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Gene transfer to cervical cancer with fiber-modified adenoviruses

Daniel T Rein1, Martina Breidenbach, Hongju Wu

  • 1Division of Human Gene Therapy, Departments of Medicine, Surgery and Pathology and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, USA.

International Journal of Cancer
|July 15, 2004
PubMed

Insights

Adenoviral (Ad) vector gene therapy for cervical cancer faces challenges with low coxsackie Ad receptor (CAR) expression. Modified Ad vectors targeting integrins and proteoglycans improved in vivo gene delivery and tumor targeting.

Area of Science:

  • Oncolytic Virotherapy
  • Gene Therapy
  • Molecular Virology

Background:

  • Adenoviral (Ad) vectors are crucial for cancer gene therapy, but in vivo gene delivery efficiency is often limited.
  • Low or variable expression of the coxsackie Ad receptor (CAR) on cancer cells hinders efficient Ad-mediated gene transfer.
  • Cervical cancer presents a significant challenge for current gene therapy approaches due to receptor expression variability.

Purpose of the Study:

  • To evaluate CAR expression on cervical cancer cells.
  • To assess CAR-independent targeting strategies using modified Ad vectors (Ad5.RGD, Ad5.pK7, Ad5.RGD.pK7).
  • To determine the in vitro and in vivo gene transfer efficiency of these modified vectors in cervical cancer models.

Main Methods:

  • Quantification of CAR mRNA expression in cervical cancer cell lines and primary patient samples.
  • Evaluation of gene transfer efficiency using fiber-modified Ad vectors targeting integrins (Ad5.RGD) and heparan sulfate proteoglycans (Ad5.pK7).
  • In vivo assessment of gene delivery efficacy in a subcutaneous cervical cancer mouse model.

Main Results:

  • Ad5.pK7 and Ad5.RGD.pK7 demonstrated significantly enhanced in vitro gene transfer efficiency.
  • The Ad5.RGD.pK7 vector significantly improved tumor targeting in vivo, leading to a better tumor/liver ratio.
  • Non-target cell infectivity remained comparable to unmodified Ad5, indicating improved tumor specificity.

Conclusions:

  • The double-modified Ad5.RGD.pK7 vector enhances gene transfer to cervical cancer cells.
  • This modified vector shows improved tumor targeting and specificity in vivo.
  • These findings suggest potential for increased clinical efficacy in cervical cancer gene therapy.

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