3 cells. This difference was a result of the hydrophilic property of the prodrugs resulting in a reduced cellular uptake. The enzyme-catalyzed hydrolysis of Dox-sp-glu by E. coli-derived beta-glucuronidase (GUS) (Km 500 microM, Vmax 21,000 mumol/min/g) was much more efficient than that of Epi-glu (Km 10 microM, Vmax 40 mumol/min/g). Incubation of OVCAR-3 cells with an enzyme-immunoconjugate prepared from monoclonal antibody 323/A3 and E. coli-derived GUS before treatment with prodrugs completely restored the cytotoxicity of the prodrugs to the level of the parent drugs.
authors.affiliation: Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: H J
authors.initials: HJ
authors.lastname: Haisma
authors.forename: M
authors.initials: M
authors.lastname: van Muijen
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: E
authors.initials: E
authors.lastname: Boven
mesh_terms: D000911:Antibodies, Monoclonal; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000627:therapeutic use*; D015251:Epirubicin / Q000627:therapeutic use*; D005260:Female; D005966:Glucuronidase; D006801:Humans; D006868:Hydrolysis; D018796:Immunoconjugates / Q000627:therapeutic use*; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D011355:Prodrugs; D015251:Epirubicin; D004317:Doxorubicin; D005966:Glucuronidase