Papers by Attila Zalatnai
Anticancer research, 2009
BACKGROUND Non-steroidal anti-inflammatory drugs (NSAIDs) may be able to enhance the antitumor ef... more BACKGROUND Non-steroidal anti-inflammatory drugs (NSAIDs) may be able to enhance the antitumor effect of cancer drugs. Cyclooxygenase-2 (COX-2) is the best characterized target of NSAIDs. It was demonstrated that elevated dihydropyrimidine dehydrogenase (DPD) and COX-2 activities influence the response to 5-fluorouracil (5-FU). We previously showed that NSAIDs increased 5-FU sensitivity only in high COX-2-expressing cancer cells. MATERIALS AND METHODS The effect of indomethacin and NS-398 on DPD activity and mRNA expression in a high COX-2-expressing (determined by Western blotting, immunoflourescence and immunohistochemistry) cell line (24-, 48-hour, 10-day treatment) and xenograft (3-week treatment) was investigated. RESULTS The coexistence of high COX-2 and DPD activity or low activities of both enzymes were detected. After treatment with NSAIDs, a simultaneous and significant decrease of both activities was also demonstrated. CONCLUSION NSAIDs could be promising modulators of fl...
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Magyar onkologia, 2006
Familial clustering is estimated in 5-10% of pancreatic cancers. In different countries Familial ... more Familial clustering is estimated in 5-10% of pancreatic cancers. In different countries Familial Pancreatic Cancer Registries have been established to investigate the epidemiology, and genetic background in these families and, to organize the screening programs for high-risk relatives and for follow-up. The largest such registry is found at Johns Hopkins University Hospital. Evaluating the available data revealed that familial pancreatic cancer is heterogeneous: it may occur in kindreds of pancreatic cancer patients, but it may also be associated with various familial cancer syndromes. Such syndromes include FAMMM-syndrome, hereditary breast cancer, Peutz-Jeghers syndrome, but other associations can also be taken into account. The germline mutations are also heterogeneous, and although they are not absolutely decisive, they significantly increase the risk of the affected persons, making the organ more susceptible for environmental carcinogens. High-risk family members should be scre...
Anticancer research, 2003
BACKGROUND Several studies have indicated that mimosine, a plant amino acid, is a potential inhib... more BACKGROUND Several studies have indicated that mimosine, a plant amino acid, is a potential inhibitor of the cell cycle giving rise to growth arrest in G1-phase. These results were mainly derived from in vitro investigations. To date only one paper is available about its applicability in xenografted lung tumor. This study revealed a tumor growth suppression and an increased apoptotic index. Our experiment was aimed at investigating the influence of mimosine in human pancreatic cancer. MATERIALS AND METHODS Subcutaneously growing human pancreatic cancer xenografts in immunosuppressed mice were treated with 30 mg/kg b.w. mimosine for 34 days and the apoptosis was assessed by flow cytometry. RESULTS Mimosine treatment resulted in a significant tumor growth suppression and the sub-G1 fraction was doubled (10.82 +/- 1.18% vs. 4.65 +/- 1.65 % in controls, p < 0.01). CONCLUSION This is the first evidence that mimosine exerts an apoptotic activity in xenotransplanted human pancreatic can...
International Journal of Molecular Sciences
The poor outcome of pancreas ductal adenocarcinomas (PDAC) is frequently linked to therapy resist... more The poor outcome of pancreas ductal adenocarcinomas (PDAC) is frequently linked to therapy resistance. Modulated electro-hyperthermia (mEHT) generated by 13.56 MHz capacitive radiofrequency can induce direct tumor damage and promote chemo- and radiotherapy. Here, we tested the effect of mEHT either alone or in combination with radiotherapy using an in vivo model of Panc1, a KRAS and TP53 mutant, radioresistant PDAC cell line. A single mEHT shot of 60 min induced ~50% loss of viable cells and morphological signs of apoptosis including chromatin condensation, nuclear shrinkage and apoptotic bodies. Most mEHT treatment related effects exceeded those of radiotherapy, and these were further amplified after combining the two modalities. Treatment related apoptosis was confirmed by a significantly elevated number of annexin V single-positive and cleaved/activated caspase-3 positive tumor cells, as well as sub-G1-phase tumor cell fractions. mEHT and mEHT+radioterapy caused the moderate accu...
Pathology oncology research : POR, Jan 3, 2018
The long-acting somatostatin analogs represent important weapons in treatment protocols of patien... more The long-acting somatostatin analogs represent important weapons in treatment protocols of patients with neuroendocrine tumors. Because these peptides preferentially bind to the specific somatostatin receptors, the targeted therapy requires detection of them. As one of the national consulting centers, here we present the results of the immunohistochemically positive neuroendocrine neoplasms diagnosed between 2010 and 2014. Twenty-four paraffin-embedded cases (14 females 10 men, 21-79 years) from different localizations were found to express somatostatin-receptor type 2 (SSTR2). None of the patients has received previous hormonal therapy. The immune reactions have shown membranous, cytoplasmic or mixed patterns. There was no correlation between the expression and the chromogranin A levels, the grades or the hormonal activity/inactivity of the given neoplasms. Our results show that the immunohistochemical detection of SSTR2 is a quick, reliable and effective tool that provides useful ...
Zeitschrift für Gastroenterologie
Pathology & Oncology Research, 2017
When 150 years ago Armand Trousseau proposed that some thrombotic events might be the first sign ... more When 150 years ago Armand Trousseau proposed that some thrombotic events might be the first sign of concealed visceral malignancies, these findings seemed to be just of anecdotal interest. Since then, however, we have learned that adenocarcinomas, including pancreatic cancers could be associated with a wide spectrum of paraneoplastic syndromes. They may precede the detection of the tumor, may occur simultaneously or may develop during its progression. Due to various hematologic, endocrine, cutaneous, articular, neuromuscular, renal or even psychiatric syndromes, their correct interpretation is intriguing, and because their early signs are not necessarily recognized first by oncologists, the paraneoplastic syndromes pose a diagnostic challenge. Unfortunately, we cannot generalize about their mechanisms, because the molecular backgrounds are far-reaching. In most of the cases, the pancreatic cancer cells release various factors into the bloodstream triggering the coagulation cascade. These patients frequently present with venous thromboembolism, and sometimes they are resistant to anticoagulation. The simultaneous thrombotic and bleeding evens do reflect the abnormal hemostasis. In other instances autoantibodies are formed against cutaneous, renal, neuromuscular or nervous tissues, but the mechanism of some syndromes remains unclear. Clinicians should be aware that pancreatic carcinoma may be associated with not just the Trousseau-syndrome.
In Vivo, 2005
Malignant neoplasms consist of heterogeneous cell populations and their cellular elements prolife... more Malignant neoplasms consist of heterogeneous cell populations and their cellular elements proliferate asynchronously. Since the tumor cells of various cell cycle phases respond differently to many chemotherapeutic drugs, attempts at synchronization seemed to be a promising way to achieve a more powerful antineoplastic effect. Mainly based on in vitro data, it was shown that numerous compounds, including hormones, were able to arrest the cell cycle in different phases, and some of them also induced apoptotic cell death. The better understanding of the molecular mechanisms of cell cycle control has brought the cyclin-dependent kinases into focus and hundreds of compounds have been synthesized in order to regulate malignant cells at their checkpoints, especially at G1 progression. Some of these compounds have been found to be effective not only in vitro, but also in in vivo experiments, and they were further evaluated in Phase I - II clinical trials. Generally speaking, these studies have yielded modest, although potentially promising, results, but the adverse effects sometimes restricted the applicability of the products. Nevertheless, extended studies in cancer patients are under way. Moreover, after encouraging preclinical investigations, the combination of cell cycle regulators with different cytostatic drugs may offer a novel therapeutic alternative in the field of oncology.
In Vivo, 2005
Malignant neoplasms consist of heterogeneous cell populations and their cellular elements prolife... more Malignant neoplasms consist of heterogeneous cell populations and their cellular elements proliferate asynchronously. Since the tumor cells of various cell cycle phases respond differently to many chemotherapeutic drugs, attempts at synchronization seemed to be a promising way to achieve a more powerful antineoplastic effect. Mainly based on in vitro data, it was shown that numerous compounds, including hormones, were able to arrest the cell cycle in different phases, and some of them also induced apoptotic cell death. The better understanding of the molecular mechanisms of cell cycle control has brought the cyclin-dependent kinases into focus and hundreds of compounds have been synthesized in order to regulate malignant cells at their checkpoints, especially at G1 progression. Some of these compounds have been found to be effective not only in vitro, but also in in vivo experiments, and they were further evaluated in Phase I-II clinical trials. Generally speaking, these studies have yielded modest, although potentially promising, results, but the adverse effects sometimes restricted the applicability of the products. Nevertheless, extended studies in cancer patients are under way. Moreover, after encouraging preclinical investigations, the combination of cell cycle regulators with different cytostatic drugs may offer a novel therapeutic alternative in the field of oncology.
1-es celkitűzes: Az N363S gyakoribb mig az A3669G ritkabb előfordulasi gyakorisagat igazoltuk hor... more 1-es celkitűzes: Az N363S gyakoribb mig az A3669G ritkabb előfordulasi gyakorisagat igazoltuk hormonalisan inaktiv mellekvese adenomas betegekben a kontroll populaciohoz kepest. Ez az osszefugges meg erősebb volt ketoldali adenomasokban. Genotipus-fenotipus osszefuggesek: az N363S a 2-es tipusu diabetes mellitussal, az A3669G magasabb testsullyal es BMI-vel, a BclI pedig emelkedett szisztoles vernyomassal es magasabb koleszterin ertekkel mutatott osszefuggest. 2-es celkitűzes: a normalis mellekvesekereghez kepest a kortizolt termelő szovetekben (CPA) fokozott GRalfa es GRbete expressziot igazoltunk mind feherje, mind pedig mRNS szinten. Immunhisztokemiaval a GRbeta erős citoplazmatikus es sejtmagi festődeset mutattuk ki a CPA-ban. 3-as celkitűzes: A 47 nuklearis kofaktor es 12 koaktivator kozul csak a HSP90B, NR2F1 volt alulexpresszalodo a CPA szovetekben, mig az RARB a hormonalisan inaktiv daganatokban. Fokozott expressziot csak az NRoB1 mutatott a CPA szovetekben. Dexamethasone kezelesre a H295R sejtvonalban 17 kofaktor expresszioja valtozottt. 4-es celkitűzes: letrehoztunk egy sejtvonalat a Caco-2GRbeta-t, ami stabilan expresszalja a GRalfa-val osszemerhető mennyisegben a receptor beta izoformajat. Teljes genom genexpresszios vizsgalat alapjan a beta izoformanak gentranszkripcios aktivitasa lehet. | Objective 1: The carrier frequency of the N363S was higher while the prevalence of A3669G (located in GRbeta) was lower in hormonally inactive (HI) than in healthy population. These associations were even stronger in patients with bilateral HI tumors. Genotype-phenotype associations: the N363S polymorphism associated with type 2 diabetes mellitus, the polymorphism A3669G associated with higher body weight and body mass index and the BclI polymorphisms of the GR associated with higher systolic blood pressure and higher cholesterol level in patietns with adrenal incidentalomas. Objective 2: Compared to normal adrenocortical tissues, both GR? and GR? mRNAs were significantly increased in cortisol producing adenomas (CPA) whereas GR?, but not GR? mRNA expression was moderately increased in HI. GR? immunostaining was absent in normal adrenal tissues and HI, while a strong cytoplasmic and nuclear immunoreaction was found in CPA Objective 3: Of 47 nuclear receptors and 12 coactivators we found 2 genes (HSP90B, NR2F1) significantly underexpresed in CPA and only the RARB was underexpressed in HI compared to normal tissue. Only one (NR0B1) was overexpressed in CPA compared to normal tissue. Expression of 17 nuclear cofactors and corepressors changed after Dex treatment in H295R cell line. Objective 4: We developed a cell line stably expressing the GR? isoform. Whole genome gene expression analysis showed that the GR? itself regulates gene transcription.
In Vivo, 2006
Background: Failure of cancer chemotherapy is largely caused by multidrug resistance in tumor cel... more Background: Failure of cancer chemotherapy is largely caused by multidrug resistance in tumor cells, mediated by ABC transporters that pump many cytostatics out from the cells. Thus, inhibition of the activity of P-glycoprotein efflux pumps can improve the therapeutic results. Disiloxanes are synthetic resistance modifiers that suppressed not only the multidrug resistance gene but also MRP in various cancer cell lines. Among these compounds, SILA-409 [1,3-dimethyl-1,3bis(4-fluorophenyl)-1,3-bis(3-morpholino-propyl)-disiloxanedihydro chloride] showed a remarkable antiproliferative effect and markedly inhibited the P-glycoprotein-mediated efflux mechanism in vitro. The efficacy of this organosilicon drug was investigated in vivo, in a xenograft system. Materials and Methods: Human pancreatic cancer xenografts (PZX-40/19G) were treated s.c. with 10 mg/kg b.w. SILA-409 every second day for 34 days. Tumor volume changes were recorded every week. At the end of the experiment, a complete autopsy was performed and all the vital organs were evaluated histologically. The apoptotic and mitotic rates were counted and evaluated by morphometric methods, and the immunohistochemical expression of P-glycoprotein was determined using a monoclonal anti-p170 antibody. Results: This large dose of the organosilicon compound did not result in histologically observable toxic effects, and some tumor growth delay was noted. SILA-409 did not affect the mitotic activity, but the number of apoptotic cells per mm 2 was significantly increased. In the untreated tumors, 60% of the cells displayed p170-positivity, while in the treated group, P-glycoprotein was expressed in just 26% of the carcinoma cells. Conclusion: The multidrug reversal effect of SILA-409 was demonstrated in vivo without any apparent toxicity. In addition, it increased the apoptotic activity, exhibited some tumor growth delay, but did not affect the mitotic rate. This new organosilicon compound deserves further attention with a combination of multidrug-resistant substrate chemotherapeutic agents, especially in multidrug-resistant tumors.
Cancer Research, Apr 1, 1989
Antitumoral effects of the agonist of luteinizing hormone-releasing hormone (p-Trp-6-LH-RH) and t... more Antitumoral effects of the agonist of luteinizing hormone-releasing hormone (p-Trp-6-LH-RH) and the somatostatin analog RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH:) on chemically induced ductal pancreatic adenocarcinomas were studied. The tumors were induced in female Syrian golden hamsters by weekly s.c. injections of /V-nitrosobis(2oxopropv Damine at a dose of 10 mg/kg b.w. for 6 weeks. 18 weeks after the last injection, the peptides in controlled-release microcapsule for mulations were administered s.c. The animals received the following therapies: Group 1 (.V = IS), vehicle only; Group 2 (N = 13), D-Trp-6-LH-RH microcapsules releasing 25 Mg/day injected s.c. once a month; Group 3 (N = 14), RC-160 microcapsules, liberating 25 Mg/day admin istered s.c. every 15 days; Group 4 (,V = 14), the combination of D-Trp-6-LH-RH plus RC-160 microcapsules. The experiment was terminated on the 80th day when all hamsters in the control group were dead, but in the treated Groups 2, 3, and 4, we observed 71, 77, and 86% of survival rate, respectively. In addition to the prolongation of survival, the combi nation treatment resulted in a significant decrease in the tumorous pancreatic weight, increase in the body weight of the animals, reduction in ascites from 100 to 8,3% and regressive histológica!changes in 67% of the specimens. Our findings suggest that somatostatin analogues and D-Trp-6-LH-RH could be considered for the development of hormonal therapy for pancreatic cancer.
In vivo (Athens, Greece)
It was previously demonstrated that octreotide (Sandostatin) induced an increased apoptotic activ... more It was previously demonstrated that octreotide (Sandostatin) induced an increased apoptotic activity in human pancreatic cancer xenografts after a high dose, 1-month treatment. In the present study the effect of smaller doses (2x100 microg/kg b.w.) administered in a short-term (4-day) experiment were investigated. CBA immunosuppressed mice bearing human pancreatic carcinoma (PXZ-40/6) were treated daily with 2x100 microg/kg b.w. Sandostatin subcutaneously for 4 consecutive days. The number of tumor cells displaying apoptotic bodies (late event) and mitotic activity were assessed by morphometry, while the earlier phase of the apoptotic process was determined using flow cytometry. A short octreotide treatment did not influence the mitotic activity, but the number of apoptotic cells decreased significantly (1.8 +/- 0.44/mm2 in controls vs. 6.8 +/- 1.0/mm2 in treated tumors, p < 0.0009). The percentage of nuclei in sub-G1 phase almost doubled (6.0 +/- 0.75% in-controls, 11.2 +/- 0.97...
Magyar onkologia, 2006
Familial clustering is estimated in 5-10% of pancreatic cancers. In different countries Familial ... more Familial clustering is estimated in 5-10% of pancreatic cancers. In different countries Familial Pancreatic Cancer Registries have been established to investigate the epidemiology, and genetic background in these families and, to organize the screening programs for high-risk relatives and for follow-up. The largest such registry is found at Johns Hopkins University Hospital. Evaluating the available data revealed that familial pancreatic cancer is heterogeneous: it may occur in kindreds of pancreatic cancer patients, but it may also be associated with various familial cancer syndromes. Such syndromes include FAMMM-syndrome, hereditary breast cancer, Peutz-Jeghers syndrome, but other associations can also be taken into account. The germline mutations are also heterogeneous, and although they are not absolutely decisive, they significantly increase the risk of the affected persons, making the organ more susceptible for environmental carcinogens. High-risk family members should be scre...
Orvosi hetilap, Jan 10, 2005
An autopsy case of a huge, rapidly progressive Bellini duct carcinoma is presented. During a 6-mo... more An autopsy case of a huge, rapidly progressive Bellini duct carcinoma is presented. During a 6-month period the patient was hospitalized many times in different medical units but her illness has not been diagnosed until the final weeks. The author discusses the pitfalls of diagnosis from clinicopathological point of view.
Orvosi hetilap, Jan 4, 2004
Intraductal lesions occurring in the vicinity of the pancreatic cancer had been recognized and de... more Intraductal lesions occurring in the vicinity of the pancreatic cancer had been recognized and described almost 50 years ago, but their relation to the malignant tumor has remained rather speculative until recently. Moreover, researchers employed several dozens of terminologies preventing the comparison between the results of different groups. The paper reviews the development of term "pancreatic intraepithelial neoplasia" (PanIN) and describes its pathological characteristics. Data collected from the world literature and from own material. Introduction of the term PanIN was based on the accumulated data from molecular studies suggesting that these preneoplastic alterations are most likely precursor lesions of the ductal adenocarcinoma rather than hyperplastic changes. PanIN-1A, PanIN-1B, PanIN-2, PanIN-3 represent consecutive steps towards the malignant phenotype but they all share a common histological finding: an intact basement membrane around them. It is highly desira...
Orvosi Hetilap, 2014
The authors present a case of an 82-year-old male patient who presented with frequent hypoglycaem... more The authors present a case of an 82-year-old male patient who presented with frequent hypoglycaemia. Four years prior to the current evaluation the patient had been diagnosed with prostate carcinoma; however, he refused surgical treatment. Initial diagnostic tests indicated organic hypoglycaemia with low serum insulin levels. Insulinoma was excluded and further laboratory tests showed reduced serum insulin-like growth factor-II and normal serum chromogranin A levels as well as normal hypophysis and peripheral hormone values. The authors hypothesised that the severe hypoglycaemia might be the consequence of synthesis and secretion of insulin-like growth factor-II (or its prohormone) by the previously diagnosed prostate tumour. Insulin-like growth factor-II and its prohormone directly increases glucose uptake of the tumour, muscle and adipose tissue, decreases glucose release from the liver and downregulates insulin synthesis due to inhibition of the pancreatic beta cells. The patient...
Zeitschrift für Gastroenterologie, 2005
Inflammopharmacology, 1997
The elucidation of the pathohiological events in chronic liver diseasessuch as cellular injury, c... more The elucidation of the pathohiological events in chronic liver diseasessuch as cellular injury, cell proliferation, remodelling of extracellular matrix-has considerable importance for establishing the rational bases of hepatopharmacology. To follow this concept, the molecular-pathological features of chemically induced liver damage in rats were characterized and modulated by potential hepatopharmacological compounds. Among the 55 chemical compounds tested, acute liver damage could he most effectively abolished by prostacyclin (PGI2). In addition, prostacyclins were also able to prevent cirrhosis in experimental animals. The modes of action of the prostacyclins were investigated in shortterm hepatocyte culture. The hepatotoxin-induced metabolic alterations (reduced gluconengenesis and protein synthesis, lipid peroxidation, etc.) could be restored by prostacyclin. It was shown that PGI 2 could circumvent the augmented catabolic rate of 4,5-phosphatidyl inositol-diphosphate (PIP2) in CC14-induced hepatocyte injury. In addition, the increased intracellular calcium concentration in the injured cells was also normalized by PGI2. Thus, PIP2 metabolism appears to he a critical process in the mechanism of hepatocyte damage and its protection. Interestingly, PGI2 was effective at an advanced stage of liver injury, whereas thiazolidines were only active when administered before the application of the hepatotoxic agent. The formation of collagen could he reduced by amino-imidazolcarboxamide and silymarin. The increase in glycosaminoglycans could be abolished by the application of 5-hexyl-2deoxynridine. The presented data provide further evidence that compounds with various targets are required in hepatopharmacology.
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Papers by Attila Zalatnai