Abstract
BackgroundCellular based therapeutic approaches for cancer rely on careful consideration of finding the optimal cell to execute the cellular goal of cancer treatment. Cell lines and primary cell cultures have been used in some studies to compare the in vitro and in vivo efficacy of autologous vs allogeneic tumour cell vaccines.MethodsThis study examines the effect of γ-irradiation on a range of tumor 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 tumor cell lines.ResultsFollowing co-culture of HSV-TK modified tumor cells and unmodified tumor cells both in vitro and in vivo we observed that the PA-STK ovarian tumor cells were sensitive to γ-irradiation, completely abolishing their ability to induce bystander killing of unmodified tumor cells. In contrast, TK-modified human and mouse mesothelioma cells were found to retain their in vitro and in vivo bystander killing effect after γ-irradiation. Morphological evidence was consistent with the death of PA-STK cells being by pyknosis after γ-irradiation. These results suggest that PA-STK cells are not suitable for clinical application of suicide gene therapy of cancer, as lethal γ-irradiation (100 Gy) interferes with their bystander killing activity. However, the human mesothelioma cell line CRL-5830-TK retained its bystander killing potential after exposure to similarly lethal γ-irradiation (100 Gy). CRL-5830 may therefore be a suitable vehicle for HSV-TK suicide gene therapy.ConclusionsThis study highlights the diversity among tumor cell lines and the careful considerations needed to find the optimal tumor cell line for this type of suicide gene therapy of cancer.
Highlights
The central objective in cancer therapy is to kill the malignant cells while causing little or preferably no collateral damage to healthy cells
It has been demonstrated that two types of “bystander tumor cell killing” mechanisms are mediated by this approach: (a) a “direct” bystander effect, due to the transfer of ganciclovir triphosphate from herpes simplex virus thymidine kinase (HSV-TK)-positive tumor cells into untransfected neighboring cells [12,13,14], (b) a systemic immunologically-mediated bystander effect due to the in vivo immune presentation of tumor-specific/associated antigens following the killing of HSV-TK—expressing cells [15, 16]
PA‐STK cells irradiated at 100 Gy lose their ability to induce bystander killing Irradiation of PA-STK cells (100 Gy) substantially reduced their ability to induce bystander killing of unmodified PA-1 cells (Fig. 1a)
Summary
The central objective in cancer therapy is to kill the malignant cells while causing little or preferably no collateral damage to healthy cells. The in vitro culture of these cells in the presence of ganciclovir provoked bystander killing, but with limited cytotoxic activity in vivo [18] The rationale for this strategy was that PASTK cells, injected in the vicinity of the patient’s tumor bulk, could make contact with, and seed themselves onto, the patient’s tumor cells in vivo and, after treatment with ganciclovir, could commit suicide and kill the patient’s tumor cells by a “direct” bystander mechanism Cell lines and primary cell cultures have been used in some studies to compare the in vitro and in vivo efficacy of autologous vs allogeneic tumour cell vaccines
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