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Combined therapy with a thymidylate synthase-inhibiting vector and S-1 has effective antitumor activity against

Kyuichi Kadota1, Cheng-Long Huang, Dage Liu

  • 1Department of General Thoracic Surgery, Breast and Endocrinological Surgery, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.

International Journal of Oncology
|December 22, 2010
PubMed

Insights

Gene therapy using an adenoviral vector targeting thymidylate synthase (TS) effectively combats 5-fluorouracil (5-FU)-resistant cancers. Combining this gene therapy with S-1 chemotherapy significantly enhances antitumor effects and promotes apoptosis in resistant tumors.

Area of Science:

  • Oncology
  • Gene Therapy
  • Cancer Research

Background:

  • High thymidylate synthase (TS) expression confers resistance to 5-fluorouracil (5-FU) chemotherapy.
  • Developing novel therapeutic strategies is crucial for overcoming 5-FU resistance in various cancers.

Purpose of the Study:

  • To investigate the efficacy of gene therapy using an adenoviral vector encoding short hairpin RNA (shRNA) targeting TS.
  • To evaluate the combined therapeutic effect of Ad-shTS and S-1 chemotherapy against 5-FU-resistant tumors.

Main Methods:

  • Construction of a replication-deficient recombinant adenoviral vector (Ad-shTS) expressing shRNA targeting TS.
  • In vitro assessment of Ad-shTS efficacy in 5-FU-resistant cell lines (DLD-1/5FU, KM12C/5FU, NUGC-3/5FU) using MTT assays.
  • In vivo evaluation of combined Ad-shTS and S-1 treatment in 5-FU-resistant DLD-1/5FU xenografts in nude mice, assessing tumor growth and apoptotic index.

Main Results:

  • Ad-shTS transduction effectively downregulated TS expression in all tested 5-FU-resistant cancer cell lines.
  • Ad-shTS treatment alone significantly inhibited the growth of 5-FU-resistant tumor cells.
  • Combined treatment with Ad-shTS and 5-FU (or S-1 in vivo) demonstrated significantly greater tumor growth inhibition compared to monotherapy.
  • The combination therapy led to a significantly higher apoptotic index in tumors.

Conclusions:

  • The developed Ad-shTS vector shows potent antitumor activity against 5-FU-resistant cancer cells.
  • Combined gene therapy with Ad-shTS and S-1 chemotherapy represents a promising strategy for treating 5-FU-resistant tumors.
  • This combination therapy effectively suppresses tumor growth and induces apoptosis in resistant cancer models.

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