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Sensitizing glioma cells to cisplatin by abrogating the p53 response with antisense oligonucleotides

Cancer Gene Therapy volume 11, pages 525–531 (2004)Cite this article

Abstract

Most gene therapy strategies related to p53 concentrate on the restoration of the activity of mutant p53, as several observations indicate that tumors and cell lines having the mutant gene are resistant to chemotherapy. However, as there is also some evidence to the contrary, we studied the relationship of the p53 status to the cellular response of glioma cells that were exposed to cisplatin. At a concentration of 2.5 μg/ml (which is about half the peak pharmacological blood level reached during chemotherapy), U373MG glioma cells, which had a mutant p53 gene, were more sensitive to the drug as compared to U87MG glioma cells (with normal p53). The U373MG cells responded with apoptosis while U87MG cells responded with a G2–M arrest. In U87MG cells, blocking the p53 response by antisense oligonucleotides also sensitized the cells to 2.5 μg/ml cisplatin, and shifted the cellular response from arrest to caspase 3-mediated apoptosis. A sensitive, p53-independent, mechanism for chemotherapy-induced apoptosis suggests that, in some cases, p53 abrogation by gene therapy or small molecule-based strategies could be a viable therapeutic strategy.

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Acknowledgements

This work was supported by the Department of Science and Technology, India vide a Swarnajayanti Fellowship Grant to Subrata Sinha. Preeti Shah is a recipient of a Senior Research Fellowship of the CSIR. We are thankful to Mathura Prasad for technical assistance and to Satish Kumar for secretarial help.

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  1. Kamal Datta

    Present address: National Institutes of Health, Bldg 10/1C401, Bethesda, MD, USA

Authors and Affiliations

  1. Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India

    Kamal Datta, Preeti Shah, Tapasya Srivastava, Srinivas G Mathur, Parthaprasad Chattopadhyay & Subrata Sinha

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Correspondence to Subrata Sinha.

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Datta, K., Shah, P., Srivastava, T. et al. Sensitizing glioma cells to cisplatin by abrogating the p53 response with antisense oligonucleotides. Cancer Gene Ther 11, 525–531 (2004). https://doi.org/10.1038/sj.cgt.7700724

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