Ganusevych I. Gelatinases as redox-dependent metastasis markers and target molecules for antitumor therapy

Dissertation presents basis for the solution of actual oncology problem - to find out the redox-dependent patterns of gelatinases (MMP-2 and MMP-9) activation during tumor progression and to determine feasibility of their use as target of targeted antitumor therapy and as markers of metastasis in patients with minimal residual disease (MRD). It was discovered that redox-dependent MMP-2 and -9 activation is regulated by formation of intracellular hypoxia in tumor cells of the stomach, rectum and mammary gland: increased levels of the superoxide radicals (SR) and NO cause a significant increase activation of the latent forms of MMP-2 and -9 (2 times, p<0.05), that demonstrate redox-mediated mechanism of their regulation. For the first time in rats with Guerin's carcinoma, it was shown that tumor cells induce redox-dependent MMP-2 and -9 activation (14 and 5 times respectively; p <0.05) in cells of the bone marrow, which forms a favorable metastatic microenvironment. These findings could have important implications for determining risk of early metastasis in patients with M0. It was proved that there is feasibility to adjust the MMP-2 and -9 activity by regulation of SR generation in order to inhibit tumor progression. It was found that redox-dependent inhibition of gelatinase activity by redox-active compounds (cobalt (III) complex AC-30 and antioxidant CoQ10) in Lewis lung carcinoma results in significant antitumor and anti-metastatic effects. It was found that the anticoagulant fraxiparine administration in patients with stage II and III rectal cancer leads to significant decrease SR generation levels in neutrophils and gelatinases total activity in blood serum (1.6 and 2 times, respectively, p <0.05) and improves the overall three-year survival of patients of 33% compared to none fraxiparine group. It was found that there is a relationship between bone marrow and blood platelets gelatinases activity – on the one side and disseminated tumor cells in bone marrow – on the other. This indicates that disseminated tumor cells in bone marrow take part in the formation of MRD in patients with gastric cancer: in the absence of disseminated tumor cells in M0 patients MMP-2 activity in bone marrow are 3 times, and MMP-9 in blood platelets - 1.7 times lower (p <0.05) than in the presence of disseminated tumor cells in the bone marrow. The expediency of gelatinases use as markers of MRD in gastric cancer was substantiated. The life expectancy of patients with gastric cancer with high MMP-2 (> 2.8 relative units (r.u.)) and MMP-9 (> 80 r.u.) activity levels in bone marrow and blood platelets respectively was significantly lower (p= 0.016 and p = 0.023 respectively) compared to their lower levels (<2.8 r.u. and 80 r.u. respectively).