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A Jeney

Publications and source records attributed to A Jeney.

At least 19 recordsLinked to original sources
PubMed2001

Alterations of K-ras and p53 mutations in colorectal cancer patients in Central Europe.

Many molecular investigations of colorectal cancer (CRC) have suggested that the accumulation of specific mutations in proto-oncogenes and tumor suppressor genes regulating cell growth via signal transduction trigger the stagewise progression to malignancy. In this study, the frequency, location, and type of mutations of the K-ras proto-oncogene exon I and p53 tumor suppressor gene exons 5-8 were analyzed in colorectal carcinomas of 65 patients from Central Europe, using polymerase chain reaction (PCR)-cold single-strand conformation polymorphism (SSCP) screening and direct sequencing. The incidence of K-ras activating mutations in these Central European samples was lower (25%) compared to that obtained in American and western European populations (40-50% at least), while the incidence of p53 inactivating mutations was similar (58%). These results suggest that some other genetically linked mechanisms may play a role in CRC development and progression, and hence K-ras and p53 mutations cannot be considered to be universal genetic markers for CRC.

Colorectal Neoplasms↗
PubMed2001

Molecular pathology of tumor metastasis. I. Predictive pathology.

Millennium reviews of oncology agreed that the last century produced major developments mainly in the management of the primary tumor, but despite all of these results, cancer still remains among the leading causes of death due to the failure of clinical management of disseminated disease. This failure is primarily due to the lack of detailed information on the molecular mechanisms of tumor metastasis. Therefore, one of the hottest fields in experimental oncology is metastasis research, which provides more and more information about the molecular mechanisms. However, this information is fragmented and is not yet exploited in clinical practice. A new field of diagnostic pathology recently emerged, which translates basic research data to diagnostic practice to provide clinically relevant information on the biological potential (in this case metastatic potential) of the malignant tumors. Since tumor cell-extracellular matrix interactions are key features of tumor dissemination, expression of genes responsible for them can define the metastatic potential of malignant tumors. This review summarizes our recent knowledge on the metastatic geno- and phenotype of major human solid tumors: lung, colon, breast, prostate cancers and malignant melanoma.

Female↗
PubMed2001

Role of the basement membrane in tumor cell dormancy and cytotoxic resistance.

OBJECTIVES AND METHODS: Tumor dormancy and resistance to cytotoxic agents are key limiting events in the treatment of malignant diseases. To determine whether both are influenced by the extracellular milieu in which tumors reside, HT1080 human fibrosarcoma, MCF-7 breast carcinoma and OSCORT osteosarcoma cell proliferation, viability, apoptosis and cytoreductive-treatment-induced death were investigated in the presence or absence of extracellular matrix (ECM). RESULTS: ECM-adherent, but not plastic-adherent HT1080 cells formed a multicellular network accompanied by reduced proliferation and lowered DNA synthetic capacity. The number of cells in S-phase was dramatically reduced. Viable cells entered a state of dormancy reminiscent of that observed in the step of metastasis after extravasation, i.e. prior to the initiation of progressive growth. Such ECM-induced dormancy could be reversed by plating cells on plastic, but only after a 48-hour lag period. No difference was indicated in clonogenicity of HT1080 cells originated from plastic or ECM gel. However, the cells released from ECM gel showed significantly reduced migration ability. The resistance of anchored cells against cytotoxic damage was increased by ECM gel. Examination of cytoreductive treatment revealed that ECM adherence at the time of injury is partially protective, a property which was also moderately apparent when injured cells were transferred to the basement membrane. CONCLUSIONS: Taken together, these results suggest that the ECM plays a key role in tumor dormancy and cytotoxic resistance, both explorable at the molecular level using our in vitro model system.

Cell Division↗
PubMed1999

[Principles of drug therapy of malignant tumors: determinants of the efficacy of cytostatic agents].

Successful therapy with the anticancer cytostatic agents are remarkably dependent on the appropriate dosage and schedules of the treatment. To this end however it is highly important to have insights into the tumorbiological, pharmacokinetics, pharmacobiochemical and molecular-biological factors which underline the efficacy of the cytostatic agents. The present communication intend to provide a comprehensive survey for the medical doctors attending cancer patients concerning the mode of action of those anti tumour agents traditionally classified as alkylating agents, antimetabolites, topoisomerase inhibitors, and antimitotic agents. It will be emphasized that the currently available agents show no specific action on the malignant cells because they are inhibitors of cell proliferation and target certain molecular mechanism implicated in the cell cycle. The basis for the relatively selective antitumour action are rather different for the various cytostatic agents, nevertheless the differential activation and also the repair capacity in the tumour and in the normal organs offer an explanation for the agents acting directly or indirectly on DNA. Knowledge of the mode of action of the cytostatic agents offer not only a better understanding for their therapeutic failure but gives guidelines for those tumorbiological features which are necessary for their efficacy. In the last years substantial data have accumulated which indicate the possibility to improve the therapeutic action by modulating the pharmacokinetic or the pharmacobiochemical determinants of the antitumour drug action.

Antineoplastic Agents↗
PubMed1999

[Principles of drug therapy of malignant tumors: the role of malignant progression in the choice of effective drugs].

The progress that has been achieved in the development of antitumour drugs and the management of the untoward side effects both contributed to the increasing importance of drug-therapy beside surgery and radiotherapy in cancer treatment. The treatment of the micrometastasis which appears very frequently already at the time of the diagnosis and also the control of the metastatic progression represent the main importance of drug therapy in cancer patients. In spite of the numerous clinical trials indicating the usefulness of drug therapy both as adjuvant in the management of the primary tumours and in the treatment of metastatic tumours there are certain reservation against chemotherapy in medical circle. It is noteworthy that at the present time the strategy of cancer-therapy is subject of considerate changes. Beside to achieve cure by eradication of the tumour cells it has been recommended in various oncological center that stabilization of the malignant disease and to offer a good quality of life for the patients should also be the aim of the therapy. The purpose of this communication is to present those factors which are necessary to consider in the planning of anticancer drug therapy. Certainly to achieve cure or to improve the quality of life of cancer patients it is important to select the most appropriate drug (cytostatics, hormones, biological response modifiers or agents improving the quality of life) and treatment schedule. Since antitumour drug therapy must be classified as active, palliative/active, palliative and supportive/terminal treatments the present survey gives emphases on the underlying role of malignant progression before deciding the type of treatment.

Antineoplastic Agents↗
PubMed1999

The site-dependent growth characteristics of a human xenotransplanted basaloid squamous cell carcinoma.

PURPOSE: To improve our understanding of the aggressive behaviour of basaloid squamous cell carcinoma (BSCC) certain biological features related to malignancy were compared in the basaloid and in the squamous cell population of this tumour. METHODS: Growth rate, cell population kinetics parameters, ploidy and collagenase activity were measured in BSCC xeno-transplanted subcutaneously or into oral submucosa. RESULTS: The basaloid component of BSCC showed a growth advantage in the subcutaneous location and formed a mainly aneuploid population (69.3%) without any sign of invasiveness. However the transplantation of this tumour into the oral submucosa resulted in the reappearance of the squamous carcinoma cell population containing diploid and aneuploid cells in equal proportion. The diploid cells in the tumour growing in the subcutis were in G1 phase, whereas 30% of the diploid and aneuploid cells growing in the oral submucosa were in the growing (S+G2) phases of the cell cycle. The mixed tumour cell population in the oral submucosa produced 92-kDa collagenase IV, indicating a potential to infiltrate surrounding tissues. CONCLUSIONS: The biological behaviour of a human oral carcinoma (BSCC) in a xenograft model depends on the site of the transplantation. The aggressive malignancy of BSCC may be associated with the capacity of the basaloid cell population to generate squamous cells that are able to produce the 92-kDa type of collagenases in an appropriate microenvironment.

Aneuploidy↗
PubMed1999

5-ethyl-2'-deoxyuridine, a modulator of both antitumour action and pharmacokinetics of 5-fluorouracil.

The aim of the present studies was to elucidate the effects and optimal modulatory conditions of 5-ethyl-2'-deoxyuridine (EtdUrd) on the antitumour efficacy, pharmacokinetics and catabolism of 5-fluorouracil (5-FU) on Colon-26 and Colon-38 murine tumours. HPLC and GC-MS techniques were used to measure the concentrations of 5-FU, dihydro-5-fluorouracil, EtdUrd, 5-ethyluracil and uridine in the plasma and that of 5-FU and 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) in the tumours. It was shown that EtdUrd, given 1 h before 5-FU, selectively enhanced the antitumour action of 5-FU, without significantly increasing its toxic side-effects, thus resulting in an approximately three times higher therapeutic index. Pharmacokinetic studies revealed that 1 h after 400 mg/kg EtdUrd administration - i.e. at the time of 5-FU treatment - the plasma concentration of EtdUrd was 269 microM, and that of 5-ethyluracil, as the major metabolite of EtdUrd, was 421 microM. It is of interest that EtdUrd pretreatment did not change the maximal plasma concentration of 5-FU; however, the half-life of the terminal elimination increased from 114.5 min to 171.2 min and thus the mean residence time of 5-FU rose significantly (P < 0.05). After the combined treatment, the maximal concentration of dihydro-5-fluorouracil in the plasma decreased from 61.06 microM to 29.70 microM (P < 0.01). The intratumoral concentrations of 5-FU were 34%-158% higher 6-96 h after the combined treatment than after the single 5-FU treatment. EtdUrd also caused a moderate increase in the intratumoral level of FdUMP. It is noteworthy, that EtdUrd increased the endogenous uridine concentration in the plasma from 18 microM to a maximum of 249 microM, and the level remained high for longer than 6 h. The present studies indicate that EtdUrd enhances the therapeutic index of 5-FU by reducing the catabolism, prolonging the plasma and intratumoral concentrations of 5-FU and, at the same time, offering protection to normal organs by increasing the endogenous uridine level.

Animals↗
PubMed1999

Modulation of 5-fluorouracil by 5-ethyl-2'-deoxyuridine on cell lines expressing different dihydropyrimidine dehydrogenase activities.

The purpose of the present study was to clarify the significance of the inhibition of dihydropyrimidine dehydrogenase (DPD) in the modulation of 5-fluorouracil (5-FU) action by 5-ethyl-2'-deoxyuridine (EUdR). Four human cell lines, which differed in their susceptibility to 5-FU and in their DPD activity, were selected as biological objects. Several other enzymes of pyrimidine metabolism, i.e. thymidylate synthase (TS), thymidine kinase (TK) and pyrimidine nucleoside phosphorylase (PNP), which might be involved in the 5-FU action were also studied to elucidate their potential role in the modulation of 5-FU cytotoxicity. Two out of the four cell lines, i.e. COLO1 and SW620, showed low (57 and 28 pmol/min/mg protein) and the other two cell lines, i.e. CAL51 and CAL33, showed high (235 and 184 pmol/min/mg protein) DPD activity, respectively. In our study, contrary to our expectation, no correlation between the DPD and TS activity of the cell lines and their 5-FU sensitivity could be observed. EUdR alone was cytotoxic only on CAL33 cells in a concentration below 1 mM (IC50=194 microM) which might be due to the high TK activity (857 pmol/min/mg protein) measured in this cell line, favoring the formation of the phosphorylated nucleotides EdUMP and EdUTP indispensable for the inhibition of TS and DNA polymerase, respectively. Surprisingly, although EUdR by metabolizing to EUra was able to reduce the high activity of DPD in CAL33 and CAL51 cells by 47 and 55%, respectively, no potentiation of the 5-FU action occurred on these cell lines. On the contrary, enhancement of the 5-FU cytotoxicity was demonstrated on COLO1 and SW620 cells with low DPD activity. Our findings suggest that the 5-FU modulatory action of EUdR may be directed on other molecular targets than DPD as well, i.e. the augmentation of TS inhibition by EdUMP as demonstrated on SW620 cells might be one of these mechanisms.

Antimetabolites, Antineoplastic↗
PubMed1998

Cytokine sensitivity of metastatic human melanoma cell lines-- simultaneous inhibition of proliferation and enhancement of gelatinase activity.

The effect of a panel of cytokines on the proliferation and type IV collagenase production was studied in four melanoma cell lines of different origin, tumorigenicity and metastatic capacity. TGF-b, TNF-a and to a lesser extent, IL-1a exhibited antiproliferative effect on the cell lines, with some lines showing varying degree of resistance. The sensitivity did not correlate directly with the origin or the biological behavior of the tumor lines, suggesting that cytokine resistance of advanced stage melanoma cells may be relative. IL-2, IL-10 and IL-12 displayed little or no effect on proliferation. The effect of cytokines on metalloproteinase production showed a cell line dependent pattern. Interestingly, those cytokines that exhibited the most pronounced antiproliferative activity, also proved most effective in stimulating collagenase secretion, often simultaneously, in the same line. The results indicate that pleiotropic cytokines can have positive and negative effects simultaneously on various steps of tumor progression.

Animals↗
PubMed1998

The antiproliferative action of a melphalan hexapeptide with collagenase-cleavable site.

PURPOSE: The objective of the present study was to examine the relevance of collagenase in the antitumor action of a melphalan peptide (MHP) with a collagenase-cleavable sequence. The question was addressed as to whether collagenase may act as an activator or a target in the antiproliferative mechanism of MHP. METHODS: Melphalan was inserted into peptides representing the sequence Pro-Gln-Gly-Ile-Ala.Gly of the collagenase-cleavable site in collagens. Changes in growth and collagenase IV activities of HT-1080, HT-29, HT-168, and MCF-7 cell cultures were investigated. RESULTS: The present investigations provide data indicating that Pro-Gln-Gly-Ile-Mel-Gly (melphalan hexapeptide, MHP) is a substrate for both bacterial and 72-kDa type IV collagenases and that in this way it can generate Ile-Mel-Gly (melphalan tripeptide, MTP) of higher cytotoxic potency. Indeed, the formation of MTP was detected in the conditioned medium of HT-1080, a collagenase IV-producing human fibrosarcoma. In a comparison of equimolar concentrations of melphalan and its two peptide derivatives (MHP and MTP), superior antiproliferative action of MTP was seen in HT-29, HT-1080, and HT-168 tumor cell cultures. However, the relatively modest cytostatic actions of MHP were increased when bacterial collagenase was added to the cell cultures. After melphalan treatment, reduced levels of both 92 and 72-kDa type IV collagenases were seen in the HT-1080 cell cultures. However, the reduction of collagenase activity and the cell counts did not run parallel in the MTP- or MHP-treated cultures; indeed, collagenase activity related to cell numbers showed an elevated level. CONCLUSIONS: As the conversion of MHP to the more toxic MTP was detected in the presence of collagenases, it is possible that collagenase-directed activation of prodrugs may be a promising approach for the development of more selective cytostatic drugs against malignant tumors with high collagenase activities.

Antineoplastic Agents, Alkylating↗
PubMed1998

Inhibition of DNA topoisomerase I activity by heparan sulfate and modulation by basic fibroblast growth factor.

Eukaryotic DNA topoisomerase I catalyzes changes in the superhelical state of duplex DNA by transiently breaking single strands thereby allowing relaxation of both positively and negatively supercoiled DNA. Topoisomerase I is a nuclear enzyme localized at active sites of transcription, and abnormal levels of the enzyme have been observed in a variety of neoplasms. Because the enzyme binds heparin and, given the presence of heparan sulfate within the nuclei of mammalian cells, we sought to investigate the interaction between topoisomerase I and sulfated glycosaminoglycans isolated from normal and neoplastic human liver. The results demonstrated that low concentrations (approximately 100 nM) of heparan sulfate from normal liver but not from its malignant counterpart effectively blocked relaxation of supercoiled DNA driven by either purified holoenzyme or topoisomerase I activity present in nuclear extracts of three malignant cell lines. Heparin acted at even lower (approximately 10 nM) concentrations. Moreover, we show that basic fibroblast growth factor could interfere with this heparan sulfate/heparin-driven inhibition and that both basic fibroblast growth factor and heparin-binding sites co-localized in the nuclei of U937 leukemic cells. Our results suggest that DNA topoisomerase I activity may be modulated in vivo by specific heparan sulfate moieties present in normal cells but markedly reduced or absent in their transformed counterparts.

Cell Nucleus↗
PubMed1998

Experimental and human liver fibrogenesis.

In this work, we provide an overview of our results obtained by studying the role of transforming growth factor beta1 and proteoglycans in liver fibrogenesis. It has been found that transforming growth factor beta1 is one of the most important stimulators of extracellular matrix synthesis in the liver. In chronic liver injury, desmin-positive non-parenchymal liver cells expressed transforming growth factor beta1. The extracellular localization of the growth factor correlated well with types I, III and IV procollagen-alpha, which were detected in the fibrous septa of chronically injured livers. A similar distribution pattern was observed in human specimens. To identify the role of transforming growth factor beta1 in liver extracellular matrix protein synthesis, transforming growth factor beta1-positive transgenic mice were generated. Animals expressing the growth factor in their liver showed spontaneous liver fibrosis. Proteoglycans also participate in fibrogenesis. The majority of liver-specific heparan sulfate proteoglycans, such as syndecan-1 and fibroglycan, are produced by hepatocytes. The extracellular matrix proteoglycans decorin and perlecan are synthesized by non-parenchymal liver cells. The amount of the latter is very low in normal liver, but increases dramatically in liver fibrosis. The effect of regulatory factors on liver proteoglycans seems to be cell type-specific. In contrast to previous observations, elevated amounts of decorin did not inhibit the action of transforming growth factor beta1 in the liver.

Animals↗
PubMed1998

Human and experimental hepatocarcinogenesis.

Human liver cancer is increasing worldwide, including in Hungary. The detection of liver tumors in premalignant or early malignant states is essential for successful treatment. MC-29 virus-induced chicken hepatoma and rodent, fish and monkey models for chemical hepatocarcinogenesis were studied and compared to humans. Changes in phenotypic enzyme alterations and in the expression of certain oncogens and growth factors characterize the experimentally induced hepatomas, and might also be characteristic of human premalignant and malignant focal liver lesions. Fish hepatocarcinogenesis is useful for studying compounds in environmental pollution. Increased expression of transforming growth factor á can be observed both in experimental and human liver tumors. Increased tumor incidence was detected in transgene mice containing both transforming growth factor alpha and c-myc genes. Animal models of hepatocarcinogenesis help to understand the development of liver tumors. Methods applied in studies using those models are useful in the study of premalignant and malignant human liver lesions.

Animals↗
PubMed1998

The pathomorphology of a human xenotransplanted basaloid squamous cell carcinoma.

To elucidate some factors related to the malignant phenotype of an oral tumor with mixed cell population the question has been raised whether the biological behavior of the basaloid or the squamous cells show any difference in an immunosuppressed host organism. Basaloid squamous cell carcinoma (BSCC) surgically removed from sublingual location was xenotransplanted either subcutaneously or in the oral submucosa and the histology, ultrastructures, LDH isoenzyme pattern were investigated. The epithelial origin of the established tumor line (HTB-1) could be recognized according to the characteristic epithelial ultrastructures, while the type of the LDH isoenzymes proved its human origin. The squamous cell population dominating the parent surgical specimen of BSCC regressed during xenotransplantation in the subcutan location, on the contrary the basaloid cells grew and maintained the tumor. Interestingly the basaloid cells transplanted from the subcutis to the oral submucosa generated a squamous cell population with an infiltrative growth pattern. The xenografted BSCC offer a promising model to investigate the contribution of each cell populations in the malignant phenotype. The presented data indicate that the basaloid cells are responsible for maintaining the tumor cell population, but certain malignant features (i.e. infiltrative growth) is associated to the squamous cells which are generated from the basaloid cells only under specific circumstances. Thus this particular model system showed that different malignant features could be associated to the basaloid and to the squamous cell component.

Animals↗
PubMed1997

[Determination of dihydropyrimidine dehydrogenase in the prediction of toxic side effects of 5-fluorouracil].

In the chemotherapy of colorectal cancers the most frequently given drug is 5-fluorouracil, which in certain cases reduces or delays the appearance of the local recurrence or metastasis. It is well known that the patient's response to 5-fluorouracil is very different concerning both, effects and side effects. More than 80% of the infused drug is catabolised in the first 20 minutes after the treatment. The first and rate limiting enzyme of the catabolism is dihydropyrimidine dehydrogenase, which has the highest activity in the liver and lymphocytes. The activity of this enzyme shows correlation with the blood level of 5-fluorouracil. The deficiency of this enzyme caused severe, in some cases lethal toxicity, its congenital deficiency is responsible for familial pyrimidinaemia. Authors intended to collect data about the dihydropyrimidine dehydrogenase activity of colorectal cancer patients, in order to screen enzyme deficiency or very low enzyme activity, which might be in connection with the appearance of severe side effects, moreover to determine the optimal dose of 5-fluorouracil before the treatment. Dihydropyrimidine dehydrogenase activity was determined in the lymphocytes of 48 colorectal cancer patients, treated by 5-fluorouracil, at the beginning of each cytostatic cycle. The enzyme activity of the patients was between 1.2 and 24.4 pmol/min/10(6) lymphocyte. The value of the enzyme activity fluctuated in a range, characteristic for the individual patients and this value was not modified by the 5-fluorouracil treatment. Dividing the patients in two groups, low (lower than 5 pmol/min 10(6) lymphocyte) and high (higher than 15 pmol/min 10(6) lymphocyte) dihydropirimidine dehydrogenase activity, we found that decrease in the white blood cell number and appearance of the side effects occurred with much higher frequency in the low activity group which resulted in the reduction of the dose or in more serious cases interruption of the treatment. Authors conclude that the determination of the dihydropyrimidine dehydrogenase activity in the lymphocytes is a valuable method in the prediction of the toxic side effects of 5-fluorouracil, in the screening of the congenital enzyme deficiency and in the individualization of the 5-fluorouracil dosage.

Adjuvants, Pharmaceutic↗
PubMed1996

The antimetabolite Tiazofurin (TR) inhibits glycoconjugate biosynthesis and invasiveness of tumour cells.

We investigated the effect of Tiazofurin (TR-2-beta-D-furanosylthiazole-4-carbamide) on tumour cell invasion using metastatic 3LL-HH murine lung carcinoma and HT168-M1 human melanoma as experimental models. TR pretreatment of 3LL-HH cells, in a dose range of 15-60 microM, caused inhibition of cell proliferation, adhesion to plastic and extracellular matrix proteins. The TR-induced altered matrix interactions of 3LL-HH cells were reflected in decreased migration through matrix-covered filters. Analysis of the expression of certain invasion markers indicated that TR suppressed the expression of alpha v beta 3 integrin and MMP2 metalloproteinase. Biochemical studies indicated that 24 h 60 microM TR treatment of 3LL-HH cells inhibited glycosylation of a wide range of glycoproteins with the most pronounced effect on proteoglycans. TR pretreatment of 3LL-HH tumour cells resulted in the loss of lung colonisation potential in vivo. Furthermore, in vivo TR treatment inhibited the formation of liver metastases of 3LL-HH murine carcinoma. TR treatment also induced inhibition of integrin and MMP2 expression, migration and liver colonisation of the human melanoma HT168-M1 cell line. Since the TR concentration which inhibited various cellular functions was much lower for cell adhesion and lung colonisation than for cell proliferation, we suggest that the predominant effect of TR is the inhibition of metastasis in these model systems. We also suggest that both the effect of TR on tumour cell proliferation and on extracellular matrix interaction contribute to its remarkable antimetastatic potential in vivo.

Amino Acid Sequence↗
PubMed1996

Effect of ethyldeoxyuridine on 5-fluorouracil-induced neutropenia.

It is supposed that the toxic effect of 5-fluorouracil (5FU) on tumour cells may be increased by pretreatment with ethyldeoxyuridine (EDU). We studied the effect of this combination on neutrophil count in mice. Our present studies demonstrated that the neutropenia induced by 5 x 20 mg/kg 5FU became more severe when each dose of 5FU was preceded by 200 mg/kg EDU.

Animals↗