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Biomedical subjects

Marek Pawlikowski

Publications and source records attributed to Marek Pawlikowski.

At least 19 recordsLinked to original sources
PubMed2006

Proliferating cell nuclear antigen (PCNA) expression in pituitary adenomas: relationship to the endocrine phenotype of adenoma.

The expression of proliferating cell nuclear antigen (PCNA) correlates to cell proliferation and for this reason it is commonly considered as one of proliferation markers. Since proliferation rate is an important factor determining the tumor aggressiveness, the evaluation of PCNA index (the percentage of PCNA-immunopositive nuclei in the investigated tumor sample) is suggested as useful in predicting pituitary adenoma outcome. Seventy three unselected, surgically removed pituitary adenomas were immunostained with antibodies against the pituitary hormones or their subunits and against the proliferating cell nuclear antigen (PCNA). The highest PCNA index was found in ACTH-immunopositive tumors without the manifestation of the Cushing's disease ("silent" corticotropinomas). This value was significantly different in comparison to other adenoma subtypes including corticotropinomas manifesting themselves by Cushing's disease. The lowest PCNA index was noticed in monohormonal GH-secreting tumors. The adenomas which express more than one hormone (plurihormonal adenomas) seem to have a higher PCNA indices than monohormonal ones; the difference was significant in the case of mono- and plurihormonal prolactinomas. The recurrent tumors presented a higher mean PCNA index as compared to the primary tumors, although the difference was significant only in the case of prolactinomas. These findings suggest that the proliferative potential of pituitary adenomas is related to the tumor recurrence and hormone expression.

Adenoma↗
PubMed2006

Growth-inhibitory action of melatonin and thiazolidinedione derivative CGP 52608 on murine 16/C breast cancer cells.

OBJECTIVES: Melatonin may influence directly tumor cells through the specific binding sites. The best known melatonin binding sites are membrane receptors. Recently, the participation of nuclear signalling via estrogen as well as RZR/ROR receptors in oncostatic action of melatonin on the breast cancer has been widely discussed. The aim of present study was to investigate effects of melatonin, the selective ligand for nuclear RZR/ROR receptors - CGP 52608, and methotrexate on growth of murine 16/C breast cancer cells. MATERIAL AND METHODS: The experiment was performed in vitro. The breast cancer cells were incubated for 2 days in the presence of melatonin, CGP 52608 (at concentrations of 10(-5)M, 10(-7)M, 10(-9)M, 10-(11)M ) and methotrexate (at concentrations of 0.25 and 0.125 microg/ml). The growth of cells was measured using the modified Mossman method. RESULTS: All examined compounds significantly inhibited the growth of cancer cells. The effects of MLT and CGP 52 608 were comparable with suppression caused by methotrexate. The significant differences of efficacy between two examined concentrations of methotrexate were not observed. CONCLUSION: The obtained data together with our previous results indicate that nuclear receptors RZR/ROR play an important, although not sufficiently recognized role in the oncostatic action of melatonin.

Adenocarcinoma↗
PubMed2006

Immunohistochemical detection of angiotensin receptors AT1 and AT2 in normal rat pituitary gland, estrogen-induced rat pituitary tumor and human pituitary adenomas.

Male rat pituitary glands, diethylstilbestrol (DES)-induced rat pituitary tumors and 12 human pituitary adenomas were immunostained with antibodies raised against AT1 and AT2 angiotensin receptor proteins. Positive immunostaining of AT1 was observed in a subpopulation of anterior and intermediate pituitary lobe cells as well as in some nerve endings of the neurohypophysis. In the DES-induced rat pituiary tumors, the subpopulation of AT1-immunnopositive cells was smaller than in the non-tumoral anterior pituitary. In human pituitary adenomas, weak AT1 immunostaining was found in 5 tumors. In the remaining adenomas, the AT1 immunostaining was trace (doubtful) or absent. The AT1 immunostaining in the peritumoral non-neoplastic pituitary tissue was stronger than that observed in the tumors. The normal rat pituitaries and rat tumors did not show immunostaining with anti-AT2 antibody. In human pituitary adenomas, the tumoral cells were AT2- negative but moderate to strong AT2 immunostaining was observed in intratumoral blood vessel walls. The data suggest that the experimental (in rat) and spontaneous (in man) pituitary tumorigenesis is associated with the down-regulation of AT1 receptors. The expression of AT2 receptors, in turn, may be connected with the process of tumoral neo-angiogenesis.

Animals↗
PubMed2005

Serum endostatin levels are elevated and correlate with serum vascular endothelial growth factor levels in patients with pituitary adenomas.

Endostatin, a cleaved fragment of collagen XVIII, is a potent endogenous angiogenesis inhibitor. Elevated serum endostatin levels have been recently reported in patients with various types of neoplasms. The purpose of our study was to evaluate serum concentrations of endostatin in patients harbouring various pituitary adenoma types and to examine the relationship of serum endostatin levels to circulating vascular endothelial growth factor (VEGF) levels. Preoperative serum endostatin and VEGF concentrations were measured using competitive enzyme immunoassays in 71 patients with pituitary adenomas (20 somatotropinomas, 3 corticotropinomas, 6 prolactinomas and 42 clinically nonfunctioning pituitary adenomas - CNFPAs) and compared with levels from age-matched controls. In 35 patients postoperative immunohistochemical investigations were performed. Serum endostatin concentrations were significantly higher in all pituitary adenoma types, except for prolactinomas (somatotropinomas: 124 +/- 16; p < 0.02, corticotropinomas: 157 +/- 42; p < 0.02, prolactinomas: 141 +/- 37; p > 0.05, CNFPAs: 169 +/- 11 ng/ml; p < 0.000005 vs 73 +/- 10 ng/ml in controls). There was a significant positive correlation between endostatin and VEGF serum levels in patients with pituitary adenomas (r = +0.322; p = 0.006). In the control group a significant negative correlation xbetween circulating endostatin and VEGF was found (r = -0.653; p = 0.00975). The simultaneous elevation of endostatin and VEGF may attenuate the pro-angiogenic action of VEGF and be responsible for rather weak neovascularization of pituitary adenomas. Prospective studies are required to assess the usefulness of circulating endostatin and VEGF as markers of progression or recurrence of pituitary tumors.

Adenoma↗
PubMed2005

Rosiglitazone, PPAR-gamma receptor ligand, decreases the viability of rat prolactin-secreting pituitary tumor cells in vitro.

OBJECTIVES: PPAR-gamma is a member of the nuclear receptor superfamily. PPAR-gamma activation is associated with glucose metabolism regulation, adipocyte differentiation, inhibition of macrophage and monocyte activation and anti-angiogenesis. PPAR-gamma ligands thiazolidinediones (TZDs) have been shown to inhibit the growth and secretory activity of several rat and murine pituitary tumors in vivo as well as in vitro (ACTH-secreting AtT20, PRL- and GH-secreting GH3, LH-secreting LbetaT2 and alpha-T3 cells). TZDs have been demonstrated to induce G0-G1 cell-cycle arrest and apoptosis in human, rat somatolactotroph, murine corticotroph and gonadotroph pituitary tumor cells. In the present study we have investigated for the first time the effects of PPAR-gamma receptor ligand rosiglitazone on the rat estrogens-induced, PRL-secreting pituitary tumor cells in vitro. MATERIAL AND METHODS: Four weeks old male Fischer 344 rats were used in the experiment. Pituitary tumors were induced by subcutaneous implantation of capsules containing diethylstilboestrol (DES). Eight weeks after the implantation of capsules the rats were sacrificed and pituitary tumors were collected. Tumorous cells were isolated and exposed in the primary culture to rosiglitazone at the concentrations 10(-10) - 10(-4)M for 24 hours. The cell growth was estimated by the measurement of the cells metabolic activity using the EZ4U system. RESULTS: We have demonstrated that rosiglitazone at the concentrations 10(-10) - 10(-4)M significantly decreases the number of viable rat PRL-secreting pituitary tumor cells in vitro. CONCLUSION: These results suggest that PPAR-gamma receptor agonists thiazolidinediones may be useful in the medical treatment of pituitary tumors.

Animals↗
PubMed2005

Adrenal cortex -- the next biological clock?

It is well known that plasma levels of dehydroepiandrosterone (DHEA), a steroid hormone secreted by zona reticularis (ZR) of the adrenal cortex, reach the maximal values in the third decade of life and then gradually decline with age. Moreover, the DHEA deficiency is probably responsible for several functional disturbances connected with aging. It was also found that ZR reaches its definitive volume at puberty and undergoes selective atrophy during the aging. Thus, the decline of DHEA may be a simple consequence of ZR atrophy in aged subjects. A hypothesis presented here attempts to explain the mechanism of the age-related ZR atrophy and is based on the adrenal cortex cell kinetics. In the adrenal cortex the cell proliferation indices are lower when we pass from zona glomerulosa (ZG) to the inner zones and are the lowest in ZR. In contrast, the apoptotic index is the highest in ZR. It is suggested that adrenocortical cells renew from the progenitor cells located in ZG /zona fasculata boundary and /or in subcapsular layer. These cells migrate centripetally undergoing the subsequent steps of differention and consecutive divisions - and - if not die en route - reach the most central localization in ZR. In consequence, ZR includes the "oldest" adrenocortical cells which probably in majority reached the "Hayflick's number" and cannot divide. This results in the preponderance of apoptosis over proliferation leading to progressive ZR atrophy followed by a decline of secretion of ZR-derived steroid hormones.

Adrenal Cortex↗
PubMed2005

Immunohistochemical detection of PPARgamma receptors in the human pituitary adenomas: correlation with PCNA.

The occurrence of peroxisome proliferator-activated receptors gamma (PPARgamma) was investigated in 51 human pituitary adenomas and in 6 non-tumoral human pituitary tissue samples. Moreover, the correlation between PPARgamma and the proliferating cells nuclear antigen (PCNA)--immunocytochemical proliferation marker was evaluated. The receptors and PCNA were detected by immunohistochemical methods using the polyclonal anti-PPARgamma and the monoclonal anti-PCNA antibodies, respectively. PPARgamma were found in all examined tissues. The mean percentage of cells with positive nuclear reaction was 3-fold higher in pituitary adenomas in comparison with non-tumoral pituitary tissues. The strongest expression of PPARgamma was observed in somatotropinomas. Besides the nuclear reaction, which is typical for PPARgamma, positive immunostaining was also observed in the cytoplasm. It was clearly stronger in pituitary adenomas than in non-tumoral pituitary tissues. A slight, statistically insignificant tendency towards negative correlation between PPARgamma and PCNA was found in somatotropinomas, prolactinomas, corticotropinomas and gonadotropinomas. On the other hand, in null cell adenomas and "silent" corticotropinomas, a strong positve correlation between the expression of PPARgamma and PCNA was observed. The strong expression of PPARgamma in human pituitary adenomas and its possible involvement in control of cell proliferation in these tumors give a good reason for the attempts of their treatment with PPARgamma ligands.

Adenoma↗
PubMed2004

Angiotensin II and its fragments (angiotensins III and IV) decrease the growth of DU-145 prostate cancer in vitro.

BACKGROUND: There is growing evidence that angiotensin II (AngII) and its smaller fragments 2-8 (AngIII) and 3-8 (AngIV) are involved in cell-growth control in the vascular smooth muscle and in some other tissues, including prostate. The aim of this paper was to investigate the effects of AngII and its fragments AngIII and AngIV on the growth of an androgen-independent human prostate cancer cell line in vitro. To see whether the conversion of Ang II into its shorter fragments plays a role in the action of the former, we used specific inhibitors of aminopeptidases: compound EC33 (inhibitor of aminopeptidase A), which blocks the conversion of AngII into AngIII, and compound PC 18 (inhibitor of aminopeptidase N), which blocks the conversion of AngIII into AngIV. MATERIAL/METHODS: Human prostate cancer DU-145 cells were exposed in culture to different concentrations of AngII, AngIII, and AngIV separately or jointly with the aminopeptidase inhibitors EC33 or PC18. To measure cell growth, the colorimetric method, based on the reduction of tetrazolium salt by viable cells, was applied. RESULTS: It was found that exposure of DU-145 cells in vitro to all the investigated angiotensins resulted in a moderate, concentration-dependent inhibition of cell growth. The joint exposure of DU-145 cells to AngII plus EC33, but not to AngII plus PC 18, abolished the effect of AngII. CONCLUSIONS: These findings suggest that angiotensin peptides (AngII as well as its smaller fragments) are involved in the negative control of prostate cancer cell growth.

Angiotensin II↗
PubMed2004

Somatostatin analogs - from new molecules to new applications.

Somatostatin (SST) was firstly discovered as a hypothalamic hormone inhibiting GH secretion. Despite its broad inhibitory effects on both endocrine and exocrine secretions, natural SST has limited therapeutic potential owing to its short plasma half-life. The synthesis of the first two metabolically stabilized and more potent SST analogs (octreotide and lanreotide) established the use of SST peptide therapy. The discovery of the five SST receptor (sst(1-5)) subtypes in the 1990s further enhanced our understanding of the biological roles of SST, created new therapeutic opportunities and highlighted the limitation of 'classical' SST analogs, which act mainly via receptor subtype 2 and are unable to reproduce all actions of native SST. To diminish these limitations, new SST analogs highly selective for particular receptor subtypes, together with so-called 'universal' analogs acting on multiple receptor subtypes, have been developed. These compounds have shown promise in preclinical studies and might further advance the use of SST analog therapy in the future. The development of SST analogs coupled to radioisotopes or cytotoxic drugs, which allows the selective destruction of tumor cells overexpressing sst receptors, constitutes another field of progress.

Animals↗
PubMed2004

The effect of octreotide and bromocriptine on expression of a pro-apoptotic Bax protein in rat prolactinoma.

It is well established that disruption of apoptosis may lead to tumor initiation, progression or metastasis. It is also well documented that many anticancer drugs induce apoptosis. In the earlier studies, the dopamine D2 receptor agonist bromocriptine (BC) and somatostatin analog octreotide (OCT) were found to inhibit the growth of the estrogen-induced rat prolactinoma. Our previous investigations, applying the TUNEL method showed the involvement of the pro-apoptotic effect in the action of BC, and to a lesser degree, in the action of OCT. The aim of the present study was to investigate whether the pro-apoptotic action of these drugs involves the increased expression of Bax--a member of Bcl-2 protein family which is known to play an important role in the regulation of apoptosis. Male four-week Fisher 344 rats were used in the experiment. Capsules containing diethylstilboestrol (DES) were implanted subcutaneously. Six weeks after the implantation the rats were given OCT (2 x 25 microg/animal/24), BC (3 mg/kg b.w./24 h) or OCT and BC at the above doses for 10 days. Bax expression was detected by immunohistochemistry. Prolactin (PRL) in blood serum was measured by radioimmunoassay (RIA). It has been found that both OCT and BC, alone or in combination, significantly reduce the tumor weight. Both OCT and BC suppressed PRL levels, but the inhibitory effect of BC was stronger than that of OCT. It has been found that the treatment with OCT and BC, alone or in combination, causes a significant increase in Bax expression in the rat prolactinoma cells. Our findings indicate that anti-tumoral action of bromocriptine and to some extent the action of octreotide in the experimental rat prolactinoma is connected with the induction of apoptosis and is associated with increased Bax expression.

Animals↗
PubMed2004

Chromogranin A in pituitary adenomas: immunohistochemical detection and plasma concentrations.

Forty one pituitary adenomas excised surgically were immunostained to reveal pituitary hormones and chromogranin A (CgA). In 23 patients, plasma CgA concentration was determined before surgery by ELISA method. The CgA immunopositivity was found in 70.7% of investigated tumors. It was observed in all tumors of gonadotropinoma type and in the majority of null cell adenomas. Elevated (>18 U/L) plasma CgA concentration was observed in approx. a half of the examined patients, being more frequent in gonadotropinomas and null cell adenomas. It may have some, although limited, diagnostic value in these types of pituitary tumors.

Adenoma↗
PubMed2003

Immunohistochemical detection of somatostatin receptor subtypes in "clinically nonfunctioning" pituitary adenomas.

Pituitary tumors diagnosed before surgery as "non-functioning" in fact represent a heterogenous group, the majority of which express glycoprotein hormones or their free subunits. It is known that some of them expresses somatostatin receptors, but the data available until now rarely refer to the receptor subtype. Five different subtypes of somatostatin receptors (sst1-5) have been cloned. We studied 18 pituitary tumors diagnosed before surgery as "non-functioning." After the surgery the tumors were immunostained with antibodies against pituitary hormones and alpha subunit as well as with antibodies against the somatostatin receptor proteins 1-5. Thirteen adenomas expressed immunoreactivity for FSH, LH, and/or alpha subunit and were classified as gonadotroph adenomas. The remaining five adenomas were immunonegative for all the examined pituitary hormones and were diagnosed as null cell adenomas. All the adenomas of both the groups showed immunopositivity for at least three receptor subtypes. The strongest immunopositivity was found in both groups with anti-sst1 and anti-sst5 antibodies. The marked immunopositivity was also revealed in both groups with anti-sst2B antibody. On the other hand, the sst2A immunopositivity was weak or absent in a majority of tumors. The main difference between two groups was in the sst4 receptor subtype which was absent in all but two gonadotroph adenomas but present in all but one null cell adenoma. These findings suggest that "non-functioning" pituitary adenomas are potential candidates for therapy with somatostatin analogs targeted mainly to the receptor subtypes 1 and 5.

Adenoma↗
PubMed2003

Melatonin inhibits growth of diethylstilbestrol-induced prolactin-secreting pituitary tumor in vitro: possible involvement of nuclear RZR/ROR receptors.

Melatonin exerts a marked antiproliferative action in numerous experimentally-induced tumors in vivo as well as in both animal and human cell lines in vitro. However, the mechanisms of oncostatic action of melatonin is not clear, and the involvement of both membrane and nuclear receptors are suggested. Therefore, the aim of this study was to investigate effects of melatonin, and both agonist (CGP 52608), and antagonist (CGP 55644) of RZR/ROR nuclear receptors on the growth of diethylstilbestrol-induced rat prolactin-secreting pituitary tumor cells in vitro. Pituitary tumors were induced by subcutaneous implantation of a single silastic capsule containing 10 mg of diethylstilbestrol in 4-wk-old male Fischer 344 rats. Four months after the implantation of capsules the animals were killed by decapitation, pituitary tumors were aseptically removed, mechanically dispersed, and enzymatically digested with 0.2% collagenase and 0.2% hyaluronidase. The cells (6 x 105 cells/well) were incubated for 24 hr in the presence of melatonin, CGP 52608, CGP 55644 and CGP 55644 plus melatonin (at the concentrations of 107 and 10-9 m) at 37 degrees C in the humidified atmosphere of 95% air and 5% CO2. The group with the addition of solvent only served as control. The growth of cell was measured using the EZ4U system. Statistical analysis was performed using ANOVA followed by LSD test. Both melatonin and CGP 52608 significantly suppressed growth of tumor cells in vitro in both used concentrations. CGP 55644 stimulated growth of tumor cells and blocked the inhibitory effects of melatonin in vitro. Results of the present study as well as other experimental evidence strongly support the hypothesis that both membrane and nuclear receptors are involved in the oncostatic action of melatonin, and indicate that nuclear signalling plays an important role in this process.

Animals↗
PubMed2003

Immunohistochemical demonstration of nitric oxide synthase (NOS) in the normal rat pituitary gland, estrogen-induced rat pituitary tumor and human pituitary adenomas.

Nitric oxide synthase (NOS) immunoreactivity was examined in normal rat anterior pituitary glands, estrogen-induced rat pituitary tumors and human pituitary adenomas using a polyclonal antibody reacting with all three isoforms of NOS in both species. It was found that NOS immunorectivity in pituitary glandular cells is stronger in rat experimental pituitary tumors than in normal pituitaries. NOS immunoreactivity is also detectable in all but two human pituitary adenomas and seems to negatively correlate with microvascularization.

Adenoma↗
PubMed2003

Angiotensins II and IV stimulate the rat anterior pituitary cell proliferation independently of the AT1 receptor subtype.

OBJECTIVES: The purpose of this study was to investigate the effect of angiotensin II (AII) and angiotensin IV (AIV, 3-8 fragment of AII) on the cell proliferation in the anterior pituitary of rat in vivo. MATERIALS AND METHODS: The female adult Wistar rats, ovariectomized 10 days before experiment were injected intraperitoneally with saline, AII, AIV and AII or AIV together with losartan--the specific AT1 receptor subtype antagonist. Bromodeoxyuridine (BrDU) incorporation into anterior pituitary cell nuclei was used as the index of cell proliferation. RESULTS: We observed the increased BrDU-labeling index (LI) in the anterior pituitary of rat treated with either AII or AIV. The proliferogenic effect of neither AII nor AIV was reversed by AT1 specific antagonist losartan. CONCLUSIONS: AII and AIV stimulate the rat anterior pituitary cell proliferation in vivo. This action of both angiotensin peptides is connected with activation of receptor different from AT1 subtype.

Angiotensin II↗
PubMed2002

Angiotensins II and IV stimulate the activity of tyrosine kinases in estrogen-induced rat pituitary tumors.

The effects of angiotensin II (AngII) and its fragment 3-8 (angiotensin IV, AngIV) on tyrosine kinase (TK) activity in estrogen-induced rat pituitary tumor homogenates were studied. It was found that both angiotensin peptides increase the TK activity. AngIV was effective in a lower concentration and its maximal effect was greater as compared to that of AngII. Moreover, the specific inhibitors of aminopeptidase A (EC33) and of aminopeptidase N (PC18) significantly attenuated the stimulatory effect of AngII. Because the action of both aminopeptidases is necessary to convert AngII into AngIV, this finding suggested that the effect of AngII on TK activity is (at least in part) exerted via AngIV.

Aminopeptidases↗
PubMed2002

Immunohistochemical localization of the somatostatin receptor subtype 2A in the rat adrenal gland.

The immunohistochemical localization of the somatostatin receptor subtype sst2A was investigated in the rat adrenal gland using SS-800 polyclonal antibody. The sst2A immunopositivity was found in all adrenocortical zones and in adrenal medulla, the reaction being slightly more intense in zona glomerulosa and medulla. The administration of the potent agonist of sst2 receptors - octreotide - resulted in the enhancement of the immunopositivity in zona glomerulosa and medulla, whereas chronic exposure of the rats to diethylstilbestrol led to enhancement of the immunopositivity in zona glomerulosa and in the external part of zona fasciculata.

Adrenal Cortex↗