Information on the thesis

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% (P
≤ 0.05) its cytotoxic activity towards lymphocytes of clinically healthy donors or
pseudonormal cells and increasing by 10-20 % (P ≤ 0.05) 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 (P ≤ 0.001), the activity of glutathione
peroxidase increasing 1.5-1.7 times (P ≤ 0.001) glutathione reductase activity and
normalizing GSH/GSSG ratio. selenomethionine and D-pantethine lead to 2-fold decrease
(P ≤ 0.01, P ≤ 0.05, respectively) 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.
Keywords: antioxidants, doxorubicin, tumor cells, reactive oxygen species,
multidrug resistance, glutathione system.