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Study of the effects of nitrosil of ruthenium compounds that release nitric oxide by photo-induction and their biological activity and application on photo-dynamic therapy


Nitric oxide (NO) is involved in several regulatory events as the control of arterial pressure via vasodilatation, neurotransmission and macrophages citotoxicity. However, this compound has a half-life of about 5 seconds in biological systems. Since it is difficult to study the effects of NO itself, it is interesting to synthesize new chemical compounds that could function as a vehicle for the controlled release of NO in biological systems. Our group has shown that nitrosothiol compounds induce spontaneous release of NO and that the photo-induction potentiates this effect (Ceron et al., 2001). However, the spontaneous release of NO could lead to side effects produced by the spontaneous NO release in other sites than those submitted to the photo-dynamic therapy (TFD). Thus, the search for species that can release NO, only when stimulated, is an interesting strategy on the development of new nitrosil drugs. Some complexes of ruthenium (II) are compounds of high stability and possible sources of NO molecules. In this project, we will study the effects of nitrosil of ruthenium compounds, which will be synthesized. Among those compounds, we will select the compounds that do not spontaneously release NO, but the compounds that only release NO under photo-induction. For this purpose, we will measure the concentration of NO released in the absence and in presence of photo-induction by amperometric detection. In addition, the selected compound(s) should have biological activity of vasodilatation only in presence of reducing substances of the compound to NO as positive control. After the compound(s) selection, in the next step we will evaluate the anti-tumor effect of the chosen compounds on murine and human melanoma cell lines from different phases of tumor progression. Selected drugs will then be tested on animal model system obtained by the subcutaneous injection of the selected tumorigenic cell lines on the dorsal region of syngenic or nude mice. We will evaluate the ability of the compounds to reverse the induced tumor. (AU)