The interrelationships of disturbances in the tumour host homeostasis.
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Biomedical subjects
Publications and source records attributed to V S Shapot.
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The rapidly growing mouse Gaelstein hepatomas 22 and 22a and rat Zajdela hepatoma are characterized both by a high thymidine kinase activity, increased TTP pool and intense 14C-thymidine incorporation into DNA. This is indicative of an intensive thymidylate biosynthesis via a short, "salvage" pathway. The predominance of this pathway for thymidylate is also characteristic for the spleens of normal animals. On the contrast, in rat and mouse thymus, where the TTP pool was the highest of all normal tissues studied, the thymidine kinase activity and thymidine incorporation into DNA were relatively low. The growth of the three hepatomas under study induces involution of tumour carrier thymus, manifested in a decrease of the TTP pool and the rate of labelled thymidine incorporation into DNA, as well as in a 4-fold decrease of the thymidine kinase activity of rat thymus. In the spleen of mice carrying ascite 22a and solid 22 hepatomas an entirely opposite response to the tumour growth was observed, i. e. in the former case the organ weight and all indices of DNA synthesis were sharply reduced, while in the latter case they were substantially enhanced. In the spleen of Zajdela hepatoma carriers the DNA synthesis is suppressed as can be evidenced from the decrease of labelled thymidine incorporation into DNA and of TTP pool; the weight of organ and the thymidine kinase activity, however, exceed the normal level more than 2-fold.
Lactate dehydrogenase (LDH) isoenzyme spectrum was studied in blood serum of healthy persons (50), cancer patients (337) and patients with benign tumors and chronic inflammatory diseases (94). The total LDH activity was found to be unchanged. In patients with cancer of different localizations (63%) the LDH-5: LDH-1 coefficient turned out to be elevated. This observation allowed us to specify the range of the coefficient values from 0.07 and more, which is characteristic of cancer patients only. The corresponding values for healthy subjects and patients with benign tumors and chronic inflammatory processes would be 0.07.
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After incorporation into DNA the thymidine analogue bromodeoxyuridine (BUDR) changes the cell phenotype, inhibiting specialized cellular functions. The biological activity of BUDR is suggested to be underlain by certain changes in DNA-protein interactions. It was shown by nucleo-protein-celite chromatography (NPC chromatography) of unfractionated cell lysates that interactions of BUDR-substituted DNA with proteins in Rauscher erythroleukemic cells are actually modified. In contrast to current views suggesting a strengthening of DNA-protein bonds in BUDR-treated cells, they are in fact relaxed. Rapidly labelled heterogeneous nuclear RNAs are divided by NPC chromatography into three subpopulations. The relative rates of their synthesis are significantly changed after BUDR treatment of erythroleukemic cells.
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The effect of purified SV40 T antigen on DNA synthesis in isolated nuclei from the confluent culture of CV-1 cells was studied. In the presence of T antigen the incorporation of [3H]TTP into DNA was found to be 2 to 3 times as high as in the control nuclei. The resulting labelled DNA was subjected to alkaline sucrose gradient centrifugation, which revealed the presence of 4S DNA species, corresponding to Okazaki fragments of animal cells. The latter finding suggests a replicative mode of DNA synthesis induced by T antigen. T antigen isolated from the cells infected with SV40 tsA-mutant and kept at a nonpermissive (41 degrees) temperature fails to stimulate DNA synthesis in isolated nuclei from resting cells. On storage at 4 degrees SV40 T antigen gradually loses its ability to stimulate DNA synthesis and by the 8th day even suppresses it when tested on isolated nuclei from a growing cell culture. No effect of T antigen on the endonuclease-induced reparative synthesis of DNA could be observed. The data described suggest that T antigen is directly involved in the control of DNA synthesis in the cells infected or transformed with SV40.
The rat hepatocytes during chemical carcinogenesis (3'-MDAB), as well as the cells of chemically-induced primary rat hepatomas preserved their response to partial hepatectomy by stimulation of the 3H-thymidine incorporation into DNA; as in the normal liver this process is inhibited by dexamethason. No impairment in the inducibility of tyrosine aminotranspherase (EC.2.6.1.5) by the hormone was observed, whereas the hormonal induction of tryptophane pyrrolase (EC.1.13.11.11) in primary hepatomas was lost completely. The problem of the adequacy of the model of chemical carcinogenesis of the organ without consideration of the cell populations heterogeneity is discussed.
In the spleen, thymus and liver of mice and rats carrying transplantable rapidly growing hepatomas a shift between the de novo and "salvage" pathways of the pyrimidine RNA nucleotides synthesis in favour of the de novo one was observed. The phenomenon was found to be the manifestation of a drastically diminished uridine utilization by the host tissues, this precursor being preferentially and avidly used by the tumour for its own RNA synthesis. The above findings are regarded as the result of a successful competition of the tumour with the host tissues for vital metabolites representing one of the forms of the systemic effects of malignant neoplasms.
The activities of glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase and transketolase were studied in the cytoplasmic fractions of transplanted mouse hepatomas differing in their growth rates, and in the liver, spleen and cortical layer of kidneys of tumour carriers and normal mice. It was shown that transplantation of hepatomas changes the activity of the pentose phosphate pathway enzymes in tumour carrier tissues unaffected by neoplasm. Deviations from normalcy were mainly similar to those observed in the hepatomas. The changes in the enzymatic activities were especially well-pronounced in the mice having rapidly growing hepatomas. This may be due to a generalized effect of the tumour on the organism, which is concurrent with malignancy.
Four types of rat liver nucleolar RNP particles with the sedimentation coefficients of 120S, 80S, 60S and 12--16S were analyzed and their chemical composition was established. The nucleolar RNP particles were found to contain a RNA set with the sedimentation coefficients of 43S, 33S, 20S and 7S. The nucleolar proteins were shown to contain endonucleases, one of which was isolated and partially purified by fractionation on DEAE-Sephadex A-50. In some of its properties this RNAse was found similar to an analogous enzyme from membrane-bound ribosomes.
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It was found that isolated plasma membranes whose purity was assayed by determinations of marker enzyme activities, specifically bind dexamethasone. The association constant and the number of binding sites were found to be equal to (7,03 +/- 4,05) . 10(9) M-1 and (1,6 +/- 0,18) . 10(-14) mol/mg protein, respectively. It was assumed that lipoprotein components of plasma membranes are involved in this binding.
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Plasma membranes (PM) of helathy rats as well as those hepatomas and PM of tumor-bearing rats were found (radioreceptor assay) to have apparently two groups of receptors for insulin with a high and low affinity for the hormone respectively and different insulin-binding capacities. Kass values of the receptors with a high affinity for insulin are drastically decreased in the PM of ascites Zajdela hepatoma (AZH) and of solid hepatoma 27 (SH-27) as well as in the liver of SH-27-bearing animals, but not in the liver of the AZH-bearing rats. Kass values of the receptors with a low affinity for insulin in the PM of AZH and in those of the liver of AZH-bearing rats appear nearly normal. In contrary, above Kass the receptors in the PM of SH-27 and SH-27-bearing animals are significantly decreased. The insulin-binding capacity of the receptors with a high affinity for the hormone in the PM of SH-27, AZH and the liver of both tumor-bearing rats is shown to be significantly higher than that in the PM of normal animals. The same property of the receptors with a low is affinity in the PM of the hepatomas and theliver of their hosts is also increased, especially in the PM of SH-27 and of the liver of SH-27-carring rats.