Abstract
BackgroundTherapeutic approaches for cancer rely on careful consideration of finding the optimal way of delivering the pro-drug for cellular-based cancer treatment. Cell lines and cell cultures have been used in these studies to compare the in vitro and in vivo efficacy of autologous vs. allogeneic tumour cellular gene therapy. Here we have investigated and are reporting for the first time the effect of prodrug ganciclovir (GCV)-preloading (pre-treatment) in suicide gene therapy of cancer.MethodsThis study examines the effect of GCV-preloading (pre-treatment) on a range of tumour cell lines in conjunction with suicide gene therapy of cancer. To determine the efficacy of this modality, a series of in vitro and in vivo experiments were conducted using genetically modified and unmodified tumour cell lines.ResultsFollowing co-culture of herpes simplex virus thymidine kinase (HSV-TK) modified tumour cells and unmodified tumour cells both in vitro and in vivo, GCV-preloading (pre-treatment) of TK-modified human and mouse mesothelioma cells and ovarian tumour cells allowed them to mediate efficiently bystander killing of neighbouring unmodified tumour cells in vitro. In contrast, GCV-preloading of TK-modified human and mouse mesothelioma cells and ovarian tumour cells abolished their in vivo ability to induce bystander killing of unmodified tumour cells, although there was some tumour regression compared to control groups but this was not statistically significant. These results suggest that preloading TK modified tumour cells with GCV needs further study to define the most effective strategy for an in vivo application to retain their bystander killing potential after exposure to lethal doses of GCV in vitro.ConclusionsThis study highlights the promising possibility of improving the efficacy of pro-drug system to prevent any damage to the immune system and enhancing this type of suicide gene therapy of cancer, as well as the need for further studies to explore the discrepancies between in vitro and in vivo results.
Highlights
Therapeutic approaches for cancer rely on careful consideration of finding the optimal way of delivering the pro-drug for cellular-based cancer treatment
It has been established that two forms of “bystander tumour cell killing” mechanisms are mediated by this method: (a) a local “direct” bystander effect, as a result of the transfer of ganciclovir triphosphate from herpes simplex virus thymidine kinase (HSV-TK)-positive tumour cells into untransfected neighbouring tumour cells [9,10,11], (b) a non-local systemic immunologically-mediated bystander effect due to the in vivo immune stimulation/presentation of tumour-specific or associated antigens following the killing of HSV-TK-expressing tumour cells [12, 13]
GCV incubation time needed for the induction of cell death in PA‐STK cells This experiment was set up to determine the minimum time of GCV treatment required to induce cell death in the TK+ve cells
Summary
Therapeutic approaches for cancer rely on careful consideration of finding the optimal way of delivering the pro-drug for cellular-based cancer treatment. The insertion of the herpes simplex virus thymidine kinase (HSV-TK) gene into tumour cells which are subsequently induced to “commit suicide” when in the presence of a non-toxic dosages of ganciclovir (GCV) [3, 4]. The pre-loading of TK+ve tumour cells with GCV may ensure that the cells have received the required dose of GCV This may reduce the possible immunotoxic effects of GCV. In this study we have shown for the first time to our knowledge the effect of GCV preloading (pre-treatment) on the fate of the bystander killing of TK-modified tumour cells, both in vitro and in vivo as well as possible ways to improve its action
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