STSM: Why 5-bromouracil is a good radiosensitizer?

STSM by Antonella Cartoni, Università di Roma “Sapienza” (IT)  with Patrick Rousseau, Université de Caen Basse-Normandie (FR)
On June  15^th, 2014 (6  days)
From ITALY to FRANCE

Study of the effect of the environment in the ion-induced fragmentation in uracil and halouracil

The halosubstituted analogues of DNA bases that can be efficiently incorporated in the DNA of fast replicating tumor cells to make them more sensitive to the lethal effect of radiation in radiotherapy are known as radiosensitisers. The 5-bromouracil (5BrU) as well as 5-fluorouracil (5FU, Figure 1), analogues of thymine, are considered good radiosensitisers even though the elementary mechanisms of their action is still not completely clear.

The main goal of the work performed at the ARIBE beamline in collaboration with Patrick Rousseau from CIMAP and Paola Bolognesi from CNR-ISM was to investigate the effect of the environment on the radiosensiting mechanisms of halouracil molecules, and  in particular on the properties and behavior of the selected target molecules by studying and comparing the ¹²C⁴⁺ ion induced fragmentation of uracil, 5BrU and 5FU considered as isolated targets and embedded in pure and hydrated clusters. The aggregation source shown in Figure 2 has been used to efficiently produce the clusters (see for example Figure 3).

The study demonstrates that the presence of water molecules in the environment surrounding the 5BrU increases the formation of 5BrU in its enol tautomers with respect to Uracil molecule. Moreover the molecular modifications probably explain the extensive and the very fast fragmentation processes taking place on the halosubstituted rather than on the natural uracil base and hence its radiosensitising effects. These results are the first experimental evidence of the hypothesized mechanism [2] for the mutagenic activity of halouracil: the existence of keto-enol tautomerization induced by the water environment.

This work will produced more than one publication and future experiments on thymine and other bases have been planned with the CIMAP, CNR-ISM and Dipartimento di Chimica (Università Sapienza di Roma) groups.