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The study was aimed at determining the changes of metal-containing proteins in blood serum and tumor tissue of animals with parental and doxorubicin-resistant strains of Walker-256 carcinosarcoma before and after the cytostatic administration. It has been shown that upon doxorubicin action the levels of total iron and transferrin in the tissues from the both groups of animals decreased while that of ferritine simultaneously increased with more pronounced pattern in the group of animals with resistant tumor strain. It has been shown that upon the action of doxorubicin in tumor tissue of animals with different sensitivity to the cytostatic there could be observed oppositely directed changes in the redox state of these cells that in turn determined the content of “ free iron” complexes, RO S generation and concentration of active forms of matrix metaloproteinase- 2 and matrix metaloproteinase-9, namely, the increase of these indexes in animals with parental strain and their decrease in animals with the resistant one. So, our study has demonstrated the remodulating effect of doxorubicin on the state of metal-containing proteins and redox characteristics of tumor dependent on its sensitivity to cytostatic, at the levels of the tumor and an organism. These data may serve as a criterion for the development of programs for the correction of malfunction of iron metabolism aimed at elevating tumor sensitivity to cytostatic agents.

Aim: To study indices of energy metabolism, content of K(+) and Mg(++) both in peripheral blood and in Walker-256 carcinosarcoma during development of resistance to doxorubicin., Methods: Resistance of Walker-256 carcinosarcoma to doxorubicin has been developed through 12 subsequent transplantations of tumor after the chemotherapy. Parental strain was inhibited by drug by 65%, while transitional resistant substrains - by 30% and 2%, respectively. Determination of biochemical indices in blood serum and homogenates of tumor tissue, level of potassium, magnesium, lactate, glucose, activities of lactate dehydrogenase and glucose-6-phosphate dehydrogenase was performed with the help of biochemical and immune-enzyme analyzer GBG ChemWell 2990 (USA) using standard kits. Polarography was used to determine indices of mitochondrial oxidative phosphorylation. Study of mitochondrial membrane potential was carried out on flow cytometer Beckman Coulter Epics XL using dye JC-1., Results: It has been determined that development of drug resistance causes the decrease of K(+), Mg(++), glucose content in blood serum and increase of these indices in tumor tissue. At the same time, gradual tumor's loss of sensitivity is characterized by decrease of glycolysis activity in it and activation of mitochondrial oxidative phosphorylation and pentose phosphate pathway of glucose degradation, which causes more intensive formation of NADPH., Conclusion: Development of drug resistance of tumor causes certain metabolic changes in organism and tumor. Further study of such changes will make possible to determine tumor and extratumor markers of resistance.

Aim: To compare the molecular profile and cell cycle of sensitive and resistant to doxorubicin MCF-7 breast cancer cells upon exposition to conventional or liposome-encapsulated forms of doxorubicin., Methods: capital EM, Cyrilliccapital TE, Cyrilliccapital TE, Cyrillic-test, immunocytochemistry, flow cytometry., Results: In sensitive MCF-7 cells the exposure to conventional but not liposomal form of doxorubicin decreased metallothionein (MT) expression demonstrating activation of MT-detoxification system. In doxorubicin-resistant cells (MCF-7/Dsmall o, Cyrillicsmall ha, Cyrillic) MT expression drastically decreased. Conventional but not liposomal form of doxorubicin reduced the levels of expression of steroid hormones receptors on MCF-7 sensitive cells. The exposure of MCF-7 cells to conventional form of doxorubicin resulted in the decrease of p53 expression and the increase of Bcl-2 expression. In MCF-7/Dsmall o, Cyrillicsmall ha, Cyrillic cells neither conventional nor liposomal form of doxorubicin altered Bcl-2 expression. The exposure of MCF-7 but not MCF-7/Dsmall o, Cyrillicsmall ha, Cyrillic to doxorubicin in conventional form caused cell cycle arrest in G0/G1. Upon exposure to doxorubicin in liposomal form, cell cycle blockage in G0/G1 phase was observed in both sensitive and resistant sublines., Conclusion: The differential effects of the conventional and liposomal forms of doxorubicin in sensitive and resistant cells have been demonstrated. Exposure of MCF-7 and MCF-7/Dsmall o, Cyrillicsmall ha, Cyrillic cells to doxorubicin in liposomal form alters the molecular profile and cell distribution over cell cycle phases.

Aim: To investigate the influence of ferromagnetic nanoparticles on antitumor effect of doxorubicin and mitochondria oxidative phosphorylation., Methods: The study was carried out on the mice-hybrids (C57Bl/6xDBA/2) with intraperitoneally (i/p) transplantated Ehrlich ascitic carcinoma. Single i/p injection of doxorubicin (Dox), stabilized ferromagnetic nanoparticles (Fe3O4; 20-40 nm; FM) or their combination were performed 7 days after tumor transplantation. The cytotoxic effect of agents, morphology and cell cycle of tumor cells were studied 24, 48 and 72 h after Dox administration., Results: The investigations showed that ferromagnetic nanoparticles increased the cytotoxic effect of doxorubicin on Ehrlich ascsmall i, Ukrainiantic carcinoma mainly 48 h after agents' administration. The largest number of apoptotic cells was observed in group of animals in which doxorubicin was administered before ferromagnetic nanoparticles. Moreover, the ferromagnetic nanoparticles at concentration 1.45 microg Fe/ml and, particularly, 7.25 microg Fe/ml decreased mitochondria oxygen consumption in phosphorylation state that may negatively influence their living capability., Conclusions: Obtained data point out the perspective of use of certain sized FM nanoparticles to increase the cytotoixc effect of antitumor drugs.