Bystander effect, tumor cells

In another study, AAV-mediated delivery of the lacZ gene by direct injection to brain tumors which were induced from human glioma cells in nude mice showed that 30% to 40% of the cells along the needle track expressed b-galactosidase subsequent delivery of the HS V-tk/IL-2 genes to these tumors with AAV and administration of GCV to the animals for 6 days resulted in a 35-fold reduction in the mean volume of tumors compared with controls by a significant contribution from the bystander effect (72). 

Xue LY, Butler NJ, Makrigiorgos GM, Adel-stein SJ, Kassis Al. Bystander effect produced by radiolabeled tumor cells in vivo. 

Studies with radioactive isotopes have been performed to facilitate a therapeutic effect - a strategy called radioimmunotherapy [124]. Radiolabels include -emitters such as Sc, and [125] (see Part V, Chap-ters 4 and 5). When compared to immuno-scintigraphy, the applied doses are higher in order to establish a cytotoxic effect. Even cells within the tumor that are inaccessible to the antibody can be killed without prior internalization (the bystander effecf). 

In addition, NIS gene therapy is associated with a substantial bystander effect based on the crossfire effect of the (3-emitter with a path length of up to 2.4mm. Since in vivo transduction efficiency is limited by low levels of vector delivery to tumor cells and by the toxicity of available vector systems, a bystander effect is desirable for any kind of gene therapy strategy because it reduces the level of transduction efficiency required for a therapeutic response (Dingli et al., 2003a, b). 

The tumor suppression approach attempts to induce apoptosis by delivering a tumor suppressor gene that is missing or defective in the tumor cells [2]. On the contrary, normal cells infected by the tumor suppressor delivery vector will not be detrimentally affected. The approach is perfectly illustrated with p53, a gene whose mutations have been associated with several tumors. The delivery of wild-type p53 gene efficiently induces apoptosis in cells of different tumors, as demonstrated in several phase I and II clinical trials [43, 71]. Additionally, this toxic effect can extend to neighbor, uninfected tumor cells, a phenomenon known as the bystander effect . This effect has been attributed to the ability of p53 to block angiogenesis... 

The above-mentioned bystander effects are expected to be of importance for understanding the response of tissues to radiation Injury, because cells in a tissue are usually connected by complex communication networks. In fact there are first indications that bystander effects cannot only be detected in in vitro systems, but also in in vivo-like systems such as, e.g., tissue explants [101]. Since bystander effects play a role at low doses and low fluences, they might be in particular relevant for studies of mutation and transformation related to radiation protection. For applications of ion beams in tumor therapy, doses and thus fluences are usually comparably high, so that the fraction of unhit cells is small. 

During the last decade it has become increasingly evident that the cytotoxic effects of radiotherapy on tumors are not only the result of the DNA damage inflicted to the tumor cells. Radiation can induce the release of several factors, with direct or indirect cytotoxic capacity, not only from tumor cells but also from different bystander cells that can trigger death of tumor cells. 

One early study of the effect of in vivo radiation could not verify any increase of iNOS in the brain after radiation although NO-inducing cytokines such as TNF-a and IL-ip were up-regulated (Hong et al. 1995). However, in vitro induction of NO in tumor cells by IFN-y treatment as well as by irradiation itself was shown to substantially increase the radiosensitivity of not only these cells but also bystander cells (Janssens et al. 1998 Matsumoto et al. 2000). 

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