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Related Experiment Videos

Enzyme-catalyzed activation of anticancer prodrugs.

Martijn Rooseboom1, Jan N M Commandeur, Nico P E Vermeulen

  • 1Leiden/Amsterdam Center for Drug Research (L.A.C.D.R.), Division of Molecular Toxicology, Department of Pharmacochemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, Amsterdam, The Netherlands. vermeule@chem.vu.nl

Pharmacological Reviews
|March 6, 2004
PubMed
Summary

Prodrugs enhance drug delivery to target cells, with numerous enzymatically activated anticancer agents developed. While successful, complete selectivity remains a challenge, necessitating further research for optimal tumor-specific activation.

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Area of Science:

  • Pharmacology
  • Biochemistry
  • Oncology

Background:

  • Prodrugs are designed for targeted delivery of higher drug concentrations to specific cells compared to direct drug administration.
  • Enzymatic activation is a key mechanism for many anticancer prodrugs developed over recent decades.
  • Understanding enzyme characteristics like tissue distribution, tumor cell up-regulation, and turnover rates is crucial for prodrug efficacy.

Purpose of the Study:

  • To review endogenous enzymes critical for prodrug activation in cancer therapy.
  • To discuss various prodrugs and their tumor-selective activation mediated by specific enzymes.
  • To explore non-endogenous enzymes used in advanced prodrug delivery strategies.

Main Methods:

  • Comprehensive review of literature on enzymes involved in prodrug activation.

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  • Analysis of enzyme properties including tissue distribution, tumor expression, and kinetics.
  • Discussion of clinically relevant prodrugs and their activation pathways for various anticancer agents.

    • Main Results:

    • Detailed description of 14 endogenous enzymes (e.g., cytochrome P450, glutathione S-transferase, alkaline phosphatase) and their roles in prodrug activation.
    • Examples of prodrugs activated by these enzymes, including those derived from 5-fluorouracil, cyclophosphamide, paclitaxel, and doxorubicin.
    • Overview of non-endogenous enzymes utilized in antibody-, gene-, and virus-directed enzyme prodrug therapies.

    Conclusions:

    • Prodrug development has shown considerable success in improving drug delivery and efficacy.
    • A significant limitation of current prodrugs is the lack of complete tumor selectivity.
    • Further research is needed to exploit differences between tumor and normal cells for developing prodrugs with enhanced substrate affinity and faster, more selective cleavage within tumor cells.