Abstract
The effect of irradiation on HSV-TK-expressing tumour cells and their bystander killing has been examined. The data presented shows that the irradiation substantially reduced the ability of PA-STK ovarian cells to induce the bystander killing of unmodified tumour cells. PA-STK cells were found to be very sensitive to irradiation and appeared to die too rapidly (even after a low dose of 500-rad) to enable metabolic conversion of GCV to its phosphorylated products, and/or fail to form gap-junctions with their neighbouring cells. Characterisation of tumour cell death showed that PA-STK cells undergo picnosis (a form of necrosis) after irradiation. In contrast, the TK-modified human and mouse mesothelioma cells were found to retain their in vitro bystander killing effect after irradiation. These results suggest that PA-STK cells are not suitable for clinical trials if the cells need to be lethally irradiated before in vivo use. However, the human mesothelioma cell line CRL-5830-TK appears to retain its bystander killing potential after lethal irradiation. In clinical trials, it may therefore be a suitable vehicle for HSV-TK suicide gene therapy for mesothelioma. The low IC50 of GCV in these cells (about 1μμ) makes them particularly attractive.
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