Mechanism of 'bystander effect' killing in the herpes simplex thymidine kinase gene therapy model of cancer treatment.
'Bystander' killing of adjacent wild-type tumor cells was seen when tumors transduced with the herpes thymidine kinase gene were treated with the antiviral agent ganciclovir (GCV). Some tumors were 'bystander-sensitive' while others were 'bystander-resistant'. Mixtures of different 'sensitive' tumor lines showed cross-transfer of bystander killing, while in mixtures of 'resistant' with 'sensitive' tumors, the resistant phenotype was predominant. Using 3H-GCV with 'sensitive' mixtures, phosphorylated 3H-GCV was found in both herpes thymidine kinase transduced and unmodified cells, while 'resistant' cell combinations showed little or no transfer of phosphorylated GCV between cells. The capacity of intracellularly produced nucleotide toxin to spread from cell to cell within a tumor mass effectively amplifies the apparent efficiency of gene transfer in the tumor and makes feasible the use of this system for therapy of localized cancer.
Ishii-Morita
H
H
Clinical Gene Therapy Branch, National Center for Human Genome Research, National Institutes of Health, Bethesda, MD, USA.
Agbaria
R
R
Mullen
C A
CA
Hirano
H
H
Koeplin
D A
DA
Ram
Z
Z
Oldfield
E H
EH
Johns
D G
DG
Blaese
R M
RM
D000230:Adenocarcinoma / Q000628:therapy; D000818:Animals; D000998:Antiviral Agents; D001692:Biological Transport; D018920:Coculture Techniques; D003131:Combined Modality Therapy; D004247:DNA / Q000096:biosynthesis; D005354:Fibrosarcoma / Q000628:therapy; D015774:Ganciclovir / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006561:Herpes Simplex / Q000201:enzymology*; D006801:Humans; D018189:Immunomagnetic Separation; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D004247:DNA; D013937:Thymidine Kinase; D015774:Ganciclovir