[Show abstract][Hide abstract] ABSTRACT: Endocannabinoids contract, relax or do not affect vessels with different calibre and tone in the pulmonary circulation in four species. The aim of the present study was to determine the mechanisms involved in the anandamide-induced relaxation of human pulmonary arteries (hPAs). Studies were performed in the isolated hPAs pre-constricted with the prostanoid TP receptor agonist, U-46619. To detect fatty acid amide hydrolase (FAAH) expression, Western blots were used. Anandamide concentration dependently relaxed the endothelium-intact hPAs pre-constricted with U-46619. The anandamide-induced relaxation was virtually abolished by removal of the endothelium and strongly attenuated by inhibitors of cyclooxygenases (indomethacin, COX-1/COX-2, and nimesulide, COX-2), nitric oxide synthase (N (G) -nitro-L-arginine methyl ester) given separately or in combination, FAAH (URB597), and the prostanoid IP receptor antagonist, RO1138452. The anandamide-evoked relaxation in the endothelium-intact vessels was attenuated in KCl pre-constricted preparations or by the inhibitor of large-conductance Ca(2+)-activated K(+) channels, iberiotoxin. In experiments performed in the presence of URB597 to exclude effects of anandamide metabolites, the antagonist of the endothelial cannabinoid receptor, O-1918, diminished the anandamide-evoked relaxation whereas the antagonists of cannabinoid CB1, CB2 and vanilloid TRPV1 receptors, AM251, SR144528 and capsazepine, respectively, had no effect. Western blot studies revealed the occurrence of FAAH protein in the hPAs. The present study shows that anandamide breakdown products, cyclooxygenase pathways, nitric oxide, potassium channels and the O-1918-sensitive cannabinoid receptor play a role in the anandamide-induced relaxation of the hPAs with intact endothelium.
Archiv für Experimentelle Pathologie und Pharmakologie 02/2014; 387(5). DOI:10.1007/s00210-014-0961-9 · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT Purpose: The matrix metalloproteinases, tissue inhibitors of metalloproteinases and angiogenesis contribute to growth and spread of cancer. We investigated the correlation between pretreatment serum levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) and vascular endothelial growth factor A (VEGF-A), and clinicopathologic features and survival in patients with esophageal cancer (EC). Material/Methods: Serum TIMP-1 and VEGF-A were measured by enzyme-linked immunosorbent assay (ELISA) in 89 patients with EC, and 30 healthy controls. Results: Serum TIMP-1 and VEGF-A levels were significantly higher in patients with esophageal carcinoma than in the control group (p=0.001 and p<0.001, respectively). High levels of TIMP-1 were associated with histological type (p<0.001), tumor depth (p<0.001), stage (p<0.001) and lymph node metastases (p=0.001). Subgroup analysis showed that tumor size (p<0.001), tumor depth (p<0.001), stage (p<0.001), lymph node metastases (p=0.002), distant metastases (p=0.009) and resectability (p=0.003), were correlated with an elevated level of VEGF-A. Patients with elevated levels of TIMP-1 and VEGF-A had a significantly lower overall survival (p=0.02 and p=0.048, respectively), and disease-free survival (TIMP-1, p<0.001). Conclusion: High serum levels of TIMP-1 and VEGF-A were found to be associated with tumor progression and unfavorable prognosis in patients with EC.
Advances in Medical Sciences 06/2013; DOI:10.2478/ams-2013-0017 · 0.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has been suggested that activation of nuclear peroxisome proliferator-activated receptors γ (PPARγ) may represent a new strategy for the treatment of pulmonary arterial hypertension. It has been demonstrated that PPARγ activation relaxed the isolated mouse pulmonary artery. The aims of the present study were to examine whether and to which extent the two PPARγ agonists rosiglitazone and pioglitazone relax the isolated human pulmonary artery and to investigate the underlying mechanism(s). Isolated human pulmonary arteries were obtained from patients without clinical evidence of pulmonary hypertension during resection of lung carcinoma. Vasodilatory effects of PPARγ agonists were examined on endothelium-intact or endothelium-denuded vessels preconstricted with the thromboxane prostanoid receptor agonist U-46619. Rosiglitazone and pioglitazone (0.01-100 μM) caused a concentration- and/or time-dependent full relaxation of U-46619-preconstricted vessels. The rosiglitazone-induced relaxation was attenuated by the PPARγ antagonist GW9662 1 μM, endothelium denudation, the nitric oxide synthase inhibitor L-NAME 300 μM, the cyclooxygenase inhibitor indomethacin 10 μM, and the KATP channel blocker glibenclamide 10 μM. The prostacyclin IP receptor antagonist RO1138452 1 μM shifted the concentration-response curve for rosiglitazone to the right. The PPARγ agonists pioglitazone and rosiglitazone relax human pulmonary arteries. The rosiglitazone-induced vasorelaxation is partially endothelium-dependent and involves PPARγ receptors, arachidonic acid degradation products, nitric oxide, and KATP channels. Thus, the relaxant effect of PPARγ agonists in human pulmonary arteries may represent a new therapeutic target in pulmonary arterial hypertension.
Archiv für Experimentelle Pathologie und Pharmakologie 03/2013; 386(5). DOI:10.1007/s00210-013-0846-3 · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In esophageal cancer, metastases in regional lymph nodes occur
early and are a poor prognostic factor. We studied intratumoral
and peritumoral lymphatic vessel density, and intratumoral and
peritumoral lymphatic vessel invasion using D2-40 immunohistochemical
staining in 74 resected esophageal cancer specimens
and correlated results with patients’ clinicopathologic features
and outcomes. Results were analyzed by univariate and multivariate
logistic regression as well as univariate and multivariate
survival analysis. The peritumoral lymphatic vessel density
was significantly higher than the intratumoral lymphatic vessel
density (p < 0.001). The peritumoral lymphatic vessel density
and intratumoral lymphatic vessel density positively correlated
with lymph node metastasis, tumor stage, depth of tumor invasion,
and residual tumor. Positive intratumoral lymphatic vessel
invasion and peritumoral lymphatic vessel invasion were significantly
correlated with lymph node metastasis, tumor size,
tumor depth, stage, and residual tumor. Multivariate logistic
regression analysis identified intratumoral lymphatic vessel
density (p = 0.028) and peritumoral lymphatic vessel invasion
(p = 0.036) as risk factors of lymph node metastasis. Cox regression
analysis showed that intratumoral lymphatic vessel invasion
and peritumoral lymphatic vessel invasion are independent
prognostic factors of disease-free survival (p = 0.018, p = 0.021),
cancer-specific survival (p = 0.016, p = 0.025), and overall survival
(p = 0.017, p = 0.02). Intratumoral lymphatics and peritumoral
lymphatic vessel invasion are predictive factors of lymph node
metastasis. Intratumoral and peritumoral lymphatic vessel invasion
are independent prognostic factors in locally advanced
Polish journal of cardio-thoracic surgery 01/2013; 10(2):120-129. DOI:10.5114/kitp.2013.36131 · 0.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: The aim of our study was (1) the pharmacological characterization of EP(3) receptors in human pulmonary arteries and (2) the examination of the potential involvement of these receptors in the regulation of neurogenic tachycardia in pithed rats. L-826266 served as the EP(3) receptor antagonist. Methods: Experiments were performed on isolated human pulmonary arteries and pithed rats. Results: The prostanoid EP(1)/EP(3) receptor agonist sulprostone (1 nM - 100 μM) concentration-dependently contracted isolated human pulmonary arteries (pEC50, 6.88 ± 0.10). The EP(1) receptor antagonist SC 19920 (100 μM) did not affect the vasoconstriction induced by sulprostone, the TP receptor antagonist sulotroban (10 μM) only slightly attenuated the effects elicited by sulprostone >3 μM, whereas L-826266 (10 μM) shifted its concentration-response curve to the right (apparent pA(2) value 6.18; incubation time 0.5 h). In rings exposed to L-826266 (0.1, 1 or 10 μM) for 3 h, a concentration-dependent inhibitory effect against the sulprostone-induced vasoconstriction was obtained, yielding a Schild plot-based pA(2) value of 7.39. In pithed rats, sulprostone (10 - 1,000 nmol/kg), but not the IP/EP(1) receptor agonist iloprost (1-100 nmol/kg), inhibited the electrically evoked increase in heart rate (HR) dose-dependently, maximally by at least 80%. L-826266 (3 μmol/kg) did not affect basal HR and diastolic blood pressure, but reduced the inhibitory effect of sulprostone 1,000 nmol/kg by about 20%. Conclusion: EP(3) receptors (1) located postsynaptically strongly contract human pulmonary arteries and (2) located presynaptically on sympathetic nerve fibers supplying the heart of pithed rats strongly inhibit the neurogenic tachycardia.
[Show abstract][Hide abstract] ABSTRACT: Elevated C-reactive protein (CRP) levels have been found in patients with several malignancies. The aim of the present study was to analyze the diagnostic and prognostic values of CRP levels measurement in esophageal cancer (EC) patients in relation to its different histological subtypes (squamous cell carcinoma-ESCC and adenocarcinoma-AC of esophagus) and compared them with classic tumor markers-carcinoembryonic antigen (CEA) and squamous cell cancer antigen (SCC-Ag). The diagnostic sensitivity, specificity, and the areas under receiver operating characteristic curves (AUC) for all the proteins tested were defined. Serum CRP levels were statistically higher in EC, ESCC, and AC patients compared to healthy subjects and significantly increased in EC and ESCC patients with the presence of lymph node and distant metastases. The percentage of elevated CRP results in all the analyzed subgroups (EC, ESCC, and AC) was higher than CEA and SCC-Ag, similarly as AUC for CRP in comparison to SCC-Ag. Serum CRP level was a significant predictor of EC and ESCC patients' survival in univariate analysis. In conclusion, these results indicate that CRP can be used as an adjunct in evaluating the tumor markers-CEA and SCC-Ag and may improve the clinical diagnosis and follow-up of EC patients, especially for ESCC subgroup.
[Show abstract][Hide abstract] ABSTRACT: It has been suggested that interleukin 6 (IL-6) plays a potential role in the growth and progression of tumors, including esophageal cancer (EC). The aim of the study was to compare clinical significance of serum IL-6 with classic tumor markers - carcinoembryonic antigen (CEA) and squamous cell cancer antigen (SCC-Ag) - in EC patients in relation to its histological types - squamous cell carcinoma of esophagus (ESCC) and adenocarcinoma (AD) of esophagus. The study included 53 EC patients and 90 healthy subjects. Serum IL-6 and CEA levels were determined using immunoenzyme assays, while SCC-Ag - chemiluminescent assay. The diagnostic criteria and prognostic values for markers were defined. The levels of all proteins tested in EC, ESCC, and AD were higher than in healthy subjects. The percentage of elevated results was substantially higher for IL-6 (86%) than for CEA (30%) and SCC-Ag (24%) in EC, similarly as in ESCC (87%, 23%, and 33%) and AD (87%, 39%, and 13%, respectively) patients. Concentrations of IL-6 depended on distant metastases and patients' survival in EC and were significantly higher in ESCC patients with more advanced tumor stage and nodal metastases. The IL-6 area under receiver operating characteristic curve (0.92) was larger than for CEA (0.84) and SCC-Ag (0.62) in EC, likewise in ESCC (0.92, 0.87, 0.77) and AD (0.91, 0.79, 0.57, respectively). Our findings indicate better usefulness of IL-6 than classic tumor markers in the diagnosis of EC, especially in patients with ESCC.
Diseases of the Esophagus 09/2011; 25(3):242-9. DOI:10.1111/j.1442-2050.2011.01242.x · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The discovery of markers to lymphatic endothelial cells and the development of novel antibodies to these markers have brought increasing attention to the lymphatics and progress in the understanding of lymphangiogenesis and cancer metastasis. In this study, we investigate the presence of lymphatic vessel invasion (LVI) detected by D2-40 immunohistochemical staining in resected esophageal cancer and correlated with clinicopathologic data and patient survival. Sixty nine patients, who had a primary resection of esophageal cancer, were analyzed by univariate and multivariate logistic regression, and univariate and multivariate survival analysis. The total rate of LVI was 72% (50/69). Positive LVI was significantly correlated with lymph node metastasis (p < 0.001), tumor size (p < 0.001), histological grading (p = 0.017), tumor depth (p = 0.001), and stage (p < 0.001). Multivariate logistic analysis identified LVI (p = 0.036) as a predictor of regional lymph node metastasis. On univariate survival analysis, patients with LVI had a significantly shorter disease-free survival, cancer-specific survival and overall survival. Multivariate analysis proved that LVI diagnosed by D2-40 is an independent prognostic factor of both disease-free survival (p = 0.04) and overall survival (p = 0.032) in resected esophageal cancer. These results show that LVI assessment identifies patients at high risk for regional lymph node metastasis and that LVI is an independent prognostic factor in patients with esophageal cancer.
[Show abstract][Hide abstract] ABSTRACT: Hematopoietic growth factors (HGFs), such as macrophage-colony stimulating factor (M-CSF) are produced aberrantly in many malignancies. Esophageal cancer (EC) is characterized by late diagnosis, rapid progression and poor survival. The purpose of the present study was to determine the clinical usefulness of M-CSF in the diagnosis of EC and its histological type - squamous cell cancer of the esophagus (ESCC).
The study included 80 patients with EC (54 with ESCC and 26 with adenocarcinoma of the esophagus) and 30 healthy subjects. The serum concentrations of M-CSF, carcinoembryonic antigen (CEA) and squamous cell cancer antigen (SCC-Ag) were determined using immunoenzyme assays. We defined the percentage of increased concentrations of proteins tested and the areas under the receiver-operating characteristics (ROC) curves.
In EC and ESCC patients, serum concentrations of M-CSF, CEA and SCC-Ag were significantly higher compared with healthy subjects. Concentrations of M-CSF in both groups analyzed (EC and ESCC) showed a tendency for increases with depth of tumor invasion, the presence of lymph node and distant metastases. The combined use of M-CSF with SCC-Ag increased their percentage of increased concentrations, and this value was higher than for classical tumor markers in both groups analyzed. The area under ROC curve for M-CSF was larger than for CEA in EC patients.
Our findings suggest the potential usefulness of serum M-CSF concentrations as a tumor marker for EC, especially in combination with SCC-Ag. However, the diagnostic value of this cytokine may be limited because of its non-specific nature.
Clinical Chemistry and Laboratory Medicine 10/2010; 48(10):1467-73. DOI:10.1515/CCLM.2010.274 · 2.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The epigenetic inactivation of tumor suppressor genes may play an important role in the development and progression of many cancer types, including lung cancer. Therefore, we investigated the association between the aberrant promoter methylation of 2 genes: the Death-Associated Protein Kinase (DAPK) and the Ras Association Domain Family 1A (RASSF1A) by using methylation-specific PCR, and the clinicopathological features and prognosis in 70 radically resected non-small cell lung cancers (NSCLCs). Hypermethylation of the DAPK and RASSF1A promoters was found in 24 (34%), and in 18 (26%) tumor DNA samples, respectively. Regarding different clinicopathological features of NSCLCs, the DAPK promoter methylation was more frequently observed in squamous cell carcinoma (46%) than in adenocarcinoma (25%) and large cell carcinoma (22%), but there were no significant statistical differences (p=0.3). On the other hand, a statistically significant trend was observed between the RASSF1A methylation and a histological type of tumor (p=0.06). 45% of adenocarcinoma tumors showed RASSF1A promoter methylation in comparison to 17% of squamous cell carcinomas and 22% of large cell carcinomas. When both markers were analyzed according to the tumor-node-metastasis (TNM) staging system, no statistically significant differences were observed between stage I, II and IIIa, and the DAPK (p=0.2) and RASSF1A methylation (p=0.1). In comparison, when stage I and II were grouped together and considered vs. stage IIIa, a significant association between RASSF1A methylation and the TNM was found (p=0.03). The group of patients with tumors showing DAPK promoter methylation had significantly poorer overall survival rates (p=0.02) than the patients with tumors that did not show DAPK promoter methylation. However, the association between the RASSF1A promoter methylation status and the overall survival rates was not statistically significant (p=0.48). In conclusion, this paper supports the importance of epigenetic gene regulation in lung cancer progression and prognosis.
[Show abstract][Hide abstract] ABSTRACT: Matrix metalloproteinase 9 (MMP-9) is a proteolytic enzyme which is associated with tumor progression including invasion, migration, angiogenesis, and metastasis due to its ability to degrade type IV collagen.
The aim of the study was to assess clinical significance of MMP-9 measurement in the diagnostic evaluation of patients with esophageal squamous cell carcinoma (ESCC).
The study included 63 patients with ESCC and 30 healthy subjects. We assayed serum MMP-9 levels and squamous cell carcinoma antigen (SCC-Ag), a tumor marker. We defined diagnostic criteria for both markers.
In ESCC patients serum levels of MMP-9 and SCC-Ag were found to be statistically higher compared with healthy subjects. Serum concentrations of MMP-9 and SCC-Ag tended to increase in patients with advanced cancer. The percentage of elevated MMP-9 concentrations (75%) was higher than that of SCC-Ag (68%) and increased for the combined use of both markers (97%).
The results suggest the potential usefulness of MMP-9 in establishing the diagnosis of ESCC, especially when analyzed in combination with SCC-Ag.
Polskie archiwum medycyny wewnȩtrznej 09/2009; 119(9):558-63. · 2.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The endocannabinoid virodhamine is a partial agonist at the cannabinoid CB(1) receptor and a full agonist at the CB(2) receptor, and relaxes rat mesenteric arteries through endothelial cannabinoid receptors. Its concentration in the periphery exceeds that of the endocannabinoid anandamide. Here, we examined the influence of virodhamine on the human pulmonary artery.
Isolated human pulmonary arteries were obtained during resections for lung carcinoma. Vasorelaxant effects of virodhamine were examined on endothelium-intact vessels precontracted with 5-HT or KCl.
Virodhamine, unlike WIN 55,212-2, relaxed 5-HT-precontracted vessels concentration dependently. The effect of virodhamine was reduced by endothelium denudation, two antagonists of the endothelial cannabinoid receptor, cannabidiol and O-1918, and a high concentration of the CB(1) receptor antagonist rimonabant (5 muM), but only slightly attenuated by the NOS inhibitor L-NAME and not affected by a lower concentration of rimonabant (100 nM) or by the CB(2) and vanilloid receptor antagonists SR 144528 and capsazepine, respectively. The COX inhibitor indomethacin and the fatty acid amide hydrolase inhibitor URB597 and combined administration of selective blockers of small (apamin) and intermediate and large (charybdotoxin) conductance Ca(2+)-activated K(+) channels attenuated virodhamine-induced relaxation. The vasorelaxant potency of virodhamine was lower in KCl- than in 5-HT-precontracted preparations.
Virodhamine relaxes the human pulmonary artery through the putative endothelial cannabinoid receptor and indirectly through a COX-derived vasorelaxant prostanoid formed from the virodhamine metabolite, arachidonic acid. One or both of these mechanisms may stimulate vasorelaxant Ca(2+)-activated K(+) channels.
British Journal of Pharmacology 10/2008; 155(7):1034-42. DOI:10.1038/bjp.2008.371 · 4.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases associated with tumor progression. It was proved that expression of MMP-9 in human esophageal cancer tissues correlated with stages of the disease. The aim of the present study was to determine potential clinical use of serum MMP-9 as a tumor marker of esophageal cancer.
The study included 89 patients with esophageal cancer and 30 healthy subjects (control group). We assayed serum levels of MMP-9 and classical tumor markers (SCC-Ag and CEA). We defined the prognostic value and diagnostic criteria for the measurands.
Serum levels of MMP-9, CEA and SCC-Ag in esophageal cancer (EC) patients were statistically higher than in the control group. MMP-9 serum concentrations were associated with clinical stages of EC and tumor size. The diagnostic sensitivity of MMP-9 (70%) was higher than tumor markers and increased in combination with SCC-Ag (92%). The area under the ROC curve for MMP-9 (0.733) was lower than for SCC-Ag (0.811) and higher than for CEA (0.673). In Cox's univariate analysis serum MMP-9, SCC-Ag and CEA were not significant for prognosis of EC.
The results suggest the usefulness of MMP-9 as a tumor marker in diagnosis, but not in prognosis of esophageal cancer.
[Show abstract][Hide abstract] ABSTRACT: Metalloproteinase-9 (MMP-9) is the proteolytic enzyme degrading type IV collagen, and plays important role in the invasiveness and metastatic potential of tumor cells. The aim of the current study was to compare the association between the intensity of MMP-9 expression in neoplastic cells and in the interstitial inflammatory infiltrate cells in esophageal cancer with clinicopathological features of esophageal cancer (EC) and in different histopatological types of EC, e.g. adenocarcinoma and esophageal squamous cell carcinoma. The study included 32 EC patients, 17 cases of squamous cell carcinoma and 15 cases of adenocarcinoma, verified histopatologically. The presence of MMP-9 in cancer tissue was investigated by immunohistochemistry on formalin-fixed, wax-embedded sections of esophageal cancers. The light microscopy was used to evaluate the expression of metalloproteinase-9 in cancer cells and in inflammatory infiltrate in the neoplastic interstitium in semi-quantitative scale. The expression of MMP-9 in cancer cells was positive in 81% of cases whereas in inflammatory cells - in 75% and increased with tumor stage, depth of tumor invasion (T factor) and lymph node metastases (N factor). In squamous cell cancer the MMP-9 expression in cancer cells and in inflammatory infiltrate was higher than those in adenocarcinoma. Mean value of MMP-9 expression in inflammatory cells was higher in early stages of EC, whereas mean expression of this enzyme in cancer cells increased with tumor stage. In conclusion, this is the first study comparing the expression of metalloproteinase-9 in cancer and inflamatory infiltrate cells in different histopatological types of esophageal cancer. We proved the synthesis of MMP-9 by cancer cells as well as by inflammatory cells and its correlation with tumor stage, tumor size, depth of tumor invasion and lymph node metastases. The results suggest the role of MMP-9 in esophageal tumorigenesis, although this issue requires further investigations.
[Show abstract][Hide abstract] ABSTRACT: The endocannabinoid anandamide is implicated in the pathogenesis of hypotension in haemorrhagic, endotoxic, and cardiogenic shock. It has been demonstrated in animal, but not in human, vessels that the vasodilatory effects of anandamide and abnormal cannabidiol are partially mediated by an as yet unidentified endothelial cannabinoid receptor. Our study was performed to examine the influence of abnormal cannabidiol on the human pulmonary artery.
Isolated human pulmonary arteries were obtained from patients without clinical evidence of pulmonary hypertension during resection of lung carcinoma. Vasodilatory effects of abnormal cannabidiol were examined on endothelium-intact vessels preconstricted with serotonin or potassium chloride.
Anandamide and abnormal cannabidiol relaxed serotonin-preconstricted vessels concentration-dependently. The effect of abnormal cannabidiol was reduced by endothelium denudation, pertussis toxin and two antagonists of the novel endothelial receptor, cannabidiol and O-1918, but not by the nitric oxide synthase inhibitor L-NAME given together with the cyclooxygenase inhibitor indomethacin. It was also diminished by blockade of calcium-activated potassium channels by the nonselective blocker tetraethylammonium or by combination of selective blockers of small (apamin) and intermediate and large (charybdotoxin) conductance calcium-activated potassium channels. The potency of abnormal cannabidiol to relax vessels was lower in potassium chloride than in serotonin-preconstriced preparations.
Abnormal cannabidiol relaxes human pulmonary arteries in an endothelium-independent and endothelium-dependent manner. The latter component is probably mediated via the putative endothelial cannabinoid receptor, activation of which may release endothelium-derived hyperpolarizing factor, which in turn acts via calcium-activated potassium channels. Abnormal cannabidiol is behaviourally inactive; it may have a therapeutic implication in vascular diseases, especially in the treatment of pulmonary hypertension.
Journal of Hypertension 12/2007; 25(11):2240-8. DOI:10.1097/HJH.0b013e3282ef7a0a · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: p53 protein is a critical regulator of cell cycle and apoptosis. Many stimuli change its expression and modify its functions. The aim of our work was to determine stability and chosen posttranslational modification of p53 protein during the treatment of lung cancer.
We investigated levels of poly-ADP-ribose- a marker of cellular DNA damage, DNA ploidy, Ki-67 expression, wild type and mutated p53 protein expression and intensity of phosphorylation of chosen p53 serine sites: C-terminal Ser392, and N-terminal Ser15, and Ser20 in fiberoptic bronchoscopy biopsy samples taken from patients suffering from recurrent squamous cell lung cancer before and after radio/chemotherapy. Analysis was based on results obtained from 23 patients after surgery in I-IIIA clinical stage of the disease.
Therapy lowered the number of G2/M cells, but increased S fraction cell population in about 50%. Therapy increased p53 expression and p53 phosphorylation at Ser392 and Ser20, and these changes correlated with poly-ADP-ribose levels and Ki-67 expression.
Our results indicate that apart from changes in p53 quantity, p53 posttranslational phosphorylation play a role in regulation of neoplastic cells proliferation in response to drugs.
Pneumonologia i alergologia polska: organ Polskiego Towarzystwa Ftyzjopneumonologicznego, Polskiego Towarzystwa Alergologicznego, i Instytutu Gruzlicy i Chorob Pluc 02/2007; 75(3):241-50.
[Show abstract][Hide abstract] ABSTRACT: The aim of our study was to examine whether non beta(1)-/beta(2)-adrenoceptors participate in the relaxation of the human pulmonary artery. For this purpose the vasodilatory effect of the non-conventional partial beta-adrenoceptor agonist cyanopindolol was examined. Cyanopindolol (1-300 microM), studied in the presence of the beta(1)-/beta(2)-adrenoceptor antagonist propranolol, relaxed the human pulmonary artery preconstricted with serotonin 1 microM in a concentration-dependent manner (maximally by about 80%). This effect was diminished by bupranolol 10 microM (an antagonist of beta(1)-beta(3)-adrenoceptors and the low affinity state of the beta(1)-adrenoceptor) and CGP 20712 10 microM (known to antagonize the low-affinity state of the beta(1)-adrenoceptor at high concentrations). In further experiments, the effect of beta-adrenoceptor ligands on the serotonin-induced vasoconstriction was examined. The concentration-response curve for serotonin was not affected by cyanopindolol 30 microM, bupranolol 10 microM and CGP 20712 10 microM but shifted to the right by cyanopindolol 100 and 300 microM; the serotonin 5-HT(2A) receptor antagonist ketanserin 0.3 microM abolished the maximum contraction elicited by serotonin. In conclusion, the present study reveals that the vasodilatory effect of cyanopindolol in the human pulmonary artery consists of two components, i.e. activation of a propranolol-insensitive atypical beta-adrenoceptor and antagonism against 5-HT(2A) receptors.
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 10/2006; 57(3):317-28. · 2.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We examined whether the beta2-adrenoceptor agonists fenoterol and salbutamol, the beta3-adrenoceptor agonists CL 316243 and ZD 2079, and the agonists of the low-affinity state of beta-adrenoceptors, cyanopindolol and CGP 12177 block alpha1-adrenoceptors in that concentration range in which they relax the human pulmonary and rat mesenteric arteries preconstricted with phenylephrine 10 microM and 1 microM, respectively. For quantification of vasodilatation pEC25 values and for the antagonism toward alpha1-adrenoceptors, pA2 values were determined. We found that in the rat mesenteric artery, (1) the pEC25 values of the beta-adrenoceptor ligands resemble their respective pA2 values (difference < or = 0.9 log units), and (2) the order of potencies is the same for both parameters, ie, cyanopindolol approximately fenoterol > CGP 12177 > salbutamol > ZD 2079 > CL 316243. In the human pulmonary artery, (1) the pEC25 values are slightly lower (by 0.6-1.3 log units) than their respective pA2 values, and (2) the rank order of potencies is the same for both parameters. In conclusion, the present study suggests that ligands of beta2-adrenoceptors and of non-beta1-non-beta2-adrenoceptors relax rat and human vessels preconstricted with phenylephrine or norepinephrine mainly through their alpha1-adrenolytic effects. Hence, for the investigation of the role of beta-adrenoceptors in vessels, the constrictor agent should be chosen with great caution.
Journal of Cardiovascular Pharmacology 08/2005; 46(1):76-82. · 2.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Circulating anti-p53 protein antibodies (p53-Abs) have been detected in some cancer patients. The aim of the study was to determine the presence of circulating anti-p53 protein antibodies and their clinical significance in patients with esophageal carcinoma. Serum specimens from 75 consecutive patients with squamous cell carcinomas and 10 healthy subjects were studied. Enzyme linked immunosorbent assay (ELISA--Pharma Cell) was used to detect p53-Abs. At the time of diagnosis 20 (26.6%) of 75 analyzed patients had positive result in the p53-Abs test, but not any of the healthy subjects. The positive rate was 25% (1/4) cases in stage I, 41% (10/24) cases in stage IIA, 0% (0/8) cases in stage IIB, 28% (8/28) cases in stage III and 9% (1/11) cases in stage IV. In respect of tumour differentiation, cases graded as G1, G2 and G3 were positive in 28.5% (4/14), 25.9% (7/27) and 26.4% (9/34), respectively. There was no correlation between presence of p53-Abs and stage, rumour differentiation, lymph nodes metastases, tumour size, patient age and sex. In conclusion, the results of the present study indicate that serum p53-Abs did not correlate with cliniocopathologic feature of esophageal carcinoma.
[Show abstract][Hide abstract] ABSTRACT: It is suggested that vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) play an important role in tumor-induced angiogenesis. The purpose of this study was to estimate the correlation between VEGF and bFGF levels and tumor pathological status according to pTNM classification in patients with squamous cell oesophageal cancer. A group of 25 healthy controls and 32 consecutive patients with oesophageal cancer were included in this study. Serum VEGF and bFGF levels were determined by enzyme-linked immunosorbent assay (Quantikine R&D Systems). Serum VEGF and bFGF levels were significantly elevated in the patient groups (VEGF: 146.0 pg/ml, 79.0-386.3 pg/ml vs. 38.0 pg/ml, 6.5-135.1 pg/ml, p<0.005, and bFGF: 5.2 pg/ml, 1.2-10.6 pg/ml vs. 2.06 pg/ml, 0.07-4.0 pg/ml, p<0.02 Fisher test). The highest correlation between serum VEGF and bFGF levels were found in patients with advanced cancers, especially with: T4, N1, and M1 factors. The VEGF and bFGF levels were significantly higher in patients with pT4 (p<0.01). Patients with N1 lymph node invasion, compared with N0 factor, have higher levels of angiogenetic factors (p<0.04). Also in patients with advanced cancers with liver metastases the serum levels VEGF and bFGF were significantly higher (M1 vs. M0, VEGF p<0.001 and bFGF p<0.05). Consecutive monitoring of VEGF and bFGF serum levels may be a useful prognostic marker for patients with squamous cell oesophageal cancer.