Abstract
PurposeThe clinical efficacy of radiation therapy is mechanistically linked to ionization-induced free radicals that cause cell and tissue injury through direct and indirect mechanisms. Free radical reaction dynamics are influenced by many factors and can be manipulated by static weak magnetic fields (WMF) that perturb singlet-triplet state interconversion. Our study exploits this phenomenon to directly increase ionizing radiation (IR) dose absorption in tumors by combining WMF with radiation therapy as a new and effective method to improve treatment. Methods and MaterialsCoils were custom made to produce both homogeneous and gradient magnetic fields. The gradient coil enabled simultaneous in vitro assessment of free radical/reactive oxygen species reactivity across multiple field strengths from 6 to 66 G. First, increases in IR-induced free radical concentrations using oxidant-sensitive fluorescent dyes in a cell-free system were measured and verified. Next, human and murine cancer cell lines were evaluated in in vitro and in vivo models after exposure to clinically relevant doses of IR in combination with WMF. ResultsCellular responses to IR and WMF were field strength and cell line dependent. WMF was able to enhance IR effects on reactive oxygen species formation, DNA double-strand break formation, cell death, and tumor growth. ConclusionsWe demonstrate that the external presence of a magnetic field enhances radiation-induced cancer cell injury and death in vitro and in vivo. The effect extends beyond the timeframe when free radicals are induced in the presence of radiation into the window when endogenous free radicals are produced and therefore extends the applicability of this novel adjunct to cancer therapy in the context of radiation treatment.
Highlights
The efficacy of conformal and intensity modulated radiation therapy is directly related to dose distribution conformality such that the ratio of tumor to normal structure doses is maximized
Application of weak magnetic fields (WMF) caused a systematic increase in the reactive oxygen species (ROS) production rates (P < .05), with an approximate 30% increase when coupled with 6 Gy in both the U87MGviii and Lewis lung carcinoma (LLC) cells at 15 G and 38 G, respectively (Fig 2)
The effect of the magnetic field on gamma radiationinduced DNA double-strand breaks, as estimated by gH2AX, in U87MGviii cells was most prominent near 15 G demonstrating an approximate 10% increase in signal compared with cells exposed to only the gamma radiation
Summary
The efficacy of conformal and intensity modulated radiation therapy is directly related to dose distribution conformality such that the ratio of tumor to normal structure doses is maximized. IR causes DNA damage and cell kill through the intermediate production of free radicals that largely stem from homolytic fission These free radicals either recombine with minimal biological consequence or interact with intracellular molecules to induce biologically relevant responses. Post-IR exposureeinduced signaling cascades are initiated that further generate free radicals to amplify and perpetuate radiation effects.[7] It follows that the free radical recombination kinetics are critical to the outcome of IR responses. Mixing occurs of the singlet (S Z 0) and triplet (S Z 1) states, but the application of external WMF modifies the outcome by coupling to the Ms Z À1 and Ms Z 1 projections These triplet radical pairs do not recombine and are a source of long-lived free radicals that can amplify primary and secondary free radicalÀmediated biological responses
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