Targeting of suicide gene delivery in pancreatic cancer cells via FGF receptors

Jörg Kleeff, Kimi Fukahi, Martha E. Lopez, Helmut Friess, Markus W. Büchler, Barbara A. Sosnowski, Murray Korc

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Pancreatic ductal adenocarcinomas (PDACs) overexpress various cell-surface tyrosine kinase receptors, including the type I high- affinity fibroblast growth factor receptor (FGFR-1). The purpose of this study was to determine whether FGFR-targeted gene therapy is feasible in this disorder. Accordingly, the effects of a conjugate consisting of fibrobrast growth factor (FGF)-2 linked to a Fab′ fragment against the adenovirus knob region were evaluated in human pancreatic cancer cell lines treated with an adenoviral vector containing the herpes simplex virus thymidine kinase (AdTK) gene. An adenoviral vector containing the firefly luciferase reporter gene (AdLuc) served to assess infection efficiency, and was initially tested in L6 rat myoblasts. In parental L6 cells that express exceedingly low levels of high-affinity FGFRs, transduction with AdLuc was enhanced 7- to 10-fold with the FGF2-Fab′ conjugate, whereas in L6 cells transfected to express FGFR-1, it was enhanced 39- to 52-fold. The pancreatic cancer cell lines expressed variable levels of the four high-affinity FGF receptors, and exhibited 2- to 34-fold increases in gene transduction in the presence of the FGF2-Fab′ conjugate. In the absence of FGF2-Fab′ there was no correlation between surface binding of FGF2 and AdLuc transduction efficiency, whereas in the presence of FGF2-Fab′, enhanced AdLuc transduction efficiency correlated with greater surface binding of FGF2. In the absence of AdTK, all the cell lines were insensitive to ganciclovir, whereas after AdTK transduction, only ASPC-1 and PANC-1 cells were resistant to ganciclovir even in the presence of FGF2-Fab′. Ganciclovir-mediated inhibition was dependent on the conjugate in CAPAN-1 and COLO-357 cells, but was independent of the conjugate in T3M4 and MIA-PaCa-2 cells. Real-time quantitative PCR of laser-captured cancer cells revealed high levels of various FGFR mRNA species in six of seven PDAC tumor samples. These findings indicate that transduction efficiency with FGF2-Fab′ in pancreatic cancer cells is independent of native adenoviral transduction efficiency and is greatest in cells that exhibit concomitant expression of various high-affinity FGFRs. In view of the overexpression of high-affinity FGFRs in the cancer cells in PDAC, our findings also suggest that the combined use of AdTK, ganciclovir, and FGF2-Fab′ may ultimately be a promising therapeutic approach in a subgroup of patients with PDAC.

Original languageEnglish (US)
Pages (from-to)522-532
Number of pages11
JournalCancer Gene Therapy
Volume9
Issue number6
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Gene Targeting
Growth Factor Receptors
Pancreatic Neoplasms
Fibroblast Growth Factor 2
Suicide
Ganciclovir
Adenocarcinoma
Cell Line
Receptor, Fibroblast Growth Factor, Type 1
Firefly Luciferases
Neoplasms
Immunoglobulin Fab Fragments
Thymidine Kinase
Myoblasts
Receptor Protein-Tyrosine Kinases
Simplexvirus
Reporter Genes
Adenoviridae
Genetic Therapy
Genes

Keywords

  • Adenovirus
  • FGF receptor
  • Gene delivery
  • Pancreatic cancer

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

Kleeff, J., Fukahi, K., Lopez, M. E., Friess, H., Büchler, M. W., Sosnowski, B. A., & Korc, M. (2002). Targeting of suicide gene delivery in pancreatic cancer cells via FGF receptors. Cancer Gene Therapy, 9(6), 522-532. https://doi.org/10.1038/sj.cgt.7700464

Targeting of suicide gene delivery in pancreatic cancer cells via FGF receptors. / Kleeff, Jörg; Fukahi, Kimi; Lopez, Martha E.; Friess, Helmut; Büchler, Markus W.; Sosnowski, Barbara A.; Korc, Murray.

In: Cancer Gene Therapy, Vol. 9, No. 6, 2002, p. 522-532.

Research output: Contribution to journalArticle

Kleeff, J, Fukahi, K, Lopez, ME, Friess, H, Büchler, MW, Sosnowski, BA & Korc, M 2002, 'Targeting of suicide gene delivery in pancreatic cancer cells via FGF receptors', Cancer Gene Therapy, vol. 9, no. 6, pp. 522-532. https://doi.org/10.1038/sj.cgt.7700464
Kleeff J, Fukahi K, Lopez ME, Friess H, Büchler MW, Sosnowski BA et al. Targeting of suicide gene delivery in pancreatic cancer cells via FGF receptors. Cancer Gene Therapy. 2002;9(6):522-532. https://doi.org/10.1038/sj.cgt.7700464
Kleeff, Jörg ; Fukahi, Kimi ; Lopez, Martha E. ; Friess, Helmut ; Büchler, Markus W. ; Sosnowski, Barbara A. ; Korc, Murray. / Targeting of suicide gene delivery in pancreatic cancer cells via FGF receptors. In: Cancer Gene Therapy. 2002 ; Vol. 9, No. 6. pp. 522-532.
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