Specific regression of human cancer cells by ribozyme-mediated targeted replacement of tumor-specific transcript.
In this study, we describe a novel approach to human cancer therapy that is based upon trans-splicing ribozyme-mediated replacement of cancer-specific RNAs with new transcripts that exert therapeutic activities. We have developed a specific ribozyme that can reprogram human telomerase reverse transcriptase (hTERT) RNA to induce transgene activity selectively in cancer cells that express the RNA. The ribozyme-mediated triggering of the transgene expression was accomplished via a high-fidelity trans-splicing reaction with the targeted residue in the hTERT-expressing cells. The ribozyme also induced cytotoxic activity in various hTERT-expressing cancer cells, hence selectively retarding the growth of those cells. Efficient and specific cell regression was also detected with ganciclovir (GCV) treatment only in hTERT-positive cancer cells, which were established to express stably the specific ribozyme that contains the herpes simplex virus thymidine kinase (HSV-tk) gene. Tissue-specific expression of the ribozyme could further augment the target specificity of the ribozyme. Importantly, we observed efficient regression of tumors with GCV treatment in mice that had been inoculated subcutaneously with hTERT-positive cancer cells that stably expressed the specific ribozyme that contains HSV-tk. These results suggest that the hTERT RNA-targeting trans-splicing ribozyme could be a powerful agent for tumor-targeted specific gene therapy.
Kwon
Byung-Su
BS
Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University, Seoul 140-714, Korea.
Jung
Heung-Su
HS
Song
Min-Sun
MS
Cho
Kyung Sook
KS
Kim
Sung-Chun
SC
Kimm
Kuchan
K
Jeong
Jin Sook
JS
Kim
In-Hoo
IH
Lee
Seong-Wook
SW
D043525:Cytosine Deaminase; D004268:DNA-Binding Proteins / Q000235:genetics*; D018390:Gene Targeting; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D016337:RNA, Catalytic / Q000235:genetics / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism*; D012334:RNA, Neoplasm; D019098:Telomerase / Q000235:genetics*; D013937:Thymidine Kinase; D020040:Trans-Splicing; D014158:Transcription, Genetic; D014162:Transfection
D004268:DNA-Binding Proteins; D016337:RNA, Catalytic; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013937:Thymidine Kinase; D019098:Telomerase; D043525:Cytosine Deaminase