Comparison of Two Anthracycline-based Prodrugs for Activation by a Monoclonal Antibody-beta-glucuronidase Conjugate in the Specific Treatment of Cancer

Overview

Journal Cell Biophys

Specialty Biophysics

Date 1994 Jan 1

PMID 7736523

Citations 2

Authors

H J Haisma

M Van Muijen

H M Pinedo

E Boven

Affiliations

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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.

Citing Articles

Diamagnetic Imaging Agents with a Modular Chemical Design for Quantitative Detection of β-Galactosidase and β-Glucuronidase Activities with CatalyCEST MRI.

Fernandez-Cuervo G, Tucker K, Malm S, Jones K, Pagel M Bioconjug Chem. 2016; 27(10):2549-2557.

PMID: 27657647 PMC: 6013409. DOI: 10.1021/acs.bioconjchem.6b00482.

Immunoliposomes as enzyme-carriers (immuno-enzymosomes) for antibody-directed enzyme prodrug therapy (ADEPT): optimization of prodrug activating capacity.

Vingerhoeds M, Haisma H, Belliot S, Smit R, Crommelin D, Storm G Pharm Res. 1996; 13(4):604-10.

PMID: 8710754 DOI: 10.1023/a:1016010524510.

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