TRAIL gene-armed oncolytic poxvirus and oxaliplatin can work synergistically against colorectal cancer

Mohammed F Ziauddin, Z. S. Guo, M. E. O'Malley, F. Austin, P. J. Popovic, M. A. Kavanagh, J. Li, M. Sathaiah, P. Thirunavukarasu, B. Fang, Y. J. Lee, D. L. Bartlett

Research output: Contribution to journalArticle

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Abstract

We have explored a unique combination therapy for metastatic colorectal cancer. This strategy combines a potent and new oncolytic poxvirus expressing a membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or TNFSF10) and oxaliplatin (Ox) chemotherapy. We hypothesized that TRAIL expression would increase the efficacy of the oncolytic poxvirus, and that the therapeutic efficacy would be further enhanced by combination with chemotherapy. The cytotoxicity to cancer cells by Ox, oncolytic vaccinia virus (VV) and trail gene-armed VV alone or in combination was tested in vitro. The trail gene armed oncolytic VV-expressed high levels of TRAIL in infected cancer cells and had greater potency as a cytotoxic agent compared with the parent VV. Ox alone exerted concentration-dependent cytotoxicity. In vitro, the combination of the two agents applied at suboptimal concentrations for individual therapy displayed synergy in inducing cancer cells into enhanced levels of apoptosis/necrosis. Western blot analyses were consistent with the notion that TRAIL induced cancer cell death mainly through apoptosis, whereas Ox and vJS6 induced cell death more through non-apoptotic death pathways. In two aggressive colorectal carcinomatosis models derived from human HCT116 and murine MC38 cells, the combination therapy displayed synergistic or additive antitumor activity and prolonged the survival of the tumor-bearing mice compared with either Ox chemotherapy or vvTRAIL-mediated oncolytic gene therapy alone. This combination strategy may provide a new avenue to treating peritoneal carcinomatosis and other types of metastases of colorectal cancer.

Original languageEnglish (US)
Pages (from-to)550-559
Number of pages10
JournalGene Therapy
Volume17
Issue number4
DOIs
StatePublished - Apr 1 2010

Fingerprint

oxaliplatin
Poxviridae
Vaccinia virus
Colorectal Neoplasms
Oncolytic Viruses
Genes
Neoplasms
Apoptosis
Cell Death
Carcinoma
Drug Therapy
Cytotoxins
Cell- and Tissue-Based Therapy
Combination Drug Therapy
Genetic Therapy
Necrosis
Therapeutics
Tumor Necrosis Factor-alpha
Western Blotting
Neoplasm Metastasis

Keywords

  • Chemotherapy
  • Colorectal cancer
  • Gene therapy
  • Vaccinia
  • Virotherapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Ziauddin, M. F., Guo, Z. S., O'Malley, M. E., Austin, F., Popovic, P. J., Kavanagh, M. A., ... Bartlett, D. L. (2010). TRAIL gene-armed oncolytic poxvirus and oxaliplatin can work synergistically against colorectal cancer. Gene Therapy, 17(4), 550-559. https://doi.org/10.1038/gt.2010.5

TRAIL gene-armed oncolytic poxvirus and oxaliplatin can work synergistically against colorectal cancer. / Ziauddin, Mohammed F; Guo, Z. S.; O'Malley, M. E.; Austin, F.; Popovic, P. J.; Kavanagh, M. A.; Li, J.; Sathaiah, M.; Thirunavukarasu, P.; Fang, B.; Lee, Y. J.; Bartlett, D. L.

In: Gene Therapy, Vol. 17, No. 4, 01.04.2010, p. 550-559.

Research output: Contribution to journalArticle

Ziauddin, MF, Guo, ZS, O'Malley, ME, Austin, F, Popovic, PJ, Kavanagh, MA, Li, J, Sathaiah, M, Thirunavukarasu, P, Fang, B, Lee, YJ & Bartlett, DL 2010, 'TRAIL gene-armed oncolytic poxvirus and oxaliplatin can work synergistically against colorectal cancer', Gene Therapy, vol. 17, no. 4, pp. 550-559. https://doi.org/10.1038/gt.2010.5
Ziauddin MF, Guo ZS, O'Malley ME, Austin F, Popovic PJ, Kavanagh MA et al. TRAIL gene-armed oncolytic poxvirus and oxaliplatin can work synergistically against colorectal cancer. Gene Therapy. 2010 Apr 1;17(4):550-559. https://doi.org/10.1038/gt.2010.5
Ziauddin, Mohammed F ; Guo, Z. S. ; O'Malley, M. E. ; Austin, F. ; Popovic, P. J. ; Kavanagh, M. A. ; Li, J. ; Sathaiah, M. ; Thirunavukarasu, P. ; Fang, B. ; Lee, Y. J. ; Bartlett, D. L. / TRAIL gene-armed oncolytic poxvirus and oxaliplatin can work synergistically against colorectal cancer. In: Gene Therapy. 2010 ; Vol. 17, No. 4. pp. 550-559.
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