p53-dependent radiobiological responses to internalised indium-111 in human cells.

Weeks, Amanda J and Blower, Philip J. and Lloyd, Daniel R. (2013) p53-dependent radiobiological responses to internalised indium-111 in human cells. Nuclear Medicine and Biology, 40 (1). pp. 73-79. ISSN 0883-2897. (doi:https://doi.org/10.1016/j.nucmedbio.2012.08.009) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Official URL
http://dx.doi.org/10.1016/j.nucmedbio.2012.08.009

Abstract

INTRODUCTION: The p53 tumour suppressor protein plays a pivotal role in the response of mammalian cells to DNA damage. It regulates cell cycle progression, apoptosis and DNA repair mechanisms and is therefore likely to influence response to targeted radionuclide therapy. This study investigated the role of p53 in the cellular response to the Auger-emitting radionuclide indium-111. METHODS: Two stable clones of a HT1080 fibrosarcoma cell line, differing only in p53 status due to RNAi-mediated knockdown of p53 expression, were incubated for 1 h with [¹¹¹In]-oxinate (0-10 MBq/ml). Radiopharmaceutical uptake into HT1080 cells was measured in situ using a non-contact phosphorimager method. Cellular sensitivity and DNA damage were measured by, respectively, clonogenic survival analysis and the single cell gel electrophoresis (Comet) assay. RESULTS: Mean uptake of [¹¹¹In]-oxinate in HT1080 cells was unaffected by p53 status, reaching a maximum of 9Bq/cell. [¹¹¹In]-oxinate-induced cytotoxicity was also identical in both clones, as measured by IC50 (0.68 MBq/ml). However the formation of DNA damage, measured immediately after treatment with [¹¹¹In]-oxinate, was found to be up to 2.5-fold higher in the p53-deficient HT1080 clone. CONCLUSIONS: The increased DNA damage induced in p53-deficient HT1080 cells suggests an early deficiency in the repair of DNA damage during the treatment period. However, the similarity in cellular sensitivity, irrespective of p53 status, suggests that reduced p53 leads to a concomitant reduction in p53-dependent cytotoxicity despite the persistence of DNA damage. The results may provide insight into how tumours that differ in p53 status respond to therapeutic radionuclides.

Item Type: Article
Uncontrolled keywords: Auger electrons; Cytotoxicity; DNA damage; P53
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Dan Lloyd
Date Deposited: 16 Apr 2013 09:04 UTC
Last Modified: 29 May 2014 11:33 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/33614 (The current URI for this page, for reference purposes)
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