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TDK conference 2014

Feeding experiments and histopathological findings with new FLT3-kinase inhibitors in mouse model
Mag Dóra Gizella - year 5
SZIU Faculty of Veterinary Science, Department of Pathology
Supervisor: Dr. Ferenc Baska


The target of our experiment was the mechanism of FLT3 receptor kinase and the toxicity of the mentioned molecules in mouse models. The FLT3 is a third type tyrosine kinase receptor, which activates proenzymes and catalyzes the transfer of the phosphate group.

The process begins when a signaling molecule binds to a receptor on the surface of the cell, and ends when the DNA in the nucleus produces a protein. Along with this, a number of changes take place in the cell, such as increased proliferation, making the process work like a „switch”. When one of the proteins in the cascade is mutated, the aforementioned "switch" ceases to function and the following cascade keeps the phosphorylation going it may increase the risk of developing cancer lesions. Since this protein mainly plays a role in the formation and maturation of blood cells, the most common forms of acute myeloid leukemia (AML) and myelodysplastic syndrome could be developed as a result. These observations suggest that FLT3 mutations functionally work together with other molecules in contributing to the development of leukemia.

There were 67 mice used, of which 10 were in the control group, 27 were fed with "A" labeled compound in three different concentrations, and 30 were fed with compound "B" in also three concentrations. Our examination focused on changes in body and liver weight of the animals. The compounds are under patent and therefore their chemical structure is not yet public.

In conclusion, we observed a more selective effect on the FLT3 receptors in case of the „A” compound on the tumor cell lines, and it did not appear to be toxic, in contrast with the „B” compound, which proved to be toxic by the results of our experiments. This toxicity was observed in the reduction in body and liver weight.

Except for the B2 and B3 groups the mice organs and tissues showed no histopathological abnormalities. Mice appear to be toxic to a median dose of compound "B" and showed simple fatty infiltration of the liver and tubulonephrosis of the proximal tubuli in the kidney were detected. Mice, who consumed the highest dose of compound "B" had serious changes int he liver tissue (necrobiosisos fatty infiltration, activation of Kupffer cells (MPS system)). The cortex of the kidney showed more extensive and severe tubulonephrosis than the former group in all instances. Other organs showed rarely distinctive histopathological changes, we have seen histopathologic picture of "atrophy numerica" several times.

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