Holotiuk V. Optimization of the Redox Status in Patients with Rectal Cancer: Molecular Mechanisms of Complex Treatment Efficiency

The dissertation put forwards a new solution to one of the pressing problems of oncology - the improvement of the results of treatment of patients with rectal cancer (RC) by dint of personalizing the therapeutic tactics and taking into account the patients' redox status main factors level, the molecular profile of the tumours and the development of a new method of radiomodification during neoadjuvant chemoradiation therapy (CRT). It has been established that the progress of rectal cancer is accompanied by the superoxide (СР) and the NO-generating activity growth in the tumour (in 4.0 and 9.3 times respectively as compared with the mucous membrane of the intestine, р 0.05) and on the systemic level, particularly in neutrophils - in 1.5 and 4.3 times correspondingly (р 0.05); in platelets - in 10.7 and 4.1 times (р 0.05) when compared to the indexes of the healthy donors. There has been revealed a bond between the redox parameters of a tumour and blood cells with the patients' main clinical and morphological characteristics, with the degree of medical pathomorphosis and the course of the disease. It was first found that the level of NO-generating activity in the tumour >2.10 nM/g·min is a positive predictive marker when slating CRT with radiomodification by tegafur and L-arginine hydrochloride. For the first time it has been shown that the analysis of CP-producing activity in a tumour before treatment and the rates of excretion of 8-oxoguanine with urine in patients with rectal cancer within one day after the first fraction of irradiation allows to predict the tumour sensitivity to radiation therapy (test sensitivity is 86.7 %, specificity - 76.4 %). The complex analysis of Ang-2, Bax, iNOS and Ki-67 markers expression in rectal cancer tumours under the influence of different neoadjuvant therapy regimens and its connection with the redox indicators and clinical morphological characteristics of patients, treatment efficacy and prognosis of the course of the disease has been performed. Molecular-biological markers related to the survival of rectal cancer patients of I-III stages, which are suggested for the first time as additional criteria in favour of the administration of adjuvant chemotherapy, have been identified. Among these are CP-generating activity of NADP·N-oxidase of neutrophils after 18-20 sessions of radiotherapy >0.31 nM/105 cells/min, Ang-2 expression> 49.0 standard units and Ki-67> 51.0 standard units in the tumour before treatment. There has been demonstrated clinical efficacy and safety of administration to the patients with rectal cancer undergoing CRT the precursor of biological synthesis of NO L-arginine hydrochloride in the complex of radiomodification. The indications for application have also been devised and provided.