Biomedical subjects
Publications and source records attributed to G I Kulik.
Olivomycin (DNA-binding antibiotic) in nanomolar concentrations induces apoptosis of human tumor cells and inhibits p53-dependent transcription of the reporter gene (basal and induced by antitumor drugs). Olivomycin aglycon induces no cytotoxicity and does not block transcription.
AIM: To study the expression of proteins that characterize drug resistance, proliferation and apoptosis of human ovarian carcinoma cells. METHODS: The study was carried out on human ovarian carcinoma A2780 cells and on the A2780/DDP8 subline resistant to cisplatin. Expression of the surface and intracellular antigens (p53, Bcl-2, CD95, antigen of proliferating cells, metallothioneins, drug resistance proteins (P-glycoprotein (P-gp), glutathione-S-transferase), molecules of adhesion (E-cadherin, alpha- and beta-catenins) was studied by immunocytochemical method. RESULTS: It has been shown that the formation of the resistance to cisplatin in A2780/DDP8 cells is accompanied by the increase of expression of glutathione-S-transferase and Bcl-2, by the decrease of expression of CD95-antigene and proliferation potential of the cells, by appearance of EGF receptors and elevation of expression level of E-cadherin, alpha- and beta-catenins, proving the enhancement of adhesive properties of tumor cells. CONCLUSION: Antiapoptotic program seems to be the leading mechanism of the development of the resistance to cisplatin in A2780/DDP8 cells and is realized via high expression of Bcl-2. During the development of drug resistance of A2780/DDP cells, the program of glutathione detoxification is functionally replacing the decrease of the content of metallothioneins.
UNLABELLED: The aim of the study was to evaluate the total proteolytic activity (TPA) and the content of alpha-1-proteinase inhibitor (alpha1PI) and alpha-2-macroblobulin (alpha2M) in the blood plasma of mice with Lewis lung carcinoma (LLC) upon the development of resistance to cisplatin. METHODS: Experimental LLC model with different sensitivity to cisplatin was obtained by sequential subcutaneous transplantation of LLC cells from cisplatin-treated animals. TPA, alpha1PI and alpha2M levels were evaluated by standard biochemical methods. RESULTS: It has been shown that the development of LLC resistance to cisplatin is accompanied by the increase of TPA activity and the level of the main proteinase inhibitor - alpha1PI. Despite the high level of alpha1PI in the resistant variant of LLC compared to parental tumor, the increase of TPA/alpha1PI ratio indicated the deficiency of that inhibitor in the blood of mice bearing cisplatin-resistant tumors, that promotes metastasis. The growth of both resistant to cisplatin LLC and sensitive variant was accompanied with the reduction of the alpha2M concentration. CONCLUSIONS: Upon the development of resistance to cisplatin in vivo the shift in the balance between proteinases and their inhibitors toward activation of TPA simultaneously with the increased metastasis is taking place.
It is known that tumour progression towards drug resistance is one of the main factors resulting in the failure of cancer treatment. As tumour progression is based on the genetic instability, the study of the structure of nucleic acid from tumour cells is of great importance both for basic knowledge and for biomedical application. We applied surface enhanced infrared absorption spectroscopy (SEIRA) of nucleic acids on gold substrate and essentially increased the sensitivity of IR spectroscopy. We observed numerous changes in infrared spectra of DNA from sensitive and resistant cells that reflect drastic changes in molecular structure of DNA from tumour cells. The DNA from resistant cancer cells could be characterised as rigid structure, the structure of DNA from sensitive cancer strain seems to be flexible and after application of anticancer drugs drastically changes and approaches to the structure of helix forms. The molecular structure of lipids from resistant and sensitive cancers after application of anti-tumour drugs is also modified. Thus, we observed a disordering in the lipid chain packing from resistant cells after application of cisplatin and, in some cases, formation of phospholipid-Pt complex.
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A comparative in vitro study between the effects of Ukrain (a new synthetic thiophosphoric acid derivative of great celandine alkaloids) and alkylating antitumor drugs cyclophosphamid and cisplatin on total thiol content in Guerin carcinoma, Guerin/cis-DDP carcinoma, and in animal livers was carried out. It is shown that Ukrain action on thiol groups in Guerin carcinoma tissue does not differ from that of cyclophospamid and cisplatin to both of which Guerin carcinoma is very sensitive. Once tumor resistance to cisplatin has developed, cisplatin does not react with tumor thiol groups and cyclophosphamid reactions with tumor thiol groups decrease. Reactions of Ukrain with thiol groups of cisplatin resistant tumors increase. This indirectly indicates the increase of tumor sensitivity to this drug. Therefore, the cytotoxicity of Ukrain is similar to that of known antitumor drugs and can probably overcome the cisplatin resistance of the tumor.
The acute toxicity of i.v. Ukrain injection in rats was studied. The interrelation between toxicity (death of animals) and dosage was determined by nonlinear regression method. White blood count (WBC) in peripheral blood, weight of animals, and weight of major organs were determined in animals during all stages of investigation. Morphological studies of toxic changes in 40 different organs of rats were performed on macro- and microscopic levels.
The growth kinetics of a cancer cell population as a function of the total number of cells and the proportion of proliferating and resting cells at the beginning of the growth has been analysed by a mathematical model. The model takes into account the processes of cell division, death and transition from proliferation to rest and backwards. It is shown that a single cell population growing under the same environmental conditions has an extremely broad spectrum of growth patterns. The whole multiplicity of possible growth patterns has been determined by the inherent cellular growth characteristics of the population, while the growth pattern actually realized of the variety of growth curves depends on the total number of cells and the proportion of proliferating and resting cells at the initial moment of growth. The model is shown to provide a good prediction of experimentally measured kinetics of regrowth of tumour cells subcultured after various times of the growth in unfed cultures, and the kinetics of tumour cell growth after severe hypoxia. The role of cell transitions between proliferating and resting stages in the problem of growth control is discussed.
The authors substantiate morphologically the protector effect of K(2)9 enterosorbent during its parallel use with the antitumour anthracyclin antibiotic carminomycin. The agent was administered intraperitoneally in animals at the maximum tolerable dose. Use of the K(2)9 enterosorbent reduces the cardiotoxic effect of carminomycin.
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Individual pattern of pharmacokinetics of an antitumor drug platin was investigated in patients with lung cancer. Pharmacokinetic parameters varied considerably with patient, directly influencing the drug efficacy.
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The toxic and antitumor effects of cisplatin were shown to depend upon the activity of microsomal oxidation system enzymes. Administration of the drug in combination with K-2-9 enterosorbent was followed by an increase in its antitumor effect and amelioration of toxicity.
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The K-2-9 preparation was determined to change cis-platinum pharmacokinetics, that resulted in its pharmacodynamics alterations. The higher Pt concentrations in the blood of animals which were given the K-2-9 preparation provided selectivity of cytostatic accumulation in the tumour tissue, that was accompanied by more prolonged inhibition of the DNA synthesis. A decrease in the toxicity of cis-platinum is associated with a change in the elimination pathway and acceleration of its removal from the organism.
It is determined that the organism may adapt in principle to alkylating antitumour preparations, to thiophosphamide in particular, being administered for a long time. The development of cell adaptation reactions in the systems of hemopoiesis and microsomal oxidation of hepatocytes is studied. An increase in the activity of enzymes of the microsomal liver oxidation system is found as accompanied by a lower concentration of 35S-thiophosphamide in the studied tissues and blood serum. The reactivity of tissue and serum SH-groups is observed to decrease with the organism adaptation to the preparation.
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The effect of complex-forming sorbent K-2-9 on cisplatin toxicity was studied experimentally. Simultaneous treatment with the preparations was shown to lower the nephro- and gastroenterotoxicity of cisplatin did not detract from the antitumor effect of cisplatin.