Enhanced antitumor effects by combination gene therapy using MDR1 gene shRNA and HSV1-tk in a xenograft mouse model

Received 31 August 2009; received in revised form 2 October 2009; accepted 5 October 2009. published online 09 November 2009.
Corrected Proof

Abstract

The use of a novel therapeutic vector containing HSV1-thymidine kinase (HSV1-tk) and a short hairpin RNA for the MDR1 gene (shMDR) was proposed previously. We investigated the antitumor effects in an in vivo mouse model of colon cancer and assessed treatment response by serial non-invasive imaging. shMDR-TK expressing (MTKG) tumors for the dual therapy group mice with ganciclovir and doxorubicin showed a decrease in size, while tumors in the single therapy group mice showed a moderate increase (p<0.05). The 131I-5-iodo-2′-fluoro-2′deoxy-1-β-d-arabinofuranosyluracil (FIAU) uptake ratio of MTKG-to-parent HCT-15 tumors decreased as treatment progressed for single or dual therapy group mice, while that of the control group mice increased gradually. This study demonstrates the enhanced antitumor effects with combination gene therapy compared with a single therapeutic approach, and provides the potential of therapeutic response monitoring.

Keywords: Combination gene therapy, HSV1-tk, shRNA, MDR1, 131I-FIAU imaging

Abbreviations: HSV1-tk, HSV1-thymidine kinase, MDR, multidrug resistance, shMDR, short hairpin RNA for the MDR1 gene, eGFP, enhanced green fluorescent protein, MTKG, stable cell line that expressed HSV1-tk-eGFP and shMDR, GCV, ganciclovir, FIAU, 5-iodo-2′-fluoro-2′deoxy-1-β-d-arabinofuranosyluracil

a Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea

b Department of Biochemistry, School of Medicine, Dongguk University, Kyungju 780-714, Republic of Korea

c Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea

d Radiological and Medical Sciences Research Center, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Republic of Korea

e Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea

Corresponding author. Tel.: +82 53 420 5586; fax: +82 53 422 0864.

1 These authors contributed equally to this work.

PII: S0304-3835(09)00623-5

doi:10.1016/j.canlet.2009.10.002