The allogeneic effect: bystander effect in the primary immune response in vitro.
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The bystander effect.
The bystander effect refers to the induction of biological effects in cells that are not directly traversed by a charged particle. The data available concerning the bystander effect fall into two quite separate categories, and it is not certain that the two groups of experiments are addressing the same phenomenon. First, there are experiments involving the transfer of medium from irradiated cells, which results in a biological effect in unirradiated cells. Second, there is the use of sophisticated single particle microbeams, which allow specific cells to be irradiated and biological effects studied in their neighbors; in this case communication is by gap junction. Medium transfer experiments have shown a bystander effect for cell lethality, chromosomal aberrations and cell cycle delay. The type of cell, epithelial vs. fibroblast, appears to be important. Experiments suggest that the effect is due to a molecule secreted by irradiated cells, which is capable of transferring damage to distant cells. Use of a single microbeam has allowed the demonstration of a bystander effect for chromosomal aberrations, cell lethality, mutation, and oncogenic transformation. When cells are in close contact, allowing gap junction communication, the bystander effect is a much larger magnitude than the phenomenon demonstrated in medium transfer experiments. A bystander effect has been demonstrated for both high- and low-LET radiations but it is usually larger for densely ionizing radiation such as alpha particles. Experiments have not yet been devised to demonstrate a comparable bystander effect on a three-dimensional normal tissue. Bystander studies imply that the target for the biological effects of radiation is larger than the cell and this could make a simple linear extrapolation of radiation risks from high to low doses of questionable validity.
Alpha Particles↗
Induction of stem cell cycling in mice increases their sensitivity to a chemical leukaemogen: implications for inherited genomic instability and the bystander effect.
Preconception paternal irradiation (PPI) modifies haemopoietic and stromal tissues of offspring and increases risk of generating lympho-haemopopietic malignancy if those offspring are then exposed to a leukaemogen. We hypothesised that this increased risk was related to inherited damage which had caused increased stem cell proliferation rates. To test for this link, in vivo, rapid stem cell proliferation was established by giving sub-lethal irradiation (3Gy gamma-rays) and allowing 3 days recovery. At this stage, 60% of haemopoietic spleen colony-forming units (CFU-S) were in DNA-synthesis, compared to <10% in unirradiated controls. Two groups of mice, unirradiated controls and irradiated animals, were then injected with 50mg/kg methyl nitrosourea (MNU) and observed daily for onset of lympho-haemopoietic malignancy. In a further control group of 60 mice, irradiated but not injected with MNU, only one leukaemia developed. In unirradiated controls, 20% of the mice developed malignancies between 3 and 8 months later: in the irradiated, MNU-treated groups, 95% developed malignancies between 2 and 7 months later. Thus, at least one powerful potentiating mechanism for induction of lympho-haemopoietc malignancy following inherited damage can be related to haemopoietic stem cell proliferation. Genomic instability is exposed by cell proliferation and has been implicated in this type of damage. However, a regulatory stromal microenvironment plays a part in inducing that proliferation. Thus, the microenvironment is the effective "bystander" which is thought to promote and amplify genomic instability, and thereby influence the induction of malignancy both in PPI offspring and in mice with induced stem cell proliferation.
Alkylating Agents↗
Radiotherapy and the potential exploitation of bystander effects.
Radiation-induced bystander effects are the subject of intense investigation in radiation protection. The effects predominate at low doses and have been discussed mainly in terms of the impact on low-dose risk assessment. Possible therapeutic implications have been alluded to, but not discussed in any detail. The purpose of this review was to consider bystander biology in areas of major importance or interest in radiotherapy. These include consideration of radiation-induced bystander effects during the cell cycle, under hypoxic conditions, when fractionated therapy modalities are used, or when combined radiochemotherapy is given. Also discussed are individual variations in toxicity of bystander factors and normal tissue "collateral" damage. The importance of considering the tumor in the context of the organ, and even the organism that supports it, is also discussed. Direct clinical radiotherapy studies that consider bystander effects are not in the public domain at the time of writing, but many in vitro studies are available that are relevant; some preliminary animal data have also been published. Because radiation-induced bystander effects appear to challenge many of the central assumptions that underlie radiotherapy practice, it is important to consider what unexplored treatment avenues might result from a consideration of these effects. The final part of this paper is devoted to this point.
Bystander Effect↗
Genetically modified CD34+ cells exert a cytotoxic bystander effect on human endothelial and cancer cells.
We and others have proposed mammalian cells as gene delivery vehicles with the potential for overcoming physiological barriers to viral vectors. To that end, we previously have shown the potential of CD34+ endothelial progenitors for systemic gene delivery in a primate angiogenesis model. Here we seek to explore the utility of CD34+ cells of human origin as vehicles for toxin genes and, in particular, to measure their capacity to effect a cytotoxic bystander effect in human endothelium and tumor cells. To this end, CD34+ cells were transduced with TOZ.1, a nonreplicative herpes simplex vector encoding thymidine kinase. To test the capacity of CD34+ cells to induce a cytotoxic bystander effect in target cells, we performed mixing experiments, whereby TOZ.1-transduced CD34+ cells were mixed with either human vascular endothelial cells or human ovarian tumor cells (SKOV3.ip1). Cell viability was measured by the MTS assay. Lastly, mixtures of TOZ.1-transduced CD34+ cells and SKOV3.ip1 tumor cells were injected s.c. to evaluate the bystander effect in vivo. After transduction of CD34+ cells with TOZ.1, treatment with ganciclovir induced the killing of 99% of cells. In cell-mixing experiments, a linear correlation was observed between the percentages of TOZ.1-transduced CD34+ cells and total cell killing. For example, when 50% of CD34+ transduced cells were mixed with nontransduced SKOV3.ip1, >70% of all cells died. Similarly, when the same percentage was mixed with human vascular endothelial cells, >80% of the total number of cells died. In vivo studies showed an abrogation of tumor formation when TOZ.1-transduced CD34+ cells and ganciclovir were administered. Our observations establish the feasibility of a method for cell-based toxin gene delivery into disseminated areas of tumor angiogenesis.
Animals↗
In vivo analysis of the 'bystander effect': a cytokine cascade.
The "bystander effect" refers to the death of unmodified tumor cells when in contact with ganciclovir (GCV)-exposed, herpes simplex virus-thymidine kinase (HSV-TK)-modified tumor cells. Although the exact mechanism or mechanisms involved in mediating the bystander effect in vivo are unknown, our findings suggest that an intact host immune system is required for the phenomenon to occur. The present study was designed to establish the effect of HSV-TK-modified tumor cells and GCV on the tumor and its microenvironment in vivo. In sublethally irradiated and immunodeficient Balb/c mice, the bystander effect was observed to be diminished or abrogated. Histopathologic examination of the tumor mass from immunocompetent mice demonstrated centralized hemorrhagic tumor necrosis (38%) after inoculation of the HSV-TK-modified tumor cells and GCV in tumor-bearing mice compared with the control mice (5%), indicating that cytokines such as tumor necrosis factor-alpha (TNF-alpha) were being released locally. This hypothesis was underscored using reverse transcriptase polymerase chain reaction (RT-PCR), by the demonstration of cytokine mRNA expression in mice treated with HSV-TK-expressing tumors and GCV. Semiquantitative PCR analysis for TNF-alpha using PCR-MIMIC on tumor samples from mice treated on days 1 and 4 showed a two-fold increase in the level on mRNA expression. Also, immunohistochemical staining for TNF-alpha showed that mononuclear inflammatory cells infiltrating the tumor were its source. Finally, characterization of tumor-infiltrating lymphocytes (TIL) in experimental animals demonstrated a two- to three-fold increase in the number of macrophages and T cells compared with control animals. These results demonstrate that, in vivo, the bystander effect is mediated in part by an antitumor response through the release of cytokines. Further, the cytokine milieu and tumor microenvironment can be modulated following injection of HSV-TK cells and GCV to enhance the host immune response, which is of potential use in clinical trials.
Animals↗
Bystander effects: a concept in need of clarification.
An increasing body of evidence indicates that the response to genotoxic agents such as radiation or drugs is a group phenomenon, rather than the summed response of individual independent cells to injury. Thus, a complex contagion-like response may spread beyond the initial impact of an agent to enlarge its effect. This indirect effect, termed "Bystander Effect," is multifaceted and may play a significant role in the therapy of tumors and in carcinogenesis. A better understanding of this phenomenon is needed in order to modulate treatment protocols to therapeutic advantage and to provide more rational guidelines for the evaluation of environmental hazards.
Animals↗
Regressions of established breast carcinoma xenografts by carboxypeptidase G2 suicide gene therapy and the prodrug CMDA are due to a bystander effect.
The role of the bystander effect in the treatment of a human breast carcinoma xenograft was studied by suicide gene therapy with carboxypeptidase G2 (CPG2) and CMDA. Cells expressing enzymatically active surface-tethered bacterial CPG2 [stCPG2(Q)3] were mixed with control beta-galactosidase (beta-Gal)-expressing cells to give stCPG2(Q)3:beta-Gal ratios of, respectively: group 1, 0:100; group 2, 10:90; group 3, 50:50; and group 4, 100:0. Four days after injection of the cells into nude mice, the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-L-glutamic acid (CMDA) was administered. Tumor growth delay correlated well with the levels of stCPG2(Q)3 expression: group 1, 0 day delay; group 2, 10 days; group 3, 16 days; and group 4, 90 days. Similarly, the number of cures was strongly correlated to the levels of stCPG2(Q)3 activity: group 1, zero of six cured; group 2, one of six cured; group 3, three of six cured and group 4, four of six cured. There was a good correlation between CPG2 enzyme activity in the tumors and the number of cures. The majority of cells from groups 2 and 3 were apoptotic whereas those from group 1 were not, indicating a substantial bystander effect in the tumors. These results suggest that a bystander effect plays a major role in suicide gene therapy regimens with stCPG2(Q)3 and CMDA.
Animals↗
Intercellular communication mediates the bystander effect during herpes simplex thymidine kinase/ganciclovir-based gene therapy of human gastrointestinal tumor cells.
A bystander effect is described when nontransduced or genetically unmodified cells are killed during death of genetically modified tumor cells transduced with a suicide gene. The "bystander effect" greatly enhances the efficacy of the herpes simplex virus-thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy approach for cancer. The mechanism of the bystander effect is controversial. In this study, we examined the role of intercellular gap junction communication (GJIC) for the bystander effect in human gastrointestinal tumor cells. Our results show that the extent of the bystander effect varied amongst the tumor cell lines; pancreatic cancer cells BXPC-3 exhibited excellent bystander effects in vitro and in vivo studies whereas other gastrointestinal tumor cell lines such as pancreatic cancer cells MIAPACA-2, and colon cancer cells HT-29 showed poor bystander effects. Bystander effects were only found in the presence of cell-to-cell contact. The extent of the bystander effect was independent of the level of HSV-TK activity in the transduced tumor cells and was correlated with GJIC as demonstrated by an in vitro dye-transfer assay. Expression of the mRNA levels of gap junction protein connexin 43 was 8- to 26-fold or greater and connexin 26 gene expression was 2- to 229-fold greater in BXPC-3 cells compared to HT-29, MIAPACA-2, and PANC3 cells. Our results suggest that intercellular communication is essential for the bystander effect. The correlation between GJIC and the extent of the bystander effect suggest a role for GJIC in mediating the bystander effect. Analysis of tumors for GJIC or expression of gap junction proteins may identify the subset of patients suitable for gene therapy with the HSV-TK/GCV approach.
Animals↗
[In vitro and in vivo bystander effect of adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene].
OBJECTIVE: To investigate in vitro and in vivo bystander effect, including distance bystander effect of adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene (HSV-tk). METHODS: In vitro, mixed tk + BEL-7402 cells and tk-BEL-7402 cells in diverse proportions and ganciclovir (GCV) was given, then tested the survival ratio of cells by MTT. In vivo, 5 x 10(6) and 5 x 10(7) tk + BEL-7402 cells were injected into the tumors in nude mice following GCV. The change of the size of the tumors was observed. To observe distance bystander effect, adenovirues with HSV-tk (1 x 10(9) PFU) were injected into the tumor, which was the one of the bilateral tumors in nude mice. Subsequently, GCV was given and the change of the tumor was observed. RESULTS: Significant bystander effect was observed in vitro and in vivo. In vitro when tk + cells: tk(-) cells was 1:9, the survival rate of mixed cells was 36.6%. When the proportion of tk(+) cells was 90%, the survival rate of mixed cells was 3.2%. In vivo, those tumors with injection of tk(+) BEL-7402 cells were suppressed (P < 0.05). But in group of distance bystander effect the tumors on another side were not suppressed. CONCLUSION: In vitro, bystander effect exists. In nude mice, if tk(+) cells and tk(-) cells are contiguous, bystander effect is significant, or probably no bystander effect.
Adenoviridae↗
Effect of herpes simplex virus thymidine kinase expression levels on ganciclovir-mediated cytotoxicity and the "bystander effect".
Transfer of the herpes simplex virus type-1 thymidine kinase (HSV-tk) gene into tumor cells followed by ganciclovir (GCV) administration, will provide selective tumor cell killing. We studied the effect of herpes simplex virus thymidine kinase (HSV-tk) expression level on the HSV-tk/GCV-mediated "bystander effect." Clones of HSV-tk-transduced rat glioma cells (9L) were isolated that stably expressed with different levels of HSV-tk. All clones studied had similar sensitivity to ganciclovir with IC50 values ranging from 0.45 to 1.3 microM. Within certain enzyme level thresholds, in vitro evaluation of the bystander effect has shown that clones with higher level of HSV-tk expression exhibited a better bystander effect. Interestingly, the bystander effect was observed between different cell types. Both the transduction efficiency and bystander effect are essential factors for the success of the antitumor effect by the HSV-tk/prodrug GCV suicide gene system.
3T3 Cells↗
HSV-tk gene therapy in head and neck squamous cell carcinoma. Enhancement by the local and distant bystander effect.
OBJECTIVES: To determine whether the bystander effect demonstrated in vitro for ganciclovir-mediated killing of a herpes simplex virus thymidine kinase (HSV-tk) gene-infected human squamous cell carcinoma is operative in vivo in a nude mouse model. DESIGN: Prospective study in a murine model. INTERVENTION: Human head and neck squamous cell carcinoma tumors were grown as xenografts on the flanks of 20 nude mice. The tumors in the left flank were then infected with the HSV-tk gene. Then, after 48 hours, the animals were treated with intraperitoneal ganciclovir twice daily. Assessment of the tumors on both flanks was performed over a 31-day period. MAIN OUTCOME MEASURES: Resolution of tumors infected with HSV-tk gene in animals treated with ganciclovir; resolution of tumors uninfected with HSV-tk gene on the contralateral flank in animals treated with ganciclovir. RESULTS: Following HSV-tk gene therapy in nude mice, complete resolution of HSV-tk-gene-infected human head and neck squamous cell carcinoma tumors was observed following ganciclovir treatment. Uninfected tumors were also noted to regress, but not completely resolve, in response to intraperitoneal ganciclovir (distant bystander effect). CONCLUSIONS: This study confirms that the local and distant bystander effects exist in this murine model, enhancing the possibility of its role for treatment of human squamous cell carcinoma of the head and neck.
3T3 Cells↗
Biophysical model of the radiation-induced bystander effect.
PURPOSE: To construct a quantitative model of the radiation-induced bystander effect based on diffusion-type spreading of bystander signal communication between the hit and non-hit cells. Cell inactivation and induced oncogenic transformation by broad- and microbeam irradiation systems are considered. MATERIALS AND METHODS: The biophysical model ByStander Diffusion Modelling (BSDM) postulates that the oncogenic bystander response observed in non-hit cells originates from specific signals received from inactivated cells. The bystander signals are assumed to be protein-like molecules spreading in the culture media by Brownian motion. The bystander signals are assumed to switch cells into a state of cell death (apoptotic/mitotic/necrosis) or induced oncogenic transformation modes. RESULTS: The bystander cell survival observed after treatment with the irradiated conditioned medium (ICM) using the broad-beam and the microbeam irradiation modalities were analysed and interpreted in the framework of the BSDM model. The model predictions for cell inactivation and induced oncogenic transformation frequencies agree well with observed data from micro and broad-beam experiments. In the case of irradiation with constant fraction of cells, transformation frequency for the bystander effect increases with increasing radiation dose. CONCLUSIONS: Bystander modelling based on diffusion of signals is in good agreement with experimental cell survival data and induced oncogenic transformation frequencies. The data confirm the protein-like nature of the bystander signal. Linear extrapolation of the cell response to low doses of radiation might underestimate carcinogenic risk, for example for domestic radon hazards, if the contribution from the bystander effect is neglected. The BSDM predicts that the bystander effect cannot be interpreted solely as a low-dose effect phenomenon. It is shown that the bystander component of radiation response can increase with dose and be observed at high doses as well as at low doses. The validity of this conclusion is supported by analysis of experimental results from high-linear energy transfer microbeam experiments.
Alpha Particles↗
Immune-dependent distant bystander effect after adenovirus-mediated suicide gene transfer in a rat model of liver colorectal metastasis.
Gene transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene sensitizes tumor cells to the toxic effect of ganciclovir (GCV). The toxic effect of GCV extends to nontransduced surrounding cells by a metabolic process known as the bystander effect. A distant bystander effect, which involves anatomically separated tumors, has been reported in vivo. Our aim was to evaluate and characterize such distant effect in a rat model of colorectal tumors implanted in the liver using adenovirus to carry the HSV-tk gene. Two colorectal tumors were implanted in two distinct liver lobes of the liver. One of the tumor was transduced with an adenoviral vector containing HSV-tk gene. The volumes of the tumors were monitored after GCV treatment. Implication of the immune system was studied histologically and after in vivo manipulations. After GCV administration, the nontransduced distant tumor regressed partially or completely in the experimental group. Immunohistochemical analysis revealed the presence of CD8+ lymphocytes in the distant lesion. HSV-tk/GCV-induced immune response against tumors was evidenced by an adoptive transfer assay (Winn assay) and the distant bystander effect was blunted after CD8+ lymphocytes depletion. However, the survival rates for treated animals were not improved. These findings demonstrate that an immune-mediated effective distant bystander effect can be obtained after limited adenoviral-mediated transfer of the HSV-tk gene.
Adenoviridae↗
Radiation-induced bystander effects. Mechanisms, biological implications, and current investigations at the Leipzig LIPSION facility.
BACKGROUND: The bystander effect is a relatively new area of radiobiological research, which is aimed at studying post-radiation changes in neighboring non-hit cells or tissues. The bystander effect of ionizing irradiation is important after low-dose irradiation in the range of up to 0.2 Gy, where a higher incidence of stochastic damage was observed than was expected from a linear-quadratic model. It is also important when the irradiation of a cell population is highly non-uniform. OBJECTIVE: This review summarizes most of the important results and proposed bystander effect mechanisms as well as their impact on theory and clinical practice. The literature, in parts contradictory, is collected, the main topics are outlined, and some basic papers are described in more detail. In order to illustrate the microbeam technique, which is considered relevant for the bystander effect research, the state of the Leipzig LIPSION nanoprobe facility is described. RESULTS: The resistance of a radiation-induced bystander effect is now generally accepted. The current state of knowledge on it is summarized here. Several groups worldwide are working on understanding its different aspects and its impact on radiobiology and radiation protection. CONCLUSION: The observation of a bystander effect has posed many questions, and answering them is a challenging topic for radiobiology in the future.
Animals↗
Cell to cell contact required for bystander effect of the TNF-related apoptosis-inducing ligand (TRAIL) gene.
We have previously reported that direct transfer of the TNF-related apoptosis-inducing ligand (TRAIL) gene resulted in an apoptotic bystander effect, and that this bystander effect was not transferable with cell culture media. To further characterize its mechanism we tested the bystander effect of TRAIL in the human ovarian cancer cell line DOV13, human lung cancer cell line A549, human hepatoma cell line Hepa G2, human breast cancer cell line MDA-MB231 and human colon cancer cell lines Lovo and DLD1. The bystander target cells were transduced with an adenovector expressing the lacZ gene (Ad/CMV-LacZ), while the effector cells were transduced with an adenovector expressing the green fluorescent protein (GFP)/TRAIL fusion gene. Effector and target cells were then cocultured in the same well with or without effector and target cell contact. In all the cell lines tested, target cells were killed if effector and target cell contact was permitted. However, no bystander effect occurred if effector and target cell contact was prevented. Furthermore, the bystander effect and apoptosis induction of TRAIL was dramatically reduced if cells were seeded at a very low density. Moreover, in all the cell lines tested, no detectable soluble TRAIL was found in media from the TRAIL-expressing cell cultures. Together, our results demonstrated that release of soluble TRAIL from transfer of the wild-type TRAIL gene is minimal, and that the bystander effect of the TRAIL gene is mainly mediated by membrane-bound TRAIL on the surface of transduced cells.
Apoptosis↗
[Bystander effect mediated by herpes simplex virus-thymidine kinase/ganciclovir approach on prostatic cancer cells and its regulation].
OBJECTIVE: To estimate the bystander effect mediated by herpes simplex virus-thymidine kanase/ganciclovir (HSV-TK/GCV) suicide gene therapy approach on PC-3m, a prostate cancer cell line, to explore the role of connexin (Cx) mediated gap junctional intercellular communication (GJIC) in the procedure of bystander effect of HSV-TK/GCV system and to investigate the modulation of apigenin, a Cx expression up-regulator on the connexin43 (Cx43) expression and GJIC of PC-3m cells. METHODS: PC-3m cells were cultured and PC-3m cells transfected with EBV-based expression vector containing HSV-TK gene (TK(+) PC-3m cells) and TK(-) PC-3m cells were mixed at the ratio of 1:9. GCV was added into the mixture. The bystander effect was evaluated by MTT assay. GJIC and HSV-TK/GCV induced bystander effect in several typical cell lines, such as NIH-3T3, Cos-7, and L-02 cells, were determined by crape loading dye tracing (SLDT) and MTT assay respectively. Cx43 mRNA expression and inherent GJIC capacity of PC-3m cells were examined by RT-PCR and SLDT. TK(+) PC-3m cells and TK(-) cells were mixed and divided into 4 groups and added with GCV, apigenin, apigenin + GCV, and apigenin + GCV + 18-alpha-glycyrrhetinic acid (AGA) respectively. Then the killing rate on PC-3m cells was examined by MTT. RESULTS: After 72 h treatment of 100 micro mol/L GCV on the mixture of wild-type PC-3m cells and HSV-TK gene modified PC-3m cells, only 23.5% +/- 3.2% cells were killed. The magnitude of HSV-TK/GCV bystander effect were more powerful in NIH-3T3, Cos-7, and L-02 cells which manifested excellent GJIC than in ACHN and HeLa cells (P < 0.001). Expression of Cx43 mRNA was shown by RT-PCR, however, it is weaker than that in ACHN cells and normal prostate tissue. With the administration of apigenin, the expression of Cx43 mRNA and the GJIC function of PC-3m cells were increased by 2.2 times (P < 0.01) The enhancing effect of apigenin on GJIC function of PC-3m cells lasted 48 hours and could be inhibited by addition of AGA. Apigenin of the concentration of 10 micro mol/L could obviously improve the bystander effect of TK system on PC-3m cells (P < 0.001). The killing rate of GCV on the mixed PC-3m cells was 59.86% +/- 2.44%, and was only 25.34% +/- 2.89% with the addition of AGA. CONCLUSION: There is a positive correlation between the magnitude of bystander effect mediated by HSV-TK/GCV approach and the potency of internal GJIC in the target cells. Down-regulated Cx43 expression and disrupted inherent GJIC potential of PC-3m cells result in the poor magnitude of HSV-TK/GCV bystander effect. Chemical agent like apigenin up-modulates Cx43 expression and invokes GJIC capacity of PC-3m cells, thus enhancing the bystander effect and augmenting the efficacy of TK suicide therapy.
3T3 Cells↗
[All-trans retinoic acid augments the bystander effect of herpes simplex virus thymidine kinase/ganciclovir system in the treatment of tongue carcinoma cell line].
OBJECTIVE: To investigate the augmentation effect and mechanism of all-trans retinoic acid (ATRA) on the bystander effect of herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) system in the treatment of tongue carcinoma cell line. METHODS: Immunocytochemistry and flow cytometry (FCM) were used to analyze the expression of Cx43 protein in Tca8113 cells after treated with ATRA; The bystander effect of HSV-TK/GCV system on tongue carcinoma cells before and after treatment with ATRA was detected by MTT assays. The interaction of ATRA and bystander effect was analyzed by factorial experiment. RESULTS: After treated by ATRA (10(-7) mol/L - 10(-5) mol/L), the expression of Cx43 protein was up-regulated in Tca8113 cells and the positive rate of Cx43 protein increased from 5.17% (before treatment) to 30.53% (10(-5) mol/L ATRA). There was significant difference between ATRA treated cells and untreated cells (P < 0.01). The bystander effect of HSV-TK/GCV system on Tca8113 cells was poor, but improved after combined with ATRA. There was cooperation effect between ATRA and bystander effect of HSV-TK/GCV (P < 0.05). CONCLUSIONS: ATRA can augment the bystander effect of HSV-TK/GCV system in the treatment of tongue carcinoma cell line. The mechanism might be due to up-regulation of Cx43 gene and restore gap junction intercellular communication.
Antineoplastic Agents↗