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PubMed2004

Bystander effects in repair-deficient cell lines.

One of the current hypotheses concerning the role of bystander effects in biological systems is that they are protective because they terminate division in cells with collateral or possibly pre-existing DNA damage that is not properly repaired. Following the logic of this hypothesis led us to consider that cell lines that are repair deficient should have larger than usual bystander effects. To test this, several different "repair- deficient" cell lines were used for bystander experiments. Response was monitored by determining the cloning efficiency or, in the case of non-adherent cell lines, the cell number. The results show that the repair-deficient human cell lines and surviving progeny produced moderate to severe bystander- induced death effects in either autologous cells or a reporter cell line. Normal "repair-proficient" lines, which were matched as far as possible, have very much less severe or absent bystander-inducible effects on cloning efficiency. Cells of hamster cell lines derived from CHO-K1 cells did not produce similar severe effects. The results suggest that repair- deficient human cell lines, irrespective of the actual repair defect, may respond to the occurrence of DNA damage in the population by removing large numbers of cells from the proliferating pool.

Animals↗
PubMed2004

Multiple bystander effect of irradiated megacolonies of melanoma cells on non-irradiated neighbours.

The multicellular megacolonies of human melanoma Me45 line growing on one part of the bottom of culture flasks were irradiated with 5 Gy (60Co), whereas megacolonies growing on the second part of the bottom were shielded. The bystander effect of radiation-traversed cells on non-traversed cells was studied during postradiation co-cultivation. Activity of superoxide dismutase (Mn and CuZn subunits), glutathione peroxidase (GSH-Pox) and malondialdehyde (MDA) concentration as a biochemical markers of bystander effect were monitored for a period of 72 h. The DNA damage was measured by the comet assay. Micronucleus induction, mitotic index and cellular death as apoptosis or necrosis were simultaneously estimated, based on morphologic criteria. The bystander effect of irradiated cells on their neighbours was observed as a slight increase of MDA concentration, comparable decrease of GSH-Pox activity, and some fluctuation of mitochondrial and cytoplasmic isoenzymes of SOD. DNA strand breaks and rejoining measured by comet assay as mean tail length, demonstrated clearly the bystander effect for nontraversed radiation cells, additionally verified by tail moment. There was also a significant increase of micronucleation and apoptosis generated by radiation traversed cells in shielded neighbours. Furthermore, significantly higher increase of necrosis in shielded neighbour cells compared to radiation traversed cells was observed. Proliferative activity showed a suppression in both, radiation traversed and shielded neighbour cells in all measured time points. The behaviour of used parameters points to the radical nature of modificators secreted by radiation traversed cells inducing bystander toxic damage in shielded neighbour cells.

Antioxidants↗
PubMed2005

Role of homologous recombination in the alpha-particle-induced bystander effect for sister chromatid exchanges and chromosomal aberrations.

The bystander effect for sister chromatid exchanges (SCEs) and chromosomal aberrations was examined in hamster cell lines deficient in either DNA-PKcs (V3 cells, deficient in nonhomologous end joining, NHEJ) or RAD51C (irs3 cells, deficient in homologous recombination, HR). Cells synchronized in G0/G1 phase were irradiated with very low fluences of alpha particles such that < 1% of the nuclei were traversed by an alpha particle. Wild-type cells showed a prominent bystander response for SCE induction; an even greater effect was observed in V3 cells. On the other hand, no significant induction of SCE was observed in the irs3 RAD51C-deficient bystander cells irradiated at various stages in the cell cycle. Whereas a marked bystander effect for chromosomal aberrations occurred in V3 cells, the induction of chromosomal aberrations in irs3 bystander cells was minimal and similar to that of wild-type cells. Based on these findings, we hypothesize that HR is essential for the induction of SCE in bystander cells; however, HR is unable to repair the DNA damage induced in NHEJ-deficient bystander cells that leads to either SCE or chromosomal aberrations.

Alpha Particles↗
PubMed2001

Adaptive response and the bystander effect induced by radiation in C3H 10T(1/2) cells in culture.

This paper discusses two phenomena of importance at low doses that have an impact on the shape of the dose-response relationship. First, there is the bystander effect, the term used to describe the biological effects observed in cells that are not themselves traversed by a charged particle, but are neighbors of cells that are; this exaggerates the effect of small doses of radiation. Second, there is the adaptive response, whereby exposure to a low level of DNA stress renders cells resistant to a subsequent exposure; this reduces the effect of low doses of radiation. The present work was undertaken to assess the relative importance of the adaptive response and the bystander effect induced by radiation in C3H 10T(1/2) cells in culture. When the single-cell microbeam delivered from 1 to 12 alpha particles through the nuclei of 10% of C3H 10T(1/2) cells, more cells were inactivated than were actually traversed by alpha particles. The magnitude of this bystander effect increased with the number of particles per cell. An adaptive dose of 2 cGy of gamma rays, delivered 6 h beforehand, canceled out about half of the bystander effect produced by the alpha particles.

Adaptation, Physiological↗
PubMed2004

Anti-liver cancer activity of TNF-related apoptosis-inducing ligand gene and its bystander effects.

AIM: To observe the anti-liver cancer activity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene and its bystander effects on hepatocellular carcinoma (HCC) cell line SMMC7721. METHODS: Full-length cDNA of human TRAIL was transferred into SMMC7721 cells with a binary adenoviral vector system. Polymerase-chain reaction following reverse transcription (RT-PCR) was used to determine the expression of TRAIL gene. Effects of the transfected gene on proliferation of SMMC7721 cells were measured by MTT assay. Its influence on apoptosis was demonstrated by fluorescence-activated cell sorting (FACS). The bystander effect was observed by co-culturing the SMMC7721 cells with and without the transfected TRAIL gene at different ratios, and the culture medium supernatant from the transfected cells was also examined for its influence on SMMC7721 cells. RESULTS: The growth-inhibition rate and apoptotic cell fraction in the cells transfected with the TRAIL gene, Bax gene or only LacZ gene were 91.2%, 48.0%, 28.8% and 29.1%, 12.5%, 6.6%, respectively. The growth-inhibition rate of transfection with these three sequences in normal human fibroblasts was 6.1%, 45.5% and 7.6%, respectively, indicating a discriminative inhibition of TRAIL transfection on the cancer cells. In the co-culturing test, addition of the transfected TRAIL to SMMC7721 cells in proportions of 5%, 25%, 50%, 75% and 100%, resulted in a growth-inhibition of 15.9%, 67%, 80.2%, 86.4% and 87.7%, respectively. We failed to observe a significant growth-inhibition effect of the culture medium supernatant on SMMC7721 cells. CONCLUSION: TRAIL gene transferred by a binary adenoviral vector system can inhibit proliferation of SMMC7721 cells and induce their apoptosis. A bystander effect was observed, which seemed not to be mediated by soluble factors.

Adenoviridae↗
PubMed2001

Production of delayed death and neoplastic transformation in CGL1 cells by radiation-induced bystander effects.

Other investigators have demonstrated by transfer of medium from irradiated cells and by irradiation with low-fluence alpha particles or microbeams that cells do not have to be directly exposed to ionizing radiation to be detrimentally affected, i.e. bystander effects. In this study, we demonstrate by transfer of medium from X-irradiated human CGL1 hybrid cells that the killing of bystander cells reduces the plating efficiency of the nonirradiated CGL1 cells by 33 +/- 6%. In addition, we show that the amount of cell death induced by bystander effects is not dependent on X-ray dose, and that the induction of apoptosis does not appear to be responsible for the cell death. Furthermore, we found that the reduction in plating efficiency in bystander cells is evident for over 18 days, or 22 cell population doublings, after medium transfer, despite repeated refeeding of the cell cultures. Finally, we report the novel observation that bystander effects induced by the transfer of medium from irradiated cells can induce neoplastic transformation. Exposing unirradiated CGL1 cells to medium from cells irradiated with 5 or 7 Gy increased the frequency of neoplastic transformation significantly from 6.3 x 10(-6) in unirradiated controls to 2.3 x 10(-5) (a factor of nearly four). We conclude that the bystander effect induces persistent, long-term, transmissible changes in the progeny of CGL1 cells that result in delayed death and neoplastic transformation. The data suggest that neoplastic transformation in bystander cells may play a significant role in radiation-induced neoplastic transformation at lower doses of X rays.

Apoptosis↗
PubMed2001

Connexin 26 enhances the bystander effect in HSVtk/GCV gene therapy for human bladder cancer by adenovirus/PLL/DNA gene delivery.

Herpes simplex thymidine kinase/ganciclovir (HSVtk/GCV) gene therapy has been used for the treatment of a variety of cancers. Its efficacy is enhanced by the bystander effect that helps overcome the delivery problems commonly observed in current gene therapy. Connexins encode proteins that produce gap junctions, which enable intercellular communication and the bystander effect. We previously demonstrated that decreased Cx 26 expression and loss of gap junctional intercellular communication were associated with human bladder cancer. To investigate the efficacy of the bystander effect in HSVtk/GCV gene therapy, the Cx 26 gene was introduced into UM-UC-3 and UM-UC-14 bladder cancer cell lines by an adenovirus poly-L-lysine conjugate using a multigenic expression plasmid that expressed both the HSVtk and Cx 26 genes. We found significantly increased cytotoxicity in HSVtk/GCV gene therapy after introduction of the HSVtk and Cx 26 genes together compared with the cytotoxicity seen after introduction of the HSVtk gene and LacZ genes in vitro and in vivo. Cytotoxicity correlated with Cx 26 expression and the induction of functional gap junctions. This study indicates that combination gene therapy with co-expression of the HSVtk and Cx 26 genes potentiates HSVtk/GCV gene therapy through the bystander effect.

Adenoviridae↗
PubMed2003

Role of gap junctional intercellular communication in radiation-induced bystander effects in human fibroblasts.

Involvement of gap junctional intercellular communication (GJIC) in bystander responses of confluent human fibroblasts irradiated with a carbon-ion beam was investigated. It was found that the lower the radiation dose, the higher the yield of radiation-induced micronuclei per nuclear traversal, suggesting the existence of bystander effects. This low-dose sensitivity was increased when GJIC was enhanced by treating cells with 8-Br-cAMP, but it was partly reduced by treating cells with DMSO, an effective scavenger of reactive oxygen species (ROS). Moreover, no low-dose sensitivity was observed when cells were treated with 100 micro M lindane, an inhibitor of GJIC. The survival of irradiated cells was increased by DMSO but was not influenced significantly by cAMP or lindane. On the other hand, G(1)-phase arrest was detected in the irradiated cells, and it was enhanced by cAMP. In contrast, this arrest was reduced or almost eliminated by DMSO or lindane, respectively, even when cells were irradiated with such a high dose that each cell received five nuclear traversals on average. Thus the bystander responses occurred after both low-dose and relatively high-dose irradiation. Our results indicated that both GJIC and ROS contributed to the radiation-induced bystander effect, but gap junctional channels might play an essential role by modulating the release of radiation-induced signaling factors.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2001

Bystander effect in uracil phosphoribosyltransferase/5-fluorouracil-mediated suicide gene therapy is correlated with the level of intercellular communication.

We examined whether a suicide gene/prodrug system using the uracil phosphoribosyltransferase (UPRT) of E. coli origin and 5-fluorouracil (5-FU) could achieve a bystander effect in two rodent tumor cell lines, murine colon carcinoma (Colon 26) and rat gliosarcoma (9L) cells. Cytotoxicity tests of mixed populations consisting of parent and transduced cells showed that the bystander effect was not produced in Colon 26 cells in either the UPRT/5-FU system or the herpes simplex virus-thymidine kinase/ganciclovir system but a strong bystander effect was evidenced by both suicide gene systems in 9L cells. The expression level of connexin 43, a protein that constitutes gap junctions, was high in 9L but low in Colon 26 cells. A gap junction-permeable fluorescein dye could be transferred among 9L cells but hardly at all among Colon 26 cells. Taken together, the efficacy of the bystander effect in the UPRT/5-FU system can be affected by gap junction-mediated intercellular communication.

Animals↗
PubMed2003

Non-targeted and delayed effects of exposure to ionizing radiation: II. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects.

The goal of this review is to summarize the evidence for non-targeted and delayed effects of exposure to ionizing radiation in vivo. Currently, human health risks associated with radiation exposures are based primarily on the assumption that the detrimental effects of radiation occur in irradiated cells. Over the years a number of non-targeted effects of radiation exposure in vivo have been described that challenge this concept. These include radiation-induced genomic instability, bystander effects, clastogenic factors produced in plasma from irradiated individuals that can cause chromosomal damage when cultured with nonirradiated cells, and transgenerational effects of parental irradiation that can manifest in the progeny. These effects pose new challenges to evaluating the risk(s) associated with radiation exposure and understanding radiation-induced carcinogenesis.

Animals↗
PubMed2001

Non-targeted radiation effects in radiotherapy--roles of radiation-induced genomic instability and of the bystander effect in cancer cure by radiotherapy.

Local tumour control by radiotherapy requires the complete sterilization of all tumour 'stem' cells in the tumour volume. Neither bystander effect nor radiation-induced genomic instability is able to contribute substantially to the probability of local tumour control of the primary cancer by radiotherapy. However, the progeny of these surviving tumour 'stem' cells are likely to suffer from radiation-induced genomic instability, which results in the persistent appearance of non-stem cells, i.e. a reduced probability of self-maintenance. This results in a slower growth rate of the recurrent tumour, a reduced stem-cell fraction and, as a consequence, an increased radiosensitivity of the recurrent tumour. In some recurrent tumours, particularly those that develop very late and grow very slowly, radiosensitivity may be further increased by increased intrinsic radiosensitivity, which could be related to the as yet poorly defined phenotype of 'small colony formation'.

Bystander Effect↗
PubMed2002

Do low dose-rate bystander effects influence domestic radon risks?

PURPOSE: Radon risks derive from exposure of bronchio-epithelial cells to high-linear energy transfer (LET) alpha-particles. alpha-particle exposure can result in bystander effects, where irradiated cells emit signals resulting in damage to nearby unirradiated bystander cells. This can result in non-linear dose-response relations, and inverse dose-rate effects. Domestic radon risk estimates are currently extrapolated from miner data, which are at both higher doses and higher dose-rates, so bystander effects on unhit cells could play a large role in the extrapolation of risks from mines to homes. Therefore, we extend an earlier quantitative mechanistic model of bystander effects to include protracted exposure, with the aim of quantifying the significance of the bystander effect for very prolonged exposures. MATERIALS AND METHODS: A model of high-LET bystander effects, originally developed to analyse oncogenic transformation in vitro, is extended to low dose-rates. The model considers radiation response as a superposition of bystander and linear direct e It attributes bystander effects to a small subpopulation of hypersensitive cells, with the bystander contribution dominating the direct contribution at very low acute doses but saturating as the dose increases. Inverse dose-rate effects are attributed to the replenishment of the hypersensitive subpopulation during prolonged irradiation. RESULTS: The model was fitted to dose- and dose-rate-dependent radon-exposed miner data, suggesting that one directly hit target bronchio-epithelial cell can send bystander signals to about 50 neighbouring target cells. The model suggests that a naïve linear extrapolation of radon miner data to low doses, without accounting for dose-rate, would result in an underestimation of domestic radon risks by about a factor of 4, a value comparable with the empirical estimate applied in the recent BEIR-VI report on radon risk estimation. CONCLUSIONS: Bystander effects represent a plausible quantitative and mechanistic explanation of inverse dose-rate effects by high-LET radiation, resulting in non-linear dose-response relations and a complex interplay between the effects of dose and exposure time. The model presented provides a potential mechanistic underpinning for the empirical exposure-time correction factors applied in the recent BEIR-VI for domestic radon risk estimation.

Air Pollution, Indoor↗
PubMed1997

A tumor suppressor gene, Cx26, also mediates the bystander effect in HeLa cells.

The connexin 26 (Cx26) gene suppresses the growth of HeLa cells in vitro and in vivo. We explored the possibility that the Cx26 gene not only suppresses growth but can also mediate the bystander effect that is observed in some gene therapy. In gene therapy mediated by the herpes simplex virus thymidine kinase, the toxicity of ganciclovir affects not only the cells transduced with the gene but also affects neighboring tumor cells; it has been suggested that gap junctional intercellular communication (GJIC) may play a role in such a bystander effect. HeLa cells expressing the Cx26 gene (Cx26+) or not expressing the Cx26 gene were transfected with the herpes simplex virus thymidine kinase (tk+) gene, producing Cx26(-)-tk-, Cx26(-)-tk+, Cx26+-tk-, and Cx26+-tk+ cells. By making different kinds of cocultures of these cells, we observed a clear bystander killing effect, assessed by the neutral red toxicity test, in the coculture of Cx26+-tk-/Cx26+-tk+ cells. The bystander effect was markedly prevented by a long-term inhibitor of GJIC, 18-alpha-glycyrrhetinic acid, demonstrating that a major part of the bystander effect seen occurred through Cx-mediated GJIC. These data suggest the possibility of using of Cxs as both tumor suppressor genes and as diffusers of ganciclovir toxicity in therapeutic approaches.

Connexin 26↗
PubMed2006

CENU treatment induced bystander effects which are effective on parental and non-parental tumors and have a phospholipid metabolism proton NMR spectroscopy signature.

We recently showed, using a parental double B16 melanoma tumor model that, in the presence of CENU-treated primary tumors, untreated secondary tumors exhibited growth inhibition. This response was shown to be related to CENU-induced bystander effects. To see whether CENU-induced bystander effects were still effective on non-parental syngeneic secondary tumors, Lewis lung (3LL) secondary tumors were inoculated in recipients bearing CENU-treated B16 melanoma tumors. Our results show that non-parental secondary 3LL tumors underwent growth inhibition, differentiation, and phospholipid metabolism alterations, all changes similar to those of parental secondary 3LL tumors. This demonstrates the lack of tumor tissue specificity of chemotherapy-induced bystander effects.

Animals↗
PubMed1995

Bystander effect caused by suicide gene expression indicates the feasibility of gene therapy for hepatocellular carcinoma.

In the field of gene therapy using retroviral vectors, it appears impossible to introduce a foreign gene into all target cells. Therefore adjacent cell killing, the socalled bystander effect, caused by genetically modified cells provides therapeutic advantages for gene therapy against cancers. We retrovirally transduced the herpes simplex virus thymidine kinase (HSV-tk) gene into murine and rat hepatocellular carcinoma (HCC) cells. These HSV-tk gene-transduced HCC cells were cocultured with the corresponding parental cells in the presence of ganciclovir, at a concentration not at all cytotoxic to the parental cells. When parental HCC cells were cocultured with their HSV-tk gene-transduced counterparts at a high density at which most cells were in contact with one another, they were markedly eliminated. Conversely, when cocultured at a low density at which none of the cells were in contact, a weak but statistically significant bystander effect was observed. Addition of lysates of HSV-tk gene-transduced cells in the presence of ganciclovir did not cause and killing of parental cells. Furthermore, media conditioned by transduced cells with ganciclovir exhibited weak cytotoxic effects on parental cells. These results indicate that cell-cell contact plays a major causative role in the bystander effect and that minor contributors to this phenomenon are some cytotoxic substance released from transduced cells. Importantly, the bystander effect was induced in vivo as well as in vitro. When mixtures of transduced and untransduced HCC cells were implanted into the flank region of mice, intraperitoneal ganciclovir administration considerably inhibited tumor development, indicating the feasibility of gene therapy with HSV-tk gene and ganciclovir against HCC.

Animals↗
PubMed2006

Modelling radiation-induced bystander effect and cellular communication.

In the last 10 years evidence has accumulated on the so-called radiation-induced 'non-targeted effects' and in particular on bystander effects, consisting of damage induction in non-irradiated cells most likely following the release of soluble factors by the irradiated ones. These phenomena were observed for different biological endpoints, both lethal and non-lethal for the cell. Although the underlying mechanisms are largely unknown, it is now widely recognised that two types of cellular communication (i.e. via gap junctions and/or release of molecular messengers into the extracellular environment) play a pivotal role. Furthermore, the effects can be significantly modulated by parameters such as cell type and cell-cycle stage, cell density, time after irradiation etc. Theoretical models and simulation codes can be of help to improve our knowledge of the mechanisms, as well as to investigate the possible role of these effects in determining deviations from the linear relationship between dose and risk which is generally applied in radiation protection. In this paper three models, including an approach under development at the University of Pavia, will be presented in detail. The focus will be on the various adopted assumptions, together with their implications in terms of non-targeted radiobiological damage and, more generally, low-dose radiation risk. Comparisons with experimental data will also be discussed.

Animals↗
PubMed1999

Bystander effect of purine nucleoside analogues in HSV-1 tk suicide gene therapy is superior to that of pyrimidine nucleoside analogues.

Introduction of the herpes simplex virus type 1 thymidine kinase gene into tumor cells, followed by the administration of the antiherpes nucleoside analogue ganciclovir has been demonstrated to be effective in eliminating solid tumors in animals. The success of this combination treatment largely depends on the bystander effect, i.e. the killing of nontransfected tumor cells by activated drug carried over from the nearby herpes thymidine kinase (tk) gene-transfected cells. We evaluated the in vitro bystander effect of several antiherpes purine and pyrimidine nucleoside analogues, using a colorimetric assay. All pyrimidine nucleoside analogues, including (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), showed low, if any, bystander killing effect. In contrast, purine nucleoside analogues, such as ganciclovir, were endowed with a pronounced bystander killer effect. Lobucavir (Cyclobut-G), a ganciclovir analogue, displayed a two- to three-fold more pronounced bystander killer effect than ganciclovir, eliminating, at a concentration of 10 microM, 75% and 90% of a cell population that contained 5% and 10% tk gene-transfected cells, respectively. These findings were corroborated by autoradiographic analysis that showed that 2'-3H-BVDU metabolites formed in the herpes tk gene-transfected tumor cells were much less efficiently incorporated in the DNA of bystander cells than 8-3H-GCV. This indicates that, under the same experimental conditions, BVDU metabolites are less prone to pass the gap junctions than GCV metabolites.

Antiviral Agents↗
PubMed2006

Enriching suicide gene bearing tumor cells for an increased bystander effect.

The success of cancer gene therapies requiring in vivo gene transfer is severely hampered by the low efficacy of gene transfer, which has been difficult to improve. We therefore established a novel strategy to increase the share of transduced cells post gene transfer. We hypothesized that in vivo selection of tumor cells transduced with a suicide gene effectively enriches these cells within a tumor, thus allowing for an increased bystander effect after the prodrug is given, leading to enhanced eradication of tumor cells. We reasoned that in vivo enrichment should be achieved by exploiting the metabolism of the suicide gene product. For this 'enrichment-eradication' strategy we chose a fusion gene of cytosine deaminase and uracil phosphoribosyl transferase. Positive selection (enrichment) was to be achieved by concurrently giving N-(phosphonacetyl)-L-aspartate, an inhibitor of pyrimidine de novo synthesis, which leads to pyrimidine depletion-mediated death of non-transduced cells, and cytosine, to rescue fusion gene expressing cells via the pyrimidine salvage pathway. Negative selection (eradication) was to be induced by giving the prodrug 5-fluorocytosine. Indeed, murine NXS2 neuroblastoma cells transduced with the fusion gene were effectively enriched in vitro, leading to a near-complete bystander effect. In vivo enrichment-eradication of NXS2 cells led to decreased tumor growth. This proof-of-principle study shows that enrichment-eradication may compensate the effects of low in vivo gene transfer efficacy, a major obstacle in cancer gene therapy.

Animals↗