Combined Action of DNA Synthesis Inhibitors and Accelerated Protons on Malignant Tumor Cells

Abstract

The modifying effect of 1-β-D-arabinofuranosylcytosine (AraC) and hydroxyurea (HU) on the formation frequency of DNA double-strand breaks (DSB) in human U87 glioblastoma and murine B16 melanoma cells after accelerated proton and nitrogen ion (¹⁵N) exposure has been studied. The DNA comet assay and immunocytochemistry methods were used to determine the dependences of the frequency of DNA DSB formation and kinetics of their repair in tumor cells upon irradiation with particles of a wide linear energy transfer (LET) range under normal conditions and in the presence of modifiers. The combination of AraC and HU has the strongest modifying effect on the DSB yield. Under the influence of radiomodifiers, the dose change factor is ~2. Under normal conditions, DSB repair proceeds with exponential kinetics. In the presence of modifiers, a certain increase in the DNA DSB yield is observed after 6 h of post-irradiation incubation, followed by a decrease after 24 h of observation. The strongest modifying effect of AraC on the formation of radiation-induced foci (RIF) in glioblastoma cells is observed for proton exposure compared with nitrogen ions. In the presence of AraC, 24 hours after proton irradiation the RIF yield was 2.3 times higher than after exposure without it. For nitrogen ions with LET = 81 keV/μm and 180 keV/μm, the RIF yield in glioblastoma cells in the presence of AraC increases by 1.7 and 1.5 times 24 hours after irradiation, respectively, compared with the control samples. Possible mechanisms of tumor cell response to exposure to radiations with different LET in the presence of radiomodifiers are discussed.