Targeting of suicide gene delivery in XXXX cells via FGF receptors.

@entity1 @entity788 @entity1124 @entity5 @entity540 @entity1334 @entity281 @entity1014 @entity35 @entity4540 @entity669 @entity7167
@entity1124 ( @entity1124 ) overexpress various cell-surface @entity669 kinase receptors, including the type I high-affinity fibroblast growth factor receptor ( @entity7167 ). 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 @entity540 linked to a @entity1334 ' fragment against the adenovirus knob region were evaluated in @entity1 @entity788 cell lines treated with an adenoviral vector containing the herpes simplex virus @entity1014 kinase (AdTK) gene. An adenoviral vector containing the firefly luciferase reporter gene (AdLuc) served to assess @entity281 efficiency, and was initially tested in L6 @entity35 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 @entity540 - @entity1334 ' conjugate, whereas in L6 cells transfected to express @entity7167 , it was enhanced 39- to 52-fold. The @entity788 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 @entity540 - @entity1334 ' conjugate. In the absence of @entity540 - @entity1334 ' there was no correlation between surface binding of @entity540 and AdLuc transduction efficiency, whereas in the presence of @entity540 - @entity1334 ', enhanced AdLuc transduction efficiency correlated with greater surface binding of @entity540 . In the absence of AdTK, all the cell lines were insensitive to @entity4540 , whereas after AdTK transduction, only @entity1 and PANC-1 cells were resistant to @entity4540 even in the presence of @entity540 - @entity1334 '. @entity4540 -mediated inhibition was dependent on the conjugate in @entity1 and COLO-357 cells, but was independent of the conjugate in T3M4 and MIA-PaCa-2 cells. Real-time quantitative PCR of laser-captured @entity5 cells revealed high levels of various FGFR mRNA species in six of seven PDAC @entity5 samples. These findings indicate that transduction efficiency with @entity540 - @entity1334 ' in @entity788 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 @entity5 cells in PDAC, our findings also suggest that the combined use of AdTK, @entity4540 , and @entity540 - @entity1334 ' may ultimately be a promising therapeutic approach in a subgroup of @entity1 with PDAC.
