Prodrug activation enzymes in cancer gene therapy
- 24 May 2000
- journal article
- review article
- Published by Wiley in The Journal of Gene Medicine
- Vol. 2 (3) , 148-164
- https://doi.org/10.1002/(sici)1521-2254(200005/06)2:3<148::aid-jgm105>3.0.co;2-q
Abstract
Among the broad array of genes that have been evaluated for tumor therapy, those encoding prodrug activation enzymes are especially appealing as they directly complement ongoing clinical chemotherapeutic regimes. These enzymes can activate prodrugs that have low inherent toxicity using both bacterial and yeast enzymes, or enhance prodrug activation by mammalian enzymes. The general advantage of the former is the large therapeutic index that can be achieved, and of the latter, the non‐immunogenicity (supporting longer periods of prodrug activation) and the fact that the prodrugs will continue to have some efficacy after transgene expression is extinguished. This review article describes 13 different prodrug activation schemes developed over the last 15 years, two of which – activation of ganciclovir by viral thymidine kinase and activation of 5‐fluorocytosine to 5‐fluorouracil – are currently being evaluated in clinical trials. Essentially all of these prodrug activation enzymes mediate toxicity through disruption of DNA replication, which occurs at differentially high rates in tumor cells compared with most normal cells. In cancer gene therapy, vectors target delivery of therapeutic genes to tumor cells, in contrast to the use of antibodies in antibody‐directed prodrug therapy. Vector targeting is usually effected by direct injection into the tumor mass or surrounding tissues, but the efficiency of gene delivery is usually low. Thus it is important that the activated drug is able to act on non‐transduced tumor cells. This bystander effect may require cell‐to‐cell contact or be mediated by facilitated diffusion or extracellular activation to target neighboring tumor cells. Effects at distant sites are believed to be mediated by the immune system, which can be mobilized to recognize tumor antigens by prodrug‐activated gene therapy. Prodrug activation schemes can be combined with each other and with other treatments, such as radiation, in a synergistic manner. Use of prodrug wafers for intratumoral drug activation and selective permeabilization of the tumor vasculature to prodrugs and vectors should further increase the value of this new therapeutic modality. Copyright © 2000 John Wiley & Sons, Ltd.Keywords
This publication has 84 references indexed in Scilit:
- The bystander effect in the HSVtk/ganciclovir system and its relationship to gap junctional communicationGene Therapy, 1998
- Enhancement of the Herpes Simplex Virus Thymidine Kinase/Ganciclovir Bystander Effect and Its Antitumor Efficacy In Vivo by Pharmacologic Manipulation of Gap JunctionsHuman Gene Therapy, 1998
- In vivo human carboxylesterase cDNA gene transfer to activate the prodrug CPT-11 for local treatment of solid tumors.Journal of Clinical Investigation, 1998
- Synergistic Anticancer Effects of Ganciclovir/Thymidine Kinase and 5-Fluorocytosine/Cytosine Deaminase Gene TherapiesJNCI Journal of the National Cancer Institute, 1998
- Expression of the bacterial nitroreductase enzyme in mammalian cells renders them selectively sensitive to killing by the prodrug CB1954European Journal Of Cancer, 1995
- In VitroEvidence That Metabolic Cooperation Is Responsible for the Bystander Effect Observed with HSVtkRetroviral Gene TherapyHuman Gene Therapy, 1993
- Temozolomide: A new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumoursEuropean Journal Of Cancer, 1993
- GanciclovirDrugs, 1990
- The differential response of resistant and sensitive strains of Escherichia coli to the cytotoxic effects of 5-aziridino-2,4-dinitrobenzamide (CB 1954)Chemico-Biological Interactions, 1971
- Tumour-growth inhibitorynitrofphenylaziridines and related compounds structure-activity relationshipsChemico-Biological Interactions, 1969