Radiosensitization of heat resistant human tumour cells by 1 hour at 41.1 degrees C and its effect on DNA repair

M Xu, R J Myerson, W L Straube, E G Moros, I Lagroye, L L Wang, J T Lee, J L Roti Roti
International Journal of Hyperthermia 2002, 18 (5): 385-403
The present study was undertaken to determine if short duration (1-2 h), moderate hyperthermia (41.1 degrees C) could radiosensitize human tumour cells. It was found that moderate hyperthermia (41.1 degrees C), for as little as 1 h, can radiosensitize heat resistant human adenocarcinoma cells, NSY42129 (NSY), provided the cells are irradiated 15 min prior to the end of the heat exposure. Analysis of the survival data showed a 2.5-3-fold increase in the alpha parameter with no significant change in the beta parameter of the survival curve, implying that the cells had become more susceptible to killing by single radiation energy deposition events as opposed to lethal events that require an interaction between two separate energy deposition events. 41.1 degrees C hyperthermia did not affect the induction or repair of alkaline labile DNA damage in a way that correlated with radiosensitivity. In contrast, heat-induced changes in the induction of micronuclei by radiation correlated with changes in cell killing. Therefore, the effect of 41.1 degrees C hyperthermia on the intracellular localization of the DNA double strand break repair protein, Mre11, was measured using in situ immunofluorescence and immunoblotting of soluble and insoluble cellular fractions. The results showed that Mre11 delocalizes from the nucleus as a function of time at 41.1 degrees C. It was then determined if 41.1 degrees C hyperthermia altered the association of Mre11 with its functional partner, Rad50. A significant decrease in the amount of Rad50 recovered with Mre11 occurred under the experimental conditions that produced significant radiosensitization. These results are consistent with the possibility that the heat-induced perturbation in Mre11 localization and its radiation-induced association with Rad50 contributes to an increase in radiosensitivity.

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