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Bystander-mediated regression of murine neuroblastoma via retroviral transfer of the HSV-TK gene.

Cho HS, Lee HR, Kim MK - J. Korean Med. Sci. (2004)

Bottom Line: A strong bystander effect was observed in vitro, whereby nontransduced tumor cells in proximity to transduced cells acquired susceptibility to ganciclovir (GCV) killing.Immunohistochemical staining showed many CD4+ and CD8+ cell infiltration but did not show anti-connexin 43+ cells.In conclusion, a strong bystander effect was observed in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Hallym University College of Medicine, Seoul, Korea.

ABSTRACT
Selective introduction of genes conferring chemosensitivity into proliferating tumor cells may be used to treat cancer. We investigated the bystander effect of retrovirus-mediated gene transfer of herpes simplex virus thymidine kinase (HSV-TK) gene to murine neuroblastoma cell line (neuro-2a) in vitro and in vivo, and we examined whether the mechanism of bystander effect in neuroblastoma would also depend on connexin-dependent gap junction and/or immune response. A strong bystander effect was observed in vitro, whereby nontransduced tumor cells in proximity to transduced cells acquired susceptibility to ganciclovir (GCV) killing. Implanted mixtures of wildtype cells and HSV-TK transduced cells showed a potent bystander effect upon administration of GCV in A/J mice. HSV-TK/GCV system in murine neuroblastoma induced systemic immunity. Immunohistochemical staining showed many CD4+ and CD8+ cell infiltration but did not show anti-connexin 43+ cells. In conclusion, a strong bystander effect was observed in vitro and in vivo. The bystander effect in murine neuroblastoma might be dependent on immune response and/or on other mechanism such as protein phosphorylation or transfer of apoptotic vesicle, rather than connexin-dependent gap junction.

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Induction of immune response in HSV-TK gene-transduced neuro-2a cells. 2×106 HSV-TK cells (Group 1) and 2×106 neuro-2a cells (Group 2) injected s.c. into the flank of the mice, respectively (N=6/group). One week after tumor cell challenge, the mice received intraperitoneally 50 mg/kg GCV twice a day for 7 days and then the animals were challenged by s.c. implantation of approximately 2×106 unmodified neuro-2a cells contralaterally to the original injection sites 14 days after the last GCV treatment. Log rank test showed group survived significantly compared with Group 2 (p<0.01).
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Figure 3: Induction of immune response in HSV-TK gene-transduced neuro-2a cells. 2×106 HSV-TK cells (Group 1) and 2×106 neuro-2a cells (Group 2) injected s.c. into the flank of the mice, respectively (N=6/group). One week after tumor cell challenge, the mice received intraperitoneally 50 mg/kg GCV twice a day for 7 days and then the animals were challenged by s.c. implantation of approximately 2×106 unmodified neuro-2a cells contralaterally to the original injection sites 14 days after the last GCV treatment. Log rank test showed group survived significantly compared with Group 2 (p<0.01).

Mentions: None of the mice, which treated by GCV after 100% HSV-TK cell injection and received the second tumor cell challenges, developed the tumor at the site of challenge of unmodified neuro-2a cells during the observation period. In contrast, all of the mice of the control group developed tumors. These results support that the death of HSV-TK positive cells by GCV treatment elicit an anti-tumor immune response (Fig. 3).


Bystander-mediated regression of murine neuroblastoma via retroviral transfer of the HSV-TK gene.

Cho HS, Lee HR, Kim MK - J. Korean Med. Sci. (2004)

Induction of immune response in HSV-TK gene-transduced neuro-2a cells. 2×106 HSV-TK cells (Group 1) and 2×106 neuro-2a cells (Group 2) injected s.c. into the flank of the mice, respectively (N=6/group). One week after tumor cell challenge, the mice received intraperitoneally 50 mg/kg GCV twice a day for 7 days and then the animals were challenged by s.c. implantation of approximately 2×106 unmodified neuro-2a cells contralaterally to the original injection sites 14 days after the last GCV treatment. Log rank test showed group survived significantly compared with Group 2 (p<0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2822245&req=5

Figure 3: Induction of immune response in HSV-TK gene-transduced neuro-2a cells. 2×106 HSV-TK cells (Group 1) and 2×106 neuro-2a cells (Group 2) injected s.c. into the flank of the mice, respectively (N=6/group). One week after tumor cell challenge, the mice received intraperitoneally 50 mg/kg GCV twice a day for 7 days and then the animals were challenged by s.c. implantation of approximately 2×106 unmodified neuro-2a cells contralaterally to the original injection sites 14 days after the last GCV treatment. Log rank test showed group survived significantly compared with Group 2 (p<0.01).
Mentions: None of the mice, which treated by GCV after 100% HSV-TK cell injection and received the second tumor cell challenges, developed the tumor at the site of challenge of unmodified neuro-2a cells during the observation period. In contrast, all of the mice of the control group developed tumors. These results support that the death of HSV-TK positive cells by GCV treatment elicit an anti-tumor immune response (Fig. 3).

Bottom Line: A strong bystander effect was observed in vitro, whereby nontransduced tumor cells in proximity to transduced cells acquired susceptibility to ganciclovir (GCV) killing.Immunohistochemical staining showed many CD4+ and CD8+ cell infiltration but did not show anti-connexin 43+ cells.In conclusion, a strong bystander effect was observed in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Hallym University College of Medicine, Seoul, Korea.

ABSTRACT
Selective introduction of genes conferring chemosensitivity into proliferating tumor cells may be used to treat cancer. We investigated the bystander effect of retrovirus-mediated gene transfer of herpes simplex virus thymidine kinase (HSV-TK) gene to murine neuroblastoma cell line (neuro-2a) in vitro and in vivo, and we examined whether the mechanism of bystander effect in neuroblastoma would also depend on connexin-dependent gap junction and/or immune response. A strong bystander effect was observed in vitro, whereby nontransduced tumor cells in proximity to transduced cells acquired susceptibility to ganciclovir (GCV) killing. Implanted mixtures of wildtype cells and HSV-TK transduced cells showed a potent bystander effect upon administration of GCV in A/J mice. HSV-TK/GCV system in murine neuroblastoma induced systemic immunity. Immunohistochemical staining showed many CD4+ and CD8+ cell infiltration but did not show anti-connexin 43+ cells. In conclusion, a strong bystander effect was observed in vitro and in vivo. The bystander effect in murine neuroblastoma might be dependent on immune response and/or on other mechanism such as protein phosphorylation or transfer of apoptotic vesicle, rather than connexin-dependent gap junction.

Show MeSH
Related in: MedlinePlus