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Combined TRAIL and Bax gene therapy prolonged survival in mice with ovarian cancer xenograft

Gene Therapy volume 9, pages 1379–1386 (2002)Cite this article

Abstract

We evaluated the antitumor activity of the Bax gene and green fluorescent protein/tumor necrosis factor-related apoptosis-inducing ligand (GFP/TRAIL) fusion gene driven by the human telomerase reverse transcriptase promoter both separately and combined in the human ovarian cancer lines SKOV3ip and DOV13 and human lung cancer line H1299. In vitro study showed that both TRAIL- and Bax-expressing vectors elicited significant cell killing in H1299 and SKOV3ip cells, but only the GFP/TRAIL gene elicited significant cell killing in DOV13 cells. Combined TRAIL and Bax therapy also produced more profound cell killing in SKOV3ip and H1299 cells, but not DOV13 cells without escalation of the vector doses. To further evaluate the combined effects of Bax and TRAIL, abdominally spread tumors were established in nude mice via intraperitoneal inoculation of SKOV3ip cells followed by that of adenoviral vectors. Tumor growth, ascites formation, survival duration and toxicity were evaluated after treatment. We found that treatment using the Bax- or TRAIL-expressing vector alone significantly suppressed tumor growth and ascites formation, and prolonged animal survival when compared with that of using PBS or a control vector. Combined TRAIL and Bax therapy further prolonged survival significantly when compared with therapy using the TRAIL or Bax gene alone. Transgene expression and apoptosis induction were not detected in normal human ovarian epithelial cells in vitro or normal mouse tissues in vivo after intraperitoneal vector administration. Also, liver toxicity was not detected after either treatment. Thus, combined TRAIL and Bax gene therapy may be useful for treatment of abdominally spread tumors.

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Acknowledgements

We thank Dr Mien-Chie Hung for providing SKOV3ip cells, Karen Ramirez for assistance in FACS analysis, Allan Prejusa and Trupti Mehta for adenovirus proparation and quality control, and Don Norwood for editorial review. This study was funded by a research project grant from the American Cancer Society (RPG-00-274-01-MGO to BF); an Institutional Start Up Fund grant (to BF); an NIH program project grant (CA78778-01A1), and an NIH Core Grant for Medium and Vectors (CA 16672). JG is an MD Anderson Cancer Center Odyssey Program Fellow supported by the Kimberly-Clark Endowment for New and Innovative Research.

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Authors and Affiliations

  1. Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    X Huang, T Lin, J Gu, L Zhang, J A Roth & B Fang

  2. Department of Veterinary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    L C Stephens

  3. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center,

    Y Yu

  4. Houston, TX, USA

    Y Yu

  5. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Liu

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  1. X Huang
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Huang, X., Lin, T., Gu, J. et al. Combined TRAIL and Bax gene therapy prolonged survival in mice with ovarian cancer xenograft. Gene Ther 9, 1379–1386 (2002). https://doi.org/10.1038/sj.gt.3301810

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