Retrovirus-mediated transfer of the herpes simplex virus thymidine kinase and connexin26 genes in pancreatic cells results in variable efficiency on the bystander killing

Implications for gene therapy

Meritxell Carri, Adela Mazo, Carmen Lpez-Iglesias, Xavier P. Estivill, Cristina Fillat

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Currently, there is no effective treatment for pancreatic cancer and prodrug-activating gene therapy with the herpes simplex virus thymidine kinase gene (HSV-tk) in combination with ganciclovir (GCV) has been suggested as a candidate approach against this disease. In the present study, we have evaluated the efficacy of the HSV-tk/GCV treatment in a panel of pancreatic tumor cells (NP-9, NP-18, NP-31) and the potentiation of the cytotoxic effect in combination with the overexpression of the connexin 26 gene (Cx26). Pancreatic cells transduced with a retrovirus containing the HSV-tk gene showed different sensitivities to GCV that seemed to be independent of HSV-tk expression levels. The extent of the bystander effect also varied among the pancreatic tumor cells and correlated with the level of gap junction intercellular communication (GJIC). Transduction of the pancreatic tumor cells with a retrovirus carrying the connexin 26 gene resulted in high levels of connexin 26 expression and in an increase in the GJIC that correlated to an extent in the bystander effect in both NP-9Cx26 and NP-18Cx26 cells. Neither an increment in GJIC nor an increase in the bystander killing was detected in NP-31Cx26. The bystander effect in NP-18 Cx26 cells was also prevented by the long term inhibitor of GJIC, 18-α-glycyrrhetinic acid (AGA). Together, these results demonstrate that pancreatic tumor cells are highly different as regards the susceptibility to HSVtk/GCV treatment. Moreover, they indicate that overexpression of the Cx26 gene does not always correspond to an increase in GJIC although they clearly suggest the role of GJIC in mediating the bystander effect.

Original languageEnglish
Pages (from-to)81-88
Number of pages8
JournalInternational Journal of Cancer
Volume94
Issue number1
DOIs
Publication statusPublished - 1 Oct 2001
Externally publishedYes

Fingerprint

Thymidine Kinase
Simplexvirus
Retroviridae
Genetic Therapy
Gap Junctions
Bystander Effect
Ganciclovir
Genes
Neoplasms
Glycyrrhetinic Acid
Prodrugs
Pancreatic Neoplasms
Therapeutics
Connexin 26
Gene Expression

Keywords

  • Gap junctions
  • Gene therapy
  • Pancreatic cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Retrovirus-mediated transfer of the herpes simplex virus thymidine kinase and connexin26 genes in pancreatic cells results in variable efficiency on the bystander killing : Implications for gene therapy. / Carri, Meritxell; Mazo, Adela; Lpez-Iglesias, Carmen; Estivill, Xavier P.; Fillat, Cristina.

In: International Journal of Cancer, Vol. 94, No. 1, 01.10.2001, p. 81-88.

Research output: Contribution to journalArticle

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abstract = "Currently, there is no effective treatment for pancreatic cancer and prodrug-activating gene therapy with the herpes simplex virus thymidine kinase gene (HSV-tk) in combination with ganciclovir (GCV) has been suggested as a candidate approach against this disease. In the present study, we have evaluated the efficacy of the HSV-tk/GCV treatment in a panel of pancreatic tumor cells (NP-9, NP-18, NP-31) and the potentiation of the cytotoxic effect in combination with the overexpression of the connexin 26 gene (Cx26). Pancreatic cells transduced with a retrovirus containing the HSV-tk gene showed different sensitivities to GCV that seemed to be independent of HSV-tk expression levels. The extent of the bystander effect also varied among the pancreatic tumor cells and correlated with the level of gap junction intercellular communication (GJIC). Transduction of the pancreatic tumor cells with a retrovirus carrying the connexin 26 gene resulted in high levels of connexin 26 expression and in an increase in the GJIC that correlated to an extent in the bystander effect in both NP-9Cx26 and NP-18Cx26 cells. Neither an increment in GJIC nor an increase in the bystander killing was detected in NP-31Cx26. The bystander effect in NP-18 Cx26 cells was also prevented by the long term inhibitor of GJIC, 18-α-glycyrrhetinic acid (AGA). Together, these results demonstrate that pancreatic tumor cells are highly different as regards the susceptibility to HSVtk/GCV treatment. Moreover, they indicate that overexpression of the Cx26 gene does not always correspond to an increase in GJIC although they clearly suggest the role of GJIC in mediating the bystander effect.",
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