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Int J Radiat Biol. 2011 Mar;87(3):274-83. doi: 10.3109/09553002.2011.530333. Epub 2010 Nov 19.

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

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  • 1Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Victoria 3002, Australia. pavel.lobachevsky@petermac.org

Abstract

PURPOSE:

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 γH2AX (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 γH2AX foci following irradiation (¹³⁷Cs γ-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 μM. 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 γH2AX focus yield per cell nucleus 45 min after irradiation decreased with drug concentration with a DMF of 2.5 at 10 μM.

CONCLUSIONS:

These results are consistent with the hypothesis that radioprotection by methylproamine is mediated by attenuation of the extent of initial DNA damage.

PMID:
21087168
[PubMed - indexed for MEDLINE]
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