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Research ArticleArticle

Enzyme-Catalyzed Activation of Anticancer Prodrugs

Martijn Rooseboom, Jan N. M. Commandeur and Nico P. E. Vermeulen
Pharmacological Reviews March 2004, 56 (1) 53-102; DOI: https://doi.org/10.1124/pr.56.1.3
Martijn Rooseboom
Leiden/Amsterdam Center for Drug Research (L.A.C.D.R.), Division of Molecular Toxicology, Department of Pharmacochemistry, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
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Jan N. M. Commandeur
Leiden/Amsterdam Center for Drug Research (L.A.C.D.R.), Division of Molecular Toxicology, Department of Pharmacochemistry, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
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Nico P. E. Vermeulen
Leiden/Amsterdam Center for Drug Research (L.A.C.D.R.), Division of Molecular Toxicology, Department of Pharmacochemistry, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
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Abstract

The rationale for the development of prodrugs relies upon delivery of higher concentrations of a drug to target cells compared to administration of the drug itself. In the last decades, numerous prodrugs that are enzymatically activated into anti-cancer agents have been developed. This review describes the most important enzymes involved in prodrug activation notably with respect to tissue distribution, up-regulation in tumor cells and turnover rates. The following endogenous enzymes are discussed: aldehyde oxidase, amino acid oxidase, cytochrome P450 reductase, DT-diaphorase, cytochrome P450, tyrosinase, thymidylate synthase, thymidine phosphorylase, glutathione S-transferase, deoxycytidine kinase, carboxylesterase, alkaline phosphatase, β-glucuronidase and cysteine conjugate β-lyase. In relation to each of these enzymes, several prodrugs are discussed regarding organ- or tumor-selective activation of clinically relevant prodrugs of 5-fluorouracil, axazaphosphorines (cyclophosphamide, ifosfamide, and trofosfamide), paclitaxel, etoposide, anthracyclines (doxorubicin, daunorubicin, epirubicin), mercaptopurine, thioguanine, cisplatin, melphalan, and other important prodrugs such as menadione, mitomycin C, tirapazamine, 5-(aziridin-1-yl)-2,4-dinitrobenzamide, ganciclovir, irinotecan, dacarbazine, and amifostine. In addition to endogenous enzymes, a number of nonendogenous enzymes, used in antibody-, gene-, and virus-directed enzyme prodrug therapies, are described. It is concluded that the development of prodrugs has been relatively successful; however, all prodrugs lack a complete selectivity. Therefore, more work is needed to explore the differences between tumor and nontumor cells and to develop optimal substrates in terms of substrate affinity and enzyme turnover rates for prodrug-activating enzymes resulting in more rapid and selective cleavage of the prodrug inside the tumor cells.

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Pharmacological Reviews: 56 (1)
Pharmacological Reviews
Vol. 56, Issue 1
1 Mar 2004
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Research ArticleArticle

Enzyme-Catalyzed Activation of Anticancer Prodrugs

Martijn Rooseboom, Jan N. M. Commandeur and Nico P. E. Vermeulen
Pharmacological Reviews March 1, 2004, 56 (1) 53-102; DOI: https://doi.org/10.1124/pr.56.1.3

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Research ArticleArticle

Enzyme-Catalyzed Activation of Anticancer Prodrugs

Martijn Rooseboom, Jan N. M. Commandeur and Nico P. E. Vermeulen
Pharmacological Reviews March 1, 2004, 56 (1) 53-102; DOI: https://doi.org/10.1124/pr.56.1.3
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  • Article
    • Abstract
    • I. Introduction
    • II. Prodrugs Activated by Endogenous Enzymes
    • III. Prodrugs Activated by Antibody-, Gene-, and Virus-Directed Enzyme Prodrug Therapy Approaches
    • IV. Concluding Remarks and Future Perspectives
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