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Antitumor Effects of Systemically Delivered Adenovirus Harboring Trans-Splicing Ribozyme in Intrahepatic Colon Cancer Mouse Model

Authors' Affiliations: ¹ Department of Pathology and Medical Research Center for Cancer Molecular Therapy, Dong-A University College of Medicine, Busan, Korea; ² Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University, Yongin, Korea; and ³ Research Institute and Hospital, National Cancer Center, Goyang, Korea

Requests for reprints: In-Hoo Kim, Molecular Imaging and Therapy Branch, Research Institute, National Cancer Center, 809 Madu-dong, Ilsan-gu, Goyang-si, Gyeonggi 410-769, Korea. Phone: 31-920-2580; Fax: 31-920-2542; E-mail: ihkim{at}ncc.re.kr.

Purpose: Our previous studies suggested that human telomerase reverse transcriptase (hTERT) RNA-targeting trans-splicing ribozyme could be a useful tool for cancer gene therapy. Here, we investigated whether adenoviruses harboring this ribozyme can be systemically delivered to mice, and whether they selectively mark tumors expressing hTERT and sensitize them to ganciclovir treatments.

Experimental Design: We constructed adenoviral vectors containing modified hTERT-targeting trans-splicing ribozyme with downstream reporter gene (Ad-Ribo-LacZ) or suicide gene (Ad-Ribo-HSVtk) driven by a cytomegalovirus promoter. The tumor-specific trans-splicing reaction and the tumor-killing effect of adenoviruses harboring ribozyme were investigated both in vitro and in vivo using mice with intrahepatic colon cancer metastasis via systemic administration. The safety of systemic administration of the viruses was also evaluated.

Results: We showed that Ad-Ribo-LacZ, when injected i.v., performs a highly specific trans-splicing reaction on hTERT mRNA and that it selectively marks tumors expressing hTERT in mice. More importantly, i.v. injection of Ad-Ribo-HSVtk plus ganciclovir significantly reduced tumor burden, with minimal liver toxicity, in mice with metastatic liver cancer, compared with the untreated group (P = 0.0009). Moreover, animals receiving Ad-Ribo-HSVtk showed improved survival compared with controls (P < 0.0001).

Conclusions: This study shows that systemically delivered adenovirus harboring trans-splicing ribozyme can recognize cancer-specific transcripts and reprogram them to combat the cancer cells. Use of trans-splicing ribozymes seems to be a potentially useful gene therapy for cancer.

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