Enzyme-Catalyzed Activation of Anticancer Prodrugs
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Open Access
- 4 March 2004
- journal article
- review article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Pharmacological Reviews
- Vol. 56 (1), 53-102
- https://doi.org/10.1124/pr.56.1.3
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.Keywords
This publication has 237 references indexed in Scilit:
- Tissue distribution of cytosolic β-elimination reactions of selenocysteine Se-conjugates in rat and humanChemico-Biological Interactions, 2002
- Metabolism and Pharmacokinetics of OxazaphosphorinesClinical Pharmacokinetics, 2000
- Carbonyl reductase and NADPH cytochrome P450 reductase activities in human tumoral versus normal tissuesEuropean Journal of Cancer, 1999
- Melanogenesis-targeted anti-melanoma pro-drug development: Effect of side-chain variations on the cytotoxicity of tyrosinase-generated ortho-quinones in a model screening systemEuropean Journal of Cancer, 1997
- Interferon alpha and 5′-deoxy-5-fluorouridine in colon cancer: Effects as single agents and in combination on growth of xenograft tumoursEuropean Journal of Cancer, 1994
- Selective assays for thymidine kinase 1 and 2 and deoxycytidine kinase and their activities in extracts from human cells and tissuesBiochemical and Biophysical Research Communications, 1992
- Comparison of the pyrimidine nucleoside phosphorylase activity in human tumors and normal tissuesExperimental pathology, 1988
- Partial purification of a thymidine phosphorylase from human gastric cancer.CHEMICAL & PHARMACEUTICAL BULLETIN, 1986
- Tissue Content and Localization of Lysosomal Enzymes in Cholestatic RatsScandinavian Journal of Gastroenterology, 1986
- Increase in liver and kidney deoxycytidine kinase activity linked to neoplastic transformationBiochemical and Biophysical Research Communications, 1980