Protection by methylproamine of irradiated human keratinocytes correlates with reduction of DNA damage

Pavel Lobachevsky, Raj Vasireddy, Sam Broadhurst, Carl Sprung, Tom Karagiannis, Andrea Smith, Ian Radford, Michael McKay, Roger Martin

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Abstract

The therapeutic ratio for ionising radiation treatment of tumour is a trade-off between normal tissue side-effects and tumour control. Application of a radioprotector to normal tissue can reduce side-effects. Here we study the effects of a new radioprotector on the cellular response to radiation. Methylproamine is a DNA-binding radioprotector which, on the basis of published pulse radiolysis studies, acts by repair of transient radiation-induced oxidative species on DNA. To substantiate this hypothesis, we studied protection by methylproamine at both clonogenic survival and radiation-induced DNA damage, assessed by gammaH2AX (histone 2AX phosphorylation at serine 139) focus formation endpoints. MATERIALS AND METHODS: The human keratinocyte cell line FEP1811 was used to study clonogenic survival and yield of gammaH2AX foci following irradiation ((1)(3)Cs gamma-rays) of cells exposed to various concentrations of methylproamine. Uptake of methylproamine into cell nuclei was measured in parallel. RESULTS: The extent of radioprotection at the clonogenic survival endpoint increased with methylproamine concentration up to a maximum dose modification factor (DMF) of 2.0 at 10 muM. At least 0.1 fmole/nucleus of methylproamine is required to achieve a substantial level of radioprotection (DMF of 1.3) with maximum protection (DMF of 2.0) achieved at 0.23 fmole/nucleus. The gammaH2AX focus yield per cell nucleus 45 min after irradiation decreased with drug concentration with a DMF of 2.5 at 10 muM. CONCLUSIONS: These results are consistent with the hypothesis that radioprotection by methylproamine is mediated by attenuation of the extent of initial DNA damage.
Original languageEnglish
Pages (from-to)274 - 283
Number of pages10
JournalInternational Journal of Radiation Biology
Volume87
Issue number3
DOIs
Publication statusPublished - 2011

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