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: H J Haisma, M van Muijen, H M Pinedo, E Boven
• Journal: Cell biophysics (Cell Biophys) Vol. 24-25 Pg. 185-92 ( 1994) ISSN: 0163-4992 [Print] United States
• PMID: 7736523 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antibodies, Monoclonal
• Immunoconjugates
• Prodrugs
• Epirubicin
• Doxorubicin
• Glucuronidase

Topics

• Antibodies, Monoclonal
• Cell Survival (drug effects)
• Doxorubicin (therapeutic use)
• Epirubicin (therapeutic use)
• Female
• Glucuronidase
• Humans
• Hydrolysis
• Immunoconjugates (therapeutic use)
• Molecular Structure
• Ovarian Neoplasms (drug therapy)
• Prodrugs (therapeutic use)
• Tumor Cells, Cultured