5-Iodo-4-thio-2′-Deoxyuridine as a Sensitizer of X-ray Induced Cancer Cell Killing

Abstract

Nucleosides, especially pyrimidines modified in the C5-position, can act as radiosensitizers via a mechanism that involves their enzymatic triphosphorylation, incorporation into DNA, and a subsequent dissociative electron attachment (DEA) process. In this paper, we report 5-iodo-4-thio-2′-deoxyuridine (ISdU) as a compound that can effectively lead to ionizing radiation (IR)-induced cellular death, which is proven by a clonogenic assay. The test revealed that the survival of cells, pre-treated with 10 or 100 µM solution of ISdU and exposed to 0.5 Gy of IR, was reduced from 78.4% (for non-treated culture) to 67.7% and to 59.8%, respectively. For a somewhat higher dose of 1 Gy, the surviving fraction was reduced from 68.2% to 54.9% and to 40.8% for incubation with 10 or 100 µM ISdU, respectively. The cytometric analysis of histone H2A.X phosphorylation showed that the radiosensitizing effect of ISdU was associated, at least in part, with the formation of double-strand breaks. Moreover, the cytotoxic test against the MCF-7 breast cancer cell line and human dermal fibroblasts (HDFa line) confirmed low cytotoxic activity of ISdU. Based on the results of steady state radiolysis of ISdU with a dose of 140 Gy and quantum chemical calculations explaining the origin of the MS detected radioproducts, the molecular mechanism of sensitization by ISdU was proposed. In conclusion, we found ISdU to be a potential radiosensitizer that could improve anticancer radiotherapy.

Uracil-5-yl O-Sulfamate: An Illusive Radiosensitizer. Pitfalls in Modeling the Radiosensitizing Derivatives of Nucleobases

“…Thus, the activation barrier calculated with the high accuracy method explains the experimental observations. Indeed, as indicated in our recent studies on radiosensitizing properties of 5-iodo-4-thio-2′-deoxyuridine 17 and 5-bromo-4-thio-2′-deoxyuridine, 18 the activation energy of ca. 7 kcal/mol is sufficient to completely quench the electron-attachment-induced release of the halide anion from the above-mentioned thiouridines.…”

“… 15 The mechanism that utilizes electrons unreactive toward native DNA and is operative under hypoxia when the damaging properties of hydroxyl radical are significantly impaired prompted us to propose several new uridine radiosensitizers. To this end, 5-selenocyanato-2′-deoxyuridine (SeCNdU), 16 5-trifluoromethanesulfonyl-2′-deoxyuridine (OTfdU), 16 5-iodo-4-thio-2′-deoxyuridine (ISdU), 17 or 5-thiocyanato-2′-deoxyuridine (SCNdU) 18 can be mentioned as representative examples. In the heart of our approach lies the quantum chemically calculated DEA profile obtained for a verified nucleoside/nucleobase.…”

Why Does the Type of Halogen Atom Matter for the Radiosensitizing Properties of 5-Halogen Substituted 4-Thio-2′-Deoxyuridines?

“…In order to explain why the radiolysis of ISdU leads to SdU, while this reaction channel is actually closed for BrSdU under the same experimental conditions, we calculated the respective DEA profile (Figure 3). We found that the kinetic barrier for the C5-Br bond had breakage as much as 26.0 kJ/mol–more than two times higher than that for C5-I in ISU (12.6 kJ/mol [27]) dissociation calculated at the same level of theory. Similarly, the thermodynamic stimulus for the release of the bromide anion from BrSU •− amounts to only −10.5 kJ/mol as compared to −24.3 kJ/mol for ISU •− [27].…”

“…In the current paper, studies on BrSdU–similar to those shown in [27] on ISdU–are described. To our surprise, BrSdU does not possess increased radiosensitizing properties.…”

“…By the same token, one may conclude that 5-haloderivatives of 4-thio-2′-deoxyuridine could also work as radiosensitizers. Indeed, we recently demonstrated the radiosensitizing properties of ISdU [27]. Under the same conditions, the yield of damage produced by 140 Gy of X-ray was 1.5-fold larger than that assayed in the irradiated BrdU aqueous solutions.…”