RT Journal Article
SR Electronic
T1 Antisense Thymidylate Synthase Electrogene Transfer to Increase Uptake of Radiolabeled Iododeoxyuridine in a Murine Model
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 478
OP 484
VO 45
IS 3
A1 Kwan-Hwa Chi
A1 Hsin-Ell Wang
A1 Yu-Shan Wang
A1 Shun-Lan Chou
A1 Hung-Man Yu
A1 Yu-Hua Tseng
A1 Ing-Ming Hwang
A1 Wing-Yiu Lui
YR 2004
UL http://jnm.snmjournals.org/content/45/3/478.abstract
AB 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.