© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 23, 1986-1989,
December 1, 1999
© 1999 Oxford University Press
EDITORIALS |
Enzyme/Prodrug-Based Tumor Vaccination: All Politics (and Immunity) Are Local
Affiliations of author: Metabolism Branch, Division of Clinical Sciences, National Cancer Institute, and Clinical Gene Therapy Branch, National Human Genome Research Institute, Bethesda, MD.
Correspondence to: John C. Morris, M.D., National Institutes of Health, Bldg. 10, Rm. 4N115, Bethesda, MD 20892-1374 (e-mail: jmorris@mail.nih.gov).
A major focus of gene therapy for cancer has been the effort to
introduce into cancer cells a number of foreign genes that encode
enzymes that will selectively convert nontoxic prodrugs into toxic
compounds, producing high local concentrations that result in tumor
cell killing—so-called "suicide" gene therapy. A number of
enzyme/prodrug systems have been described [reviewed in
(1)], including herpes simplex virus-thymidine kinase
(HSV-tk)/ganciclovir (GCV) and Escherichia coli cytosine
deaminase (CD)/5-fluorocytosine. A surprising early observation in many
of these systems was that not every cell in a tumor need express the
transgene to achieve meaningful cell killing and tumor regression
(2,3). This phenomenon, the bystander effect, is defined as
the ability of the genetically modified cells, in the presence of the
prodrug, to cause cytotoxic effects in cells that lack the suicide
gene. The result is that the fraction of cells killed is in
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