Abstract
Hypoxia—a hallmark of solid tumors—dramatically impairs radiotherapy, one of the most common anticancer modalities. The adverse effect of the low-oxygen state can be eliminated by the concomitant use of a hypoxic cell radiosensitizer. In the present paper, we show that 5-(N-trifluoromethylcarboxy) aminouracil (CF3CONHU) can be considered as an effective radiosensitizer of DNA damage, working under hypoxia. The title compound was synthesized in the reaction of 5-aminouracil and trifluoroacetic anhydride in trifluoroacetic acid. Then, an aqueous and deoxygenated solution of the HPLC purified compound containing tert-butanol as a hydroxyl radical scavenger was irradiated with X-rays. Radiodegradation in a 26.67 ± 0.31% yield resulted in only one major product—N-uracil-5-yloxamic acid. The mechanism that is possibly responsible for the formation of the observed radioproduct has been elucidated with the use of DFT calculations. The cytotoxic test against the PC3 prostate cancer cell line and HDFa human dermal fibroblasts confirmed the low cytotoxicity of CF3CONHU. Finally, a clonogenic assay and flow cytometric analysis of histone H2A.X phosphorylation proved the radiosensitization in vitro.
Highlights
Tumor hypoxia, defined as a low level of oxygenation, causes resistance to radiotherapy, which is one of the treatments of choice in many types of cancer [1]
We demonstrate that stationary radiolysis leads to the efficient radiochemical transformation of CF3CONHU to N-uracil-5-yloxamic acid and that CF3CONHU sensitizes prostate cancer cells (PC3 line) to X-rays
The title compound belongs to the group of modified nucleobases, which undergoes dissociative electron attachment (DEA) induced by solvated electrons
Summary
Tumor hypoxia, defined as a low level of oxygenation, causes resistance to radiotherapy, which is one of the treatments of choice in many types of cancer [1]. The first group of radiosensitizers enhances the radiation effects only in hypoxic cells (characteristic of tumor tissue) but not in normoxic ones For this reason, the selectivity toward cancer is due to the difference in oxygenation levels between cancer and normal cells. If nucleosides are appropriately modified, their radiosensitizing properties may occur only under hypoxia Such a modification should rely on the introduction of suitable substituents in nucleobases, which increases nucleosides’ sensitivity to degradation induced by solvated electrons [7]. A modified, radiosensitizing nucleobase has usually an electrophilic substituent and undergoes an efficient dissociative electron attachment (DEA) that leaves behind a nucleoside radical, which, in secondary reactions, is able to produce DNA damage leading to cancer cell death [7]. FTihgeuyreiel6d).oTf hCeF3yCieOldNHofUCdFe3gCrOadNaHtioUn,d2e6g.6ra7d±a0ti.o31n%, 2, 6h.a6s7b±ee0n.3d1e%te,rhmaisnebdeebny dcoemterpmariinnegdthbeyacreoams pofaritisnHg PthLeCasrigeansalosfbeitfsorHe PanLdCasftigernIaRlsexbpefoosruerea.nIdt isafwteorrtIhRneoxtipnogsuthraet. tIhteisdewcaoyrtohf nBordtiUng—tahwatetlhl-ekndoewcanyraodf iBorsdenUs—itizaewr—elils-kenquowalntor1a9d.3io1s±en0s.8it6i%zeru—ndiseretqhueaslatmoe1e9x.3p1er±im0e.8n6t%al cuonnddeirtiothnes. sAalmtoegetehxepre, trhime eanbotavle-mcoenndtiitoinoends.reAsultltosgseuthggere,st tthheat 5a-b(Nov-ter-imflueonrtoiomneetdhylrceasrublotsxys)uagmgiensoturtahcailt sh5o-(uNldterxifhluiboirtormadeitohsyelncsairtbizoixnyg)parmopineortuieras.cil should exhibit radiosensitizing properties
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