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Purine and Pyrimidine-Based Analogs and Suicide Gene Therapy

  • Zoran Gojkovic
  • Anna Karlsson
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Nucleobase and nucleoside analogs are widely used chemotherapeutic agents in the treatment of cancer and viral diseases. These compounds inhibit or disrupt DNA synthesis, and as tumor cells usually divide more rapidly than normal cells, there is a narrow therapeutic window to be exploited. Suicide gene therapy delivers genes to the cancer cells, enabling them to convert relatively nontoxic prodrugs into active chemotherapeutic agents. With this strategy, drug activation occurs primarily in the cancer cells, thereby maximizing damage to the cancer cells while keeping the systemic toxicity low. A number of suicide gene systems utilizing nucleobase and nucleoside analogs have been described. The best-known and most studied examples are the herpes simplex virus thymidine kinase gene in combination with ganciclovir and the Escherichia coli cytosine deaminase gene, which activates 5-fluorocytosine. Additional promising genes for use in suicide systems include the bacterial purine nucleoside phosphorylase gene; different deoxyribonucleoside kinases, such as the multisubstrate insect nucleoside kinase; and several other genes acting on a variety of different analogs. The efficiency of the currently used suicide systems depends on various biological parameters, such as the potential of activation, degree of activation, and bystander effect. In addition to these parameters, in-depth understanding of the biopharmaceutical properties of the prodrugs and suicide system kinetics should be known before selecting a specific system. Each suicide system offers not only specific advantages but also some limitations, and full understanding of the system can help overcome a number of problems associated with this type of gene therapy. Effective tumor destruction also depends on the delivery systems. Various vectors, including liposomes, retroviruses, and different adenoviruses, have been used to transfer suicide genes to tumor cells. Several of these approaches have been successful in many early clinical trials. Advances in new suicide systems, improved modulation of existing systems, and cell-specific delivery will definitely improve the clinical efficacy of suicide gene therapy and hopefully lead to better cancer treatments.

Key Words

Acyclovir cytosine deaminase deoxynucleoside kinase drug delivery system fluorocytosine ganciclovir gene therapy herpes thymidine kinase suicide genes thymidine kinase 

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Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Zoran Gojkovic
    • 1
  • Anna Karlsson
    • 2
  1. 1.ZGene A/SHørsholmDenmark
  2. 2.Department of Laboratory Medicine, Division of Metabolic DisordersKarolinska InstitutetStockholmSweden

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