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Assessment of DNA damage in target tumor cells after thermoablation in mice
Ingrid Hilger1, Alexander Rapp, Karl-Otto Greulich
1Institute of Diagnostic and Interventional Radiology, University Hospital Jena, Postfach, D-07740 Jena, Germany. ingrid.hilger@med.uni-jena.de
Purpose:
To determine the effects of temperature on cell death for cells in culture and to compare these effects with the results of in vivo experiments in which heating is induced in mice with implanted human adenocarcinoma by using magnetic methods.
Materials And Methods:
Experimentation was approved by the regional animal care committee. Human adenocarcinoma cells (MX-1) and human fibroblasts (HTB-125) were exposed to defined temperatures of 45 degrees -90 degrees C for 4 minutes. Single- and double-strand DNA breaks (expressed as a percentage of the total DNA in tail) were identified by using the alkaline comet assay, and cell survival was determined by using the cloning assay and trypan blue exclusion. For in vivo experiments, MX-1 tumors were implanted into 14 mice. Magnetic heating at temperatures of 59 degrees -96 degrees C was subsequently performed by injecting magnetic material into the tumor (7 mg +/- 3 [+/- standard deviation] magnetite per tumor) and applying an alternating magnetic field (8.8 kA/m; 400 kHz) for 4 minutes. The efficiency of the temperature-dependent induction of DNA damage in isolated tumor cells was quantified and compared with that in cultured cells.
Results:
Results of experiments with cell cultures revealed a strong correlation between DNA damage, cell survival, and temperature, as determined with the cloning assay and trypan blue exclusion. The threshold thermoablasive temperature for tumor cell elimination was found to be 55 degrees-60 degrees C. Moreover, a strong impairment in cell survival was found when damaged DNA accounted for more than 50% of the total DNA. The heating sensitivities of malignant and nonmalignant cells did not differ. After the magnetic heating of tumors in vivo to temperatures of up to 96 degrees C (rectal temperatures between 27 degrees C +/- 2 and 29 degrees C +/- 2), isolated tumor cells showed a mean of 71.9% +/- 24.5 of total DNA in the tail per cell compared with nontreated tumors, which showed 8.0% +/- 3.1.
Conclusion:
There appears to be a threshold temperature for the induction of irreversible DNA damage. This is reflected by the results of in vivo experiments in tumor-bearing mice after high temperatures were applied to tumors by using magnetic heating.
