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Adenovirus-mediated p53 gene therapy in osteosarcoma cell lines: sensitization to cisplatin and doxorubicin

Abstract

The poor prognosis for patients with metastatic osteosarcoma (OS) indicates that new therapeutic options should be explored. Studies with adenoviral-mediated p53 gene transfer have been conducted in many cancer types including cervical, ovarian, prostatic and head and neck tumors. However, limited work has been carried out with pediatric cancers, including OS. Using three viral constructs containing cDNA for wild-type p53, mutant p53 (Cys135Ser) and lacZ, we studied the effect of adenoviral-mediated gene therapy in four OS cell lines: Saos-2 (p53−/−), HOS (R156P), KHOS/NP (R156P) and MNNG (R156P, F270L). We demonstrated that the virus efficiently enters the cells using the β-galactosidase assay. Using the MTT 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. We have also shown that treatment with Ad-wtp53 significantly increases sensitivity of the cell lines to cisplatin and doxorubicin, chemotherapeutic agents commonly used in the treatment of OS. Our results indicate that restoration of wt p53 function in OS cells provides 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, MK and NP were funded through studentships of the Ontario Student Opportunity Trust Fund – Hospital for Sick Children Foundation Student Scholarship Program. AN is supported by a Research Scientist award from the Kids Cancer Care Foundation of Alberta. 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 Hanna Fisher Research Fund.

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Correspondence to D Malkin.

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Ganjavi, H., Gee, M., Narendran, A. et al. Adenovirus-mediated p53 gene therapy in osteosarcoma cell lines: sensitization to cisplatin and doxorubicin. Cancer Gene Ther 13, 415–419 (2006). https://doi.org/10.1038/sj.cgt.7700909

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