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Article

Enzyme-Catalyzed Activation of Anticancer Prodrugs

Leiden/Amsterdam Center for Drug Research (L.A.C.D.R.), Division of Molecular Toxicology, Department of Pharmacochemistry, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

Abstract

I. Introduction

A. General Introduction

B. Prodrugs Designed to Increase the Bioavailability of Antitumor Drugs

C. Prodrugs Designed to Increase the Local Delivery of Antitumor Drugs

D. Prodrugs Activated by Enzyme Immunoconjugates and by Gene Therapy

E. Aim and Scope of This Review

II. Prodrugs Activated by Endogenous Enzymes

A. Class 1 Oxidoreductases

1. Aldehyde Oxidase

a. Enzymology of Aldehyde Oxidase.

b. Localization of Aldehyde Oxidase.

c. Activation of Prodrugs by Aldehyde Oxidase.

d. Discussion of Aldehyde Oxidase as a Prodrug-Activating Enzyme.

2. Amino Acid Oxidase

a. Enzymology of Amino Acid Oxidase.

b. Localization of Amino Acid Oxidase.

c. Activation of Prodrugs by Amino Acid Oxidase.

d. Discussion of Amino Acid Oxidase as a Prodrug-Activating Enzyme.

3. Cytochrome P450 Reductase

a. Enzymology of Cytochrome P450 Reductase.

b. Localization of Cytochrome P450 Reductase.

c. Activation of Prodrugs by Cytochrome P450 Reductase.

d. Discussion of Cytochrome P450 Reductase as a Prodrug-Activating Enzyme.

4. DT-diaphorase

a. Enzymology of DT-Diaphorase.

b. Localization of DT-Diaphorase.

c. Activation of Prodrugs by DT-Diaphorase.

d. Discussion of DT-Diaphorase and Cytochrome P450 Reductase (Section II.A.3.) as Prodrug-Activating Enzymes.

5. Cytochrome P450

a. Enzymology of Cytochrome P450.

b. Localization of Cytochrome P450.

c. Activation of Prodrugs by Cytochrome P450.

d. Discussion of Cytochrome P450 as a Prodrug-Activating Enzyme.

6. Tyrosinase

a. Enzymology of Tyrosinase.

b. Localization of Tyrosinase.

c. Activation of Prodrugs by Tyrosinase.

d. Discussion of Tyrosinase as a Prodrug-Activating Enzyme.

B. Class 2 Transferases

1. Thymidylate Synthase

a. Enzymology of Thymidylate Synthase.

b. Localization of Thymidylate Synthase.

c. Activation of Prodrugs by Thymidylate Synthase.

d. Discussion of Thymidylate Synthase as a Prodrug-Activating Enzyme.

2. Thymidine Phosphorylase

a. Enzymology of Thymidine Phosphorylase.

b. Localization of Thymidine Phosphorylase.

c. Activation of Prodrugs by Thymidine Phosphorylase.

d. Discussion of Thymidine Phosphorylase as a prodrug-Activating Enzyme.

3. Glutathione S-Transferase

a. Enzymology of Glutathione

b. Localization of Glutathione

c. Activation of Prodrugs by Glutathione

d. Discussion of Glutathione

4. Deoxycytidine Kinase

a. Enzymology of Deoxycytidine Kinase.

b. Localization of Deoxycytidine Kinase.

c. Activation of Prodrugs by Deoxycytidine Kinase.

d. Discussion of Deoxycytidine Kinase as a Prodrug-Activating Enzyme.

C. Class 3 Hydrolases

1. Carboxylesterase

a. Enzymology and Localization of Carboxylesterase.

b. Activation of Prodrugs by Carboxylesterase.

2. Alkaline Phosphatase

a. Enzymology and Localization of Alkaline Phosphatase.

b. Activation of Prodrugs by Alkaline Phosphatase.

3. {beta}-Glucuronidase

a. Enzymology and Localization of

b. Activation of Prodrugs by

4. Discussion of Hydrolase Enzymes as Prodrug-Activating Enzymes.

D. Class 4 Lyases

1. Cysteine Conjugate {beta}-Lyase

a. Enzymology of Cysteine Conjugate {beta}-Lyase.

b. Localization of Cysteine Conjugate

c. Activation of Prodrugs by Cysteine Conjugate

d. Discussion of Cysteine Conjugate {beta}-Lyase as a prodrug-Activating Enzyme.

III. Prodrugs Activated by Antibody-, Gene-, and Virus-Directed Enzyme Prodrug Therapy Approaches

A. Nitroreductase

1. Enzymology of Nitroreductase.

2. Activation of CB 1954 by Nitroreductase.

B. Cytochrome P450

1. Activation of Prodrugs by Nonhuman Cytochromes P450.

C. Purine-Nucleoside Phosphorylase

1. Enzymology of Purine-Nucleoside Phosphorylase.

2. Activation of Prodrugs by Purine-Nucleoside Phosphorylase.

D. Thymidine Kinase

1. Enzymology of Thymidine Kinase.

2. Activation of Ganciclovir by Thymidine Kinase.

E. Alkaline Phosphatase

1. Activation of Prodrugs by Nonhuman Alkaline Phosphatase.

F. {beta}-Glucuronidase

1. Activation of Prodrugs by Nonhuman {beta}-Glucuronidase.

G. Carboxypeptidase

1. Enzymology of Carboxypeptidase.

2. Activation of Prodrugs by Carboxypeptidase.

H. Penicillin Amidase

1. Enzymology of Penicillin Amidase.

2. Activation of Prodrugs by Penicillin Amidase.

I. {beta}-Lactamase

1. Enzymology of {beta}-Lactamase.

2. Activation of Prodrugs by

J. Cytosine Deaminase

1. Enzymology of Cytosine Deaminase.

2. Activation of 5-Fluorocytosine by Cytosine Deaminase.

K. Methionine {gamma}-Lyase

1. Enzymology of Methionine {gamma}-Lyase.

2. Activation of Prodrugs by Methionine {gamma}-Lyase.

IV. Concluding Remarks and Future Perspectives

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, -glucuronidase and cysteine conjugate -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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