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Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin

Cancer Gene Therapy volume 12, pages 397–406 (2005)Cite this article

Abstract

Sarcomas, or tumors of connective tissue, represent roughly 20% of childhood cancers. Although the cure rate for sarcomas in general has significantly improved in the last 10 years, there continue to be subgroups that are difficult to treat. High-grade or metastatic soft-tissue sarcomas and rhabdomyosarcomas (RMS) of the extremities remain therapeutic challenges and their prognosis is often poor. The future of sarcoma therapy will likely include molecular approaches including gene/protein expression profiling and gene-based therapy. Most sarcomas harbor defects in the p53 or pRb pathways. The tumor suppressor p53 is central to regulation of cell growth and tumor suppression and restoring wild-type p53 function in pediatric sarcomas may be of therapeutic benefit. Studies with adenoviral-mediated p53 gene transfer have been conducted in many cancer types including cervical, ovarian, prostatic and head and neck tumors. Studies of this approach, however, remain limited in pediatric cancers, including sarcomas. Using three viral constructs containing cDNA for wild-type p53, mutant p53 (C135S) and lacZ, we studied the effect of adenoviral-mediated gene therapy in four pediatric sarcoma cell lines, RD and Rh4 (RMS), Rh1 (Ewing's sarcoma) and A204 (undifferentiated sarcoma). Using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, we have shown a dose-dependent decrease in cell viability 72 h post-treatment that occurs with Ad-wtp53 but not with Ad-mutp53. Cells treated with Ad-wtp53 show upregulation of the p53 downstream targets, p21CIP1/WAF1 and bax. Growth curves demonstrate suppression of cell growth over a period of 4 days and cells treated with Ad-wtp53 demonstrate a significant increase in sensitivity to the chemotherapeutic agents, cisplatin and doxorubicin. Our results indicate that restoration of wild-type p53 function in pediatric sarcoma cells could provide a basis for novel approaches to treatment of this disease.

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Acknowledgements

HG is supported by funds from the Canadian Institutes of Health Research. MG was funded by a Restracomp Studentship (Research Institute, The Hospital for Sick Children). AN is supported by a Research Scientist award from the Kids Cancer Care Foundation of Alberta. DM is a Research Scientist of the National Cancer Instititute of Canada/Canadian Cancer Society. This work was supported in part by a Seed Grant of the Research Institute, The Hospital for Sick Children, the Andrew Mizzoni Cancer Research Fund, and the Harry and Hannah Fisher Research Fund.

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  1. Aru Narendran

    Present address: Southern Alberta Children's Cancer Program, Alberta Children's Hospital, Calgary, Alberta, Canada

Authors and Affiliations

  1. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    Hooman Ganjavi

  2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Matthew Gee

  3. Department of Paediatrics, Division of Haematology-Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    Aru Narendran, Melvin H Freedman & David Malkin

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Ganjavi, H., Gee, M., Narendran, A. et al. Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin. Cancer Gene Ther 12, 397–406 (2005). https://doi.org/10.1038/sj.cgt.7700798

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