Biomedical subjects

A Jeney

Publications and source records attributed to A Jeney.

At least 37 records · Page 2Linked to original sources

PubMed1995

The biological activity of cisplatin and dibromodulcitol in combination therapy.

The efficacy and modes of action of dibromodulcitol (DBD) and cisplatin (CDDP) were studied in several model systems. Combination treatments produced a longer survival time in mice bearing P388 solid lymphomas than either of the drugs alone. In the human metastatic melanoma HT-168 xenograft model the combined application of DBD and CDDP was also very effective, inducing a reduction in the number and volume of metastatic nodules. For V79 spheroids, DBD was mainly cytotoxic against the internal, quiescent cells, whereas cisplatin primarily killed cells in the proliferating, external regions of the spheroids. When combined, the drugs appeared to act synergistically throughout the spheroids. Studies on plasmid DNA showed that CDDP primarily generates cross-links, whereas single-strand breaks were dominant after DBD treatment. Upon using an assay for cleavage by restriction nuclease, antagonistic action of DBD and CDDP in combination may occur, nevertheless more strand breaks were always observed in these samples. These results suggest that the efficacy of combined DBD and CDDP is in part a result of 'spatial cooperation' by the drugs (i.e. affecting different cells) and in part the result of DNA damage produced by the combination treatments.

Animals↗

PubMed1993

[Proteoglycans (their structure, function and role in liver diseases)].

Proteoglycans are macromolecules containing a core protein to which glycosaminoglycan chains are covalently attached. The family contains several members with different structures and various functions. Some of them are elements of the extracellular matrix, while others are located to the cell surface playing important role in cell-cell and cell-extracellular matrix interactions. Present paper discusses the possible consequences of the alterations of proteoglycans observed in liver cirrhosis and liver tumors. It has to be emphasized however, that they are also involved in the pathomechanism of arteriosclerosis, Alzheimer-disease, immune diseases, arthritis, tumor progression and metastasis formation.

Extracellular Matrix Proteins↗

PubMed1993

Potential markers (enzymes, proteoglycans) for human liver tumors.

In the present work the activities of GGT and G-6-Pase and the content of Cyt P-450 were determined in surgically removed liver specimens (16 hepatocellular carcinomas, 8 focal nodular hyperplasias and 4 adenomas). The activities were compared to the surrounding seemingly normal liver tissue. In the adenomas neither of the enzymes studied showed alterations, characteristic for hepatocarcinogenesis. Four out of 8 FNHs had the enzyme pattern that was found in experimental liver carcinogenesis. Liver carcinoma specimens proved to be heterogenous. Neither elevated GGT nor reduced G-6-Pase activity was consistent in these samples although the average of G-6-Pase activity decreased to 50 percent. Cytochrome P-450 was significantly reduced in the majority of cases, showing the best agreement with the tendency observed in experimental models. As an other approach, the qualitative and quantitative alterations of proteoglycans (PG) were analized in the same tumor samples. The amount of sugar components of PGs the glycosaminoglycans (GAG) increased by many times in liver tumors. Carcinoma samples were characterized by about twentyfold increase in chondroitin sulfate content, compared to normal liver. The enhancement of GAGs is partly the consequence of a selective alteration in PG expression. The amount of perlecan and decorin was found to be increased, while syndecan disappeared from liver carcinomas. These data suggest that malignant transformation in liver is accompanied by specific alteration in the content, composition and structure of PGs. Presumably, these changes have significance in tumor progression and have also the potential to be used as markers for liver tumors.

Adenoma↗

PubMed1992

Modification of DENA-induced hepatocarcinogenesis by CCl4 cirrhosis. Comparison of the marker enzyme patterns.

The modifying action of chronic liver injury on the process of hepatocarcinogenesis was investigated. To induce cirrhosis or fibrosis F344 rats received CCl4 alone or in combination with phenobarbital, either before (model 1) or after (model 2) the application of initiator, diethylnitrosamine (DENA). In these models, morphology, tumor incidence as well as polysubstrate monooxygenase system, gamma-glutamyltransferase (GGT) and glucose-6-phosphatase (G-6-Pase) were studied. The data presented show that in model 1 the tumor incidence was much lower than in rats treated with DENA alone. This reduction appeared to be associated with the decrease in cytochrome P450 content occurring in model 1 after DENA administration. Promotion of the hepatocarcinogenic process was observed when CCl4 injury followed the application of DENA (model 2). Comparison of marker enzymes in cirrhotic livers and in tumors either with or without cirrhosis indicated that changes in cytochrome P450 and G-6-Pase were rather the results of parenchymal damage, while GGT was elevated only in tumorous livers. In tumorous livers none of the xenobiotic metabolizing activities decreased as much as the cytochrome P450 content of the same samples. Thus conceivably the cytochrome P450 operates more rapidly in tumors than in normal livers.

Animals↗

PubMed1992

Conventional and prospective molecular targets in antitumour drug design. Concepts in antitumour research.

To introduce a rationale in a drug development program the molecular base of the pathological lesion must be carefully considered both for selecting test compounds and to apply the most appropriate assay systems. From the beginning of antitumour drug research the principal aim has always been to select chemical compounds which could selectively inhibit tumour growth. This strategy was in full harmony with the concept that tumours are build up by fast proliferating cells. Research based on this concept has resulted in the development of more than 40 cytostatic agents, which are rather diverse in their chemical properties, but all act on one of the molecular mechanisms participating in cell proliferation. However the unsatisfactory therapeutic responses which could be obtained by the cytostatic agents focused the attention on those molecular events in the tumour cells which may be more closely related to the progression of the malignant disease.

Animals↗

PubMed1992

The diverse modification of N-butyl-N-(4-hydroxybutyl) nitrosamine induced carcinogenesis in urinary bladder by dibromodulcitol and dianhydrodulcitol.

The effects of intravesical therapy with adriamycin, 1.6-dibromo-1.6-dideoxydulcitol (DBD) or with 1.6-dianhydrodulcitol (DAD) on bladder carcinogenesis were investigated in rats. To induce premalignant lesions in the urinary bladder female Sprague-Dawley rats received 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in their drinking water for 4 weeks and then post-treated intravesically with one of the antitumor drugs and examined once a week for 3 months. These antitumor drugs in healthy rats (i.e. without the pre-administration of BBN) did not cause any significant morphological changes in the urinary bladder after intravesical application once a week for 3 months. In the applied dose BBN alone induced only premalignant lesions in the urinary bladder. However, neoplastic lesions occurred in the groups treated with BBN and adriamycin (9 papillomas and 3 carcinomas in 14 animals). Similarly intravesical application of DBD after BBN administration resulted 5 carcinomas among the 11 animals. On the contrary no urinary bladder tumor was found in the animals treated with BBN and DAD. As DAD is one of the conversion products of DBD it is conceivable that the difference between DBD and DAD action may be due to the formation of other solvolytic product from DBD than DAD.

Administration, Intravesical↗

PubMed1992

Synthesis and characterization of some collagen sequence analogs.

Some analogs of natural collagen sequences (773-779) were synthesized. The peptides were hydrolyzed at the Gly-Ile bond not only by crude collagenase isolated from normal rat liver, but also by the bacterial Clostridium histolyticum collagenase. The reason for this unusual cleavage site in the latter case may lie in the unordered secondary structure of the substrates measured by CD spectroscopy.

Amino Acid Sequence↗

PubMed1991

The effect of D-penicillamine on CCl4-induced experimental liver cirrhosis.

The effect of D-penicillamine (Pe) on liver fibrosis-cirrhosis induced by chronic CCl4 and phenobarbital (Pb) administration in Fischer 344 male rats was studied. Morphometric analysis did not reveal a decrease in the amount of connective tissue fibers after Pe-treatment. Compared to the CCl4 and Pb-treated control groups, Pe had no significant effect on the concentrations of hydroxyproline, a parameter of collagen degradation, either; however, it increased the glycosaminoglycan concentrations. Lymphocyte stimulation by Con-A in the Pe-treated groups did not differ from that of the CCl4 and Pb-treated ones. According to our studies, Pe-treatment was ineffective in rats with liver fibrosis-cirrhosis induced by CCl4 and Pb administration. It seems that Pe can be effective only in the cirrhosis types accompanied by a considerable copper accumulation due to suppression of the toxic effects of copper.

Animals↗

PubMed1991

Alkaline phosphatase activity in human and rat liver tumors.

Enzyme activity measurements of alkaline phosphatase in surgically removed human liver tumors showed elevated level of the enzyme in 6 focal nodular hyperplasias, reduction in 8 primary hepatocellular carcinomas, and no change in the 4 adenoma samples. The activity represented liver type of alkaline phosphatase nearly in all cases because it could be inhibited by L-homoarginine more extensively than by L- phenylalanine. Studies on polyacrylamide gel electrophoresis indicated the presence of a variant type isoenzyme only in one focal nodular hyperplasia and in two hepatocellular carcinomas, one of which showed a fibrolamellar structure whereas the other was associated to cirrhosis. The importance of the elevated amount of connective tissue in the tumor, resulting in an isoenzyme shift of alkaline phosphatase, received substantial support upon comparing chemically induced rat liver tumors with and without cirrhosis.

Alkaline Phosphatase↗

PubMed1991

Liver damaging effect of suramin in normal and carbon-tetrachloride treated rats.

Male Fischer 344 (F344) rats were treated with phenobarbital + carbon tetrachloride (CCl4) for 16 weeks to induce liver cirrhosis. Another group of rats received 50 mg/kg iv suramin once a week for 16 weeks. The third group of rats was treated with both phenobarbital + CCl4 and suramin. After 16 weeks of suramin treatment, a massive periportal infiltration composed of macrophages, many of them containing glycosaminoglycans in their cytoplasm, mast cells, and other inflammatory cells were observed. This lesion was added to the liver cirrhosis caused by CCl4 in the group treated with suramin and CCl4. The changes in glycosaminoglycan metabolism caused by suramin did not influence the CCl4 cirrhosis. Since suramin has been reported to be a prototype of a new generation of antitumor compounds, we suggest caution in the use of chronic suramin treatment, especially in patients with livers which are already damaged.

Animals↗

PubMed1990

Investigations on the antitumor effect and mutagenicity of alpha-MSH fragments containing melphalan.

alpha-MSH fragments containing melphalan were tested in vivo on L1210 leukemia and on human amelanotic melanoma xenograft in mice and in vitro on human amelanotic melanoma cell lines. The compounds exhibit significant antitumor activity, but no selectivity in targeting of melanoma can be achieved. There is a difference between melphalan and the melphalyl-peptide in their action on protein synthesis. The peptide derivatives also are less mutagenic than melphalan, according to the SCE assay, furnishing further evidence for the positive effect of natural carrier molecules.

Amino Acid Sequence↗

PubMed1990

Modification of the inhibitory effects of CCl4 on phospholipid and protein biosynthesis by prostacyclin.

CCl4 induced cellular injury and its modification by prostacyclin (PGI2) was studied in cultured rat hepatocytes. Biosynthesis of both intracellular and serum proteins and that of phospholipids decreased upon CCl4 treatments (IC50 7.0, 2.5 and 3.2 mM, respectively). After 1 hr exposure of the cells to CCl4, the reductions in the biosynthesis increased further with time. PGI2 treatments (10(-5)-10(-9) M) of the hepatocytes subsequent to CCl4 poisoning resulted in partial recovery from the cell injury evaluated at the fifth hour of the experiment. Optimal effects of PGI2 were found at a concentration of 10(-7)-10(-8) M, while higher and lower concentrations offered less protection. Upon the addition of CCl4 a higher catabolic rate of PIP2 and an increased formation of inositol phosphates were observed. This alteration was shown to precede the defects in the labelling of the major phospholipid components. Furthermore, these changes were circumvented in the presence of PGI2. Thus, PIP2 metabolism appears to be a critical process in the mechanism of this type of cellular injury and its protection by PGI2.

Animals↗

PubMed1990

5-Hexyl-2'-deoxyuridine blocks the cytotoxic effects of 5-fluorodeoxyuridine or deoxyadenosine in leukemia L1210 cells in culture.

Antitumor agents which block the de novo synthesis of nucleotides can be circumvented by the presence of salvage pathways for the reutilization of nucleobases and nucleosides. Studies have been carried out which show that 5-hexyl-2'-deoxyuridine (HdUrd) effectively blocks the cytotoxic effects of deoxyadenosine and fluorodeoxyuridine in L1210 cells. Although HdUrd (500 microM) had essentially no effect on the growth of L1210 cells in culture, the total uptake of [14C]cytidine into these cells was inhibited 99% by this concentration of HdUrd. The inhibitory effects of fluorodeoxyuridine (FdUrd) and deoxyadenosine could be completely prevented by the presence of HdUrd (200 microM). The growth inhibitory effects of fluorouracil were not prevented by HdUrd. Dipyridamole prevented the inhibition of L1210 cell growth by FdUrd but not by deoxyadenosine or fluorouracil. 5-Isopropyl-, 5-pentyl-, and 5-octyldeoxyuridine were not effective in preventing the cytotoxic effects of deoxyadenosine. The data suggest that HdUrd might be useful in blocking the salvage of nucleosides, thereby potentiating the effects of inhibitors of de novo nucleotide synthesis.

Animals↗

PubMed1990

Altered glycosaminoglycan composition in reactive and neoplastic human liver.

We have investigated the glycosaminoglycan composition of normal human liver, focal nodular hyperplasia, hepatic adenoma, and hepatocellular carcinoma. Uronic acid increased about 4 fold in the benign and reactive lesions, and greater than 7 fold in the carcinoma. Whereas in focal nodular hyperplasia and adenoma dermatan sulfate was the predominant glycosaminoglycan, in hepatocellular carcinoma chondroitin sulfate was the predominant species; it increased 24 fold over normal liver and 3-5 fold over all the other tissues. HPLC analysis of chondroitinase ABC or AC digests showed a 58 fold increase in Delta-Di-OS disaccharides in hepatocellular carcinoma, indicating significant undersulfation of chondroitin sulfate. Surprisingly, the normal-appearing liver surrounding the carcinoma showed glycosaminoglycan changes similar to adenoma and nodular hyperplasia. These results thus indicate that specific glycosaminoglycan changes occur in hepatocellular carcinoma, and suggest for the first time that proteoglycan metabolism is also altered in the non-cirrhotic, hepatic parenchyma adjacent to liver carcinoma.

Adenoma↗

PubMed1990

Modulation of membrane phenotype, matrix adhesion and microinvasiveness of metastatic tumour cells by HUdR.

The effect of HUdR, proved to be anti-metastatic in vivo, was studied in vitro on cell proliferation, nucleoside uptake, membrane fluidity, expression of galactosylated glycans and proteoglycans in metastatic HM tumour cells. The observed increase in membrane fluidity and the suppression of nucleoside transport were early events of the HUdR action followed by decrease of galactosylated glycan and HSPG expression. However, these changes did not influence the proliferation capacity of the cells at the concentrations studied. As a consequence of the membrane alterations a reduced adhesiveness and spreading on extracellular matrix components was detected. In addition, the HUdR treated HM cells showed reduced capacity to invade fibroblast monolayers in vitro. Based on these observations, HUdR could be the prototype of new anti-metastatic agents acting at the level of tumour-host interaction.

Animals↗

PubMed1990

Methylcellulose prevents the regression of carbon tetrachloride-induced liver fibrosis and cirrhosis in rats.

Male F344 rats were treated with carbon tetrachloride (CCl4; 0.3 ml/kg per os, 3 times a week) for 2 mo. At the end of the CCl4 administration out of the 65 animals 30 received methylcellulose (MCL; 3.85 ml/kg, 5% solution, per os, 3 times a week) for 6 wk. Thirty-five rats did not receive any further treatment. The fibrotic change caused by CCl4 reached its maximum 2 wk after the end of the treatment. After this, the severity of the fibrotic change regressed spontaneously. This regression was not observable in the liver of rats that received MCL. The fact that MCL is used as a solvent for drugs and as a food additive underlines the importance of the effect of this compound on chronic liver injury.

Animals↗

PubMed1990

Alterations of glycosaminoglycans in human liver and kidney tumors.

Glycosaminoglycans were investigated in surgically removed human liver and kidney tumours by applying biochemical methods. Four liver adenoma, 6 focal nodular hyperplasia and 9 primary hepatocellular carcinoma samples were compared with normal liver from autopsy cases and also with liver tissue adjacent to PHC. The studies on kidney included 14 renal cell carcinoma and 4 wilms' tumour samples. Three findings emerged from the quantitative and qualitative characterization of the tumours with epithelial origin. 1) The rise in the amount of total GAG was not limited to the malignant lesion. Similar increase was observed in benign liver tumours and also in the tissue adjacent to liver or kidney malignant tumours. 2) The dominant type of the GAG subclasses varies with the histology of the tumours. In benign liver tumours dermatan sulfate, in PHC and renal cell carcinoma chondroitin sulfate, but in Wilms' tumour hyaluronate was the prominent GAG subclass. 3) In all tumour-affected tissues dermatan and chondroitin sulfates had lower degree of sulfation. However, in the histologically different tumours various disaccharides showed reduced level of sulfation. The GAG alteration in renal cell carcinoma was compared with the prognostic factors of each individual case. This analysis showed a good correlation between HS/CS ratio and the prognostic factors of the kidney tumour cases.

Chromatography, High Pressure Liquid↗

PubMed1990

Glycosaminoglycans as novel target in antitumor therapy.

Considering the importance of intercellular contacts in the metastasis of malignant tumours drug action on glycosaminoglycan production as one of the underlying mechanisms in metastasis was investigated. 5-hexyl-2-deoxyuridine/HUdR/was shown to inhibit the conversion of glucosamine to UDP-sugars. Consequently various glycoconjugates were affected, especially the synthesis of heparan sulfate was reduced. It is noteworthy that HUdR inhibited the synthesis of glycosaminoglycans in tumour cells with high metastatic capacity. The biological consequence of the alterations in glycosaminoglycan production was studied on measuring HUdR action on cell surface markers, microinvasion and tumour metastasis in experimental systems. It was concluded that HUdR has remarkable antimetastatic activity which by all probability is due to the inhibition of heparane sulfate synthesis.

Animals↗