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Antisense Thymidylate Synthase Electrogene Transfer to Increase Uptake of Radiolabeled Iododeoxyuridine in a Murine Model

¹ Cancer Center, Veterans General Hospital-Taipei, National Yang-Ming University, Taipei, Taiwan
² Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
³ Institute of Radiation Science, National Yang-Ming University, Taipei, Taiwan
⁴ School of Technology for Radiological Medicine, Department of Medical Research, Kaohsiung Medical University, Kaohsiung, Taiwan
⁵ Department of Surgery, Veterans General Hospital-Taipei, National Yang-Ming University, Taiwan

In vitro and in vivo experiments from our laboratory and others have suggested that the combination of thymidylate synthase (TS) inhibitor and radiolabeled iododeoxyuridine (IdUrd) is synergistic. Efficacy is limited by drug resistance, which is often mediated by TS overexpression. We designed an in vivo electrogene transfer (EGT) model for delivering antisense TS plasmid (ATS) into tumor to increase the subsequent efficacy of ¹³¹I-IdUrd therapy. Methods: Plasmid complementary to nucleotide 531-710 in the coding region of the mouse TS (mTS) mRNA was constructed. TS activity and ¹³¹I-IdUrd DNA incorporation were determined 48 h after in vitro EGT of ATS to CT26 cells. In vivo therapeutic effect and radioactivity retained in tumor after various combinations of EGT ATS, 5-fluorouracil (5-FU), and continuous infusion of ¹³¹I-IdUrd by osmotic minipump were determined. Results: A reduction of TS activity was achieved after in vitro EGT ATS. Flow cytometry analysis indicated that ATS-treated cells were arrested at S phase. In the in vivo tumor model, the combination of EGT ATS and 5-FU was able to partially overcome 5-FU drug resistance. Sixty percent of tumors can be eradicated by the combination of EGT ATS, 5-FU, and infusion of ¹³¹I-IdUrd. The tumors treated by EGT ATS had higher radioactivity retained 1 wk after ¹³¹I-IdUrd therapy than after EGT of control plasmid. Conclusion: In situ EGT ATS can downregulate TS and increase the therapeutic effect of radiolabeled IdUrd therapy. The combination of EGT ATS, 5-FU, and ¹³¹I-IdUrd may result in tumor eradication.

Key Words: 5-fluorouracil • antisense • electrogene transfer • radiolabeled iododeoxyuridine • thymidylate synthase inhibitor

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