Kurzfassung

L-arginine is a semi-essential amino acid which plays a crucial role on the one hand as an important component for protein biosynthesis and on the other hand as a signal modulator (e.g. of the mTOR-pathway). Despite these vital functions, it is also known that many tumor cells lose their ability to synthesize L-arginine. L-canavanine is a natural L-arginine analogue, which can also be used by the respective aminoacyl tRNA synthetase instead of L-arginine, leading to an accumulation of...L-arginine is a semi-essential amino acid which plays a crucial role on the one hand as an important component for protein biosynthesis and on the other hand as a signal modulator (e.g. of the mTOR-pathway). Despite these vital functions, it is also known that many tumor cells lose their ability to synthesize L-arginine. L-canavanine is a natural L-arginine analogue, which can also be used by the respective aminoacyl tRNA synthetase instead of L-arginine, leading to an accumulation of misfolded proteins. Under physiological conditions the plasma L-arginine levels are high enough to prevent antitumor effects within non-toxic L-canavanine concentrations. L-canavanine substitution becomes highly effective, though, in the context of L-arginine limitation and anti-tumoral cytotoxicity is extremely potent in tumor entities that are not able to synthesize their own L-arginine, i.e. are L-arginine auxotrophic like many Multiple Myeloma cell lines as we could see earlier. In preliminary work in mice we could show that a combined therapy with L-arginine depletion and L-canavanine substitution leads to a significant delay of death due to tumor growth inhibition. The aim of this translational project is (I) to analyse potential changes in crucial intracellular signaling cascades, which are regulated by L-arginine and therefore can lead to resistance mechanisms, (II) to investigate in vitro how these mechanisms can be overcome and (III) in accordance with these data to test potential drug candidates in combination with L-arginine depletion and L-canavanine exposure in vivo (TransMed Fellowship)» weiterlesen» einklappen