Kozak Y. Mechanisms of antioxidants action in the modulation of the therapeutic effect of antitumor drugs on experimental tumor models in the mice.

The thesis is devoted to the study of biochemical and molecular mechanisms of tissue-protective properties of antioxidants (selenium derivatives, precursor of coenzyme A) and their ability to improve the antitumor activity of chemotherapeutic compounds (in particular doxorubicin) in mice with NK/Ly lymphoma and B16F10/wt melanoma. It was found that selenomethionine and D-pantethine improved the therapeutic activity of doxorubicin (5 mg / kg), increasing by 1.3-fold the life expectancy of mice with NK/Ly lymphoma compared to their survival rate under the action of this antibiotic alone. A combined use of doxorubicin with selenomethionine exhibits a pronounced synergistic effect on the progression of melanoma B16F10/wt, effectively inhibiting its growth (by 3 fold). Antioxidants reduce the negative side effects caused by the growth of experimental tumors and the toxic effect of doxorubicin by normalizing the total number of erythrocytes, leukocytes, indicators of leukocyte formula, creatinine level, activity of lactate dehydrogenase and aspartate aminotransferase, and also value of the de Ritis coefficient in the blood of tumor-bearing mice. The reason for the above noted actions of selenomethionine and D-pantethine is their ability to improve the selectivity of doxorubicin action via suppressing by 10-20% its cytotoxic activity towards lymphocytes of clinically healthy donors or pseudonormal cells and increasing by 10-20 % this effect in resistant malignant cells. This is due to the ability of antioxidants to reduce doxorubicin -induced oxidative stress in human keratinocytes by reducing 1.3 times , the activity of glutathione peroxidase increasing 1.5-1.7 times glutathione reductase activity and normalizing GSH/GSSG ratio. selenomethionine and D-pantethine lead to 2-fold decrease in the activity of glutathione reductase and a decrease in the level of reduced glutathione accompanying by inhibition of glutathione-S-transferase activity by 2 (P ≤ 0.001) and 2.5 times (P ≤ 0.001), accordingly, compared with these parameters under the doxorubicin action in subline cells HL-60/vinc (P-gp overexpression). This leads to the sensitization of the resistant leukemic cells with overexpression of the P-gp protein to doxorubicin action. It has been shown that selenomethionine and D-pantethine possess a pronounced cytoprotective action towards normal mammalian cells protecting them against the effects of conventional antitumor drugs, both in vitro and in vivo. This phenomenon can be explained by a modulatory effect of these antioxidants on the glutathione system of target cells. At the same time, their action was opposite in malignant cells resistant to chemotherapy which constitutional defects in a system of the antioxidant defense. As a consequence, both compounds increased the effect of drugs on tumor cells with the MDR-phenotype, and this effect is fully preserved in experimental tumor models used for studing therapeutic efficacy. The obtained results suggest a perspectiveness of joint using of antitumor drugs together with antioxidant compounds capable of significant increasing their therapeutic efficacy and reducing negative side effects of drugs. During such treatment, a dosage of both antitumor drugs and antioxidants, as well as a possibility of their specific action towards various types of tumors, should be taken in consideration in order to achieve a synergistic effect in their action.