EXPERIMENTAL STUDY OF ANTITUMOR ACTIVITY OF NEW NITRIC OXIDE SYNTHASE INHIBITOR T1023

DOI: https://doi.org/None

M.V. Filimonova, V.V. Yuzhakov, L.I. Shevchenko, L.N. Bandurko, L.E. Sevankaeva, V.M. Makarchuk, E.A. Chesnakova, A.S. Shevchuk, M.G. Tsyganova, N.K. Fomina, I.E. Ingel, V.I. Surinova Medical Radiological Research Center, 4, Korolyova Str., 4, Obninsk, Kaluga Region, Russian Federation, 249036

Introduction. Activation of eNOS/sGC/cGMP-pathway is a common link in the development of angiogenic action of the majority of pro-angiogenic factors. In this regard, the chemical inhibition of NOS (Nitric Oxide Synthase) may cause a nonspecific angiostatic effect on the tumor. The aim of the research was to study the effect of S-alkyl-N-acyl-isothiourea derivative (Compound T1023), considered as a competitive inhibitor of NOS, on the growth, metastasis and functional morphology of transplantable solid tumor. Methods. included immunostaining for PCNA (Proliferating Cell Nuclear Antigen) and PECAM- 1 (Platelet / Endothelial Cell Adhesion Molecule-1) – CD31, as well as computer analysis of microscopic images. Results. Subchronic administration of T1023 to tumor-bearing mice caused a significant inhibition of growth (by 45–75%) and the suppression of metastasis (by 45–80%) of Lewis lung carcinoma. NOS inhibitor significantly reduced the tumor vascularization of peritumoral nodes. Morphometric studies have shown that under the influence of T1023 the volume content of PCNA-positive carcinoma cells, their quantitative density and mitotic activity were significantly reduced by 20–25%, and the apoptotic index increased by more than 3 times. Conclusion. The data obtained suggest that the antitumor activity of T1023 is realized as an anti-angiogenic effect. In this connection it is useful to study the application prospects of T1023 or other NOS inhibitors in multimodal angiostatic therapy of tumors in combination with existing anti-angiogenic drugs.
Keywords: 
inhibitors of NOS, angiogenesis, anti-tumor activity, PCNA, CD31
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