Structure-function analysis of vitamin D(2) analogs as potential inducers of leukemia differentiation and inhibitors of prostate cancer proliferation.

We characterized a structure-function relationships of four analogs of vitamin D(2) with extended and branched side-chains. We tested their ability to induce differentiation of human acute myeloid leukemia (AML) cells both in vitro and ex vivo. Our experiments on five human cell lines revealed substantial differences among tested analogs. Analogs with side-chains extended by one (PRI-1906) or two carbon units (PRI-1907) displayed similar or elevated cell-differentiating activity in comparison to 1,25-dihydroxyvitamin D(3) (1,25D), whereas further extending side-chain resulted in substantially lower biological activity (PRI-1908 and PRI-1909). Similar pattern of cell-differentiating activities to that observed in human cell lines has also been shown in blast cells isolated from patients diagnosed with AML. The ability of the analogs to activate expression of CYP24A1 gene has been studied in HL60 cell line. The analog PRI-1906 activated expression of CYP24A1 similarly to 1,25D, while PRI-1907 weaker than 1,25D. In addition, the analogs PRI-1906 and PRI-1907 were able to moderately inhibit proliferation and significantly activate expression of CYP24A1 mRNA in prostate cancer cells PC-3. Finally, we examined the molecular actions triggered by these analogs and found that their biological activity was related to their ability to induce expression and nuclear translocation of VDR and C/EBPß.

A run for a membrane vitamin D receptor.

1,25-Dihydroxyvitamin D(3) is the hormonally active form of vitamin D(3). Its involvement in regulation of calcium and phosphate homeostasis as well as in differentiation and regulation of the immune system is well documented. Extensive data indicate that there are two mechanisms of the molecular mode-of-action of 1,25-dihydroxyvitamin D(3). One involves the activation of nuclear vitamin D receptor (nVDR) and transcriptional regulation of many vitamin D-responsive genes. The other involves activation of nongenomic signal transduction pathways in target cells. This second mechanism is likely to engage a membrane vitamin D receptor (mVDR). Recently discovered 64.5 kDa protein from chick epithelium, which specifically binds 1,25-dihydroxyvitamin D(3) and is responsible for some rapid cellular actions of 1,25-dihydroxyvitamin D(3) is a candidate for mVDR. This article provides a brief description of a search for a putative mVDR that lasted for over a decade.

Evading apoptosis by calcitriol-differentiated human leukemic HL-60 cells is not mediated by changes in CD95 receptor system but by increased sensitivity of these cells to insulin.

Previous studies revealed that 1,25-dihydroxyvitamin D(3) (calcitriol)-induced differentiation of human promyelocytic leukemia cells leads to an increased resistance of the cells to apoptosis-inducing agents. However many attempts were made to explain it, the mechanism underlying this effect still remains unclear. Our results suggest that the acquired resistance to apoptosis-inducing agents in HL-60 cells is not mediated by the CD95 receptor/ligand system. The expression of CD95 on the surface of HL-60 cells is very low and does not change during the calcitriol-induced differentiation of HL-60 cells. Studies presented here provide a strong indication that this receptor is unable to transmit the death signal in either differentiated or undifferentiated HL-60 cells. We therefore asked if evading apoptosis by differentiated human leukemia HL-60 cells may be caused by their increased sensitivity to growth factors contained in fetal calf serum. This study demonstrates that HL-60 promyelocytic leukemia cells, differentiated by exposure to calcitriol, undergo apoptosis in serum-free conditions. As low as 1% of fetal calf serum is enough to prevent cell death of differentiated HL-60 cells. The ability of 1% fetal calf serum to prevent apoptosis can be blocked by the specific inhibitor of phosphatidylinositol 3-kinase, LY294002. We then tried to find out which component of fetal calf serum may be able to prevent serum-free cell death of differentiated cells. It appeared that serum-free cell death of differentiated HL-60 cells is reversed by addition of 10 microM insulin to the culture medium. The antiapoptotic activity of insulin can be inhibited by LY294002. Moreover, insulin increases the viability of differentiated, but not of undifferentiated, HL-60 cells.

Evidence that activation of MEK1,2/erk1,2 signal transduction pathway is necessary for calcitriol-induced differentiation of HL-60 cells.

Calcitriol (1,25-dihydroxyvitamin D3) induces differentiation and inhibits proliferation of human promyelocytic leukemia cells. The mechanisms involved in the regulation of these processes are not clearly understood. Previous studies have shown that calcitriol mediates cell differentiation not only by interaction with nuclear vitamin D receptor, but also by numerous rapid, membrane--mediated effects. Since in the light of past studies, involvement of raf/MEK1,2/erk1,2 signal transduction pathway in calcitriol-induced cell differentiation was questionable, another attempt was undertaken in this study in order to investigate the problem. PD 98059, the specific inhibitor of MEK1 and MEK2 was found to inhibit calcitriol-induced monocytic differentiation of HL-60 cells. This finding proves that activation of the raf/MEK1,2/erk1,2 signal transduction pathway is essential for monocytic differentiation of human leukemia cells. The results reported in this paper suggest that inhibition of protein kinase C, which upstream regulates activation of erk1 and erk2, may be bypassed during the process of calcitriol-induced leukemia cell differentiation.

Assessment of myocardial perfusion and viability with stress Tc-99m-MIBI SPECT before surgical revascularisation. Correlation with postoperative perfusion improvement.

BACKGROUND: The immediate result of successful revascularisation of the myocardium is the improvement of perfusion (and in patients with depressed ventricular function, functional recovery is expected as an effect of coronary flow improvement). The main goal of the work was to assess the value of myocardial stress-rest MIBI perfusion scintigraphy in predicting myocardial perfusion state measured early (< 5 months) after CABG. MATERIAL AND METHODS: Forty-three patients (39 males, mean age 52 +/- 9 years) with chronic coronary artery disease underwent prerevascularisation and postrevascularisation stress-rest Tc-99m-MIBI SPECT studies. Eighty-one percent of patients had a history of myocardial infarction, the number of stenosed main coronary arteries was 2.3 +/- 0.6 per patient, and the left ventricle ejection fraction was 18-70% (mean 46 +/- 14%). Preoperative perfusion defects were considered as small, medium or severe (depending upon stress uptake deficiency) and as transient or persistent (depending upon uptake improvement in rest). Changes in perfusion defects (improvement, lack of changes or deterioration) were evaluated very early after CABG (mean 31 +/- 12 days) in all patients and additionally about 3 months later (mean 119 +/- 17 days after CABG) in 36 patients. RESULTS: In transient perfusion defects, the probability of early postoperative perfusion improvement was 80% (in small defects: 89%, CI(0,95) = 80-94%) and was significantly higher than in small persistent defects (51%) and than in medium-and-severe persistent defects (21%). In medium-and-severe persistent defects, the lack of changes in perfusion was observed in 76% of defects (in severe defects: 81%, CI(0,95)= 69-91%) and was significantly higher than in small persistent defects (37%), than in medium-and-severe transient defects (17%), and than in small transient defects (4%). The probability of later postoperative perfusion improvement was 78% in transient perfusion defects (in small defects: 85%, CI(0,95)=74-92%) and was significantly higher than in small, medium, and severe persistent defects (28%). In medium-and-severe persistent defects, the lack of changes in perfusion was observed in 71% of defects (in severe defects: 81%, CI(0,95)=66-91%) and was significantly higher than in small persistent defects (40%), and than in severe, medium, and small transient defects (11%). CONCLUSIONS: 1. The result of preoperative stress-rest Tc-99m-MIBI SPECT myocardial perfusion study is an exact predictor of the state of perfusion measured early (< 5 months) after CABG; the postoperative regional perfusion improvement is most dependent upon reversibility and also upon severity of stress defect. 2. In small persistent defects, changes in perfusion are different than in other types of defects - so they should not be considered together with transient defects (as "viable") or with persistent defects (as "nonviable"). 3. Preoperative viability assessment on the basis of Tc-99m-MIBI study performed solely in rest is unjustified: at the similar perfusion defect at rest, the presence of even minimal inducible ischaemia is associated with increased probability of perfusion improvement after CABG.

Biological activity in vitro of side-chain modified analogues of calcitriol.

The results of our studies on the biological activity of side-chain modified analogues of vitamin D are reviewed. These analogues appeared to be effective in induction of cell differentiation, inhibition of tumour cell proliferation in vitro and in increasing of antitumour effect of cytostatics. On the other hand, inhibition of cytostatic-induced apoptosis by these compounds was observed. The mechanism of the antiproliferative effect of calcitriol analogues in vitro is discussed. The induction of antigens CD14 and CD11b expression and phagocytic activity of HL-60 cells after exposure to these compounds is related to their effect on cell differentiation. The differentiation of the HL-60 leukaemia cells induced by side-chain modified analogues of calcitriol increases their sensitivity to the antiproliferative effect of cisplatin, doxorubicin and genistein, despite of that this pretreatment causes resistance of these cells to cytostatics-induced apoptosis. We observed a synergistic antiproliferative effect of the combined therapy using analogues of calcitriol with subsequent treatment with the above-mentioned cytostatics. This effect was measured as a significant decrease of the ID50 values for each cytostatic applied after pretreatment of the tumour cells with the calcitriol analogues. The results presented suggest that the improved therapeutic effect may be achieved also in vivo by the combined application of the analogues (without calcemic activity) of calcitriol with antitumour agents.

Evaluation of the impact of transmyocardial laser (CO2) revascularisation on myocardial perfusion--6-months observations.

BACKGROUND: Transmyocardial laser revascularisation (TMLR) is a relatively new surgical approach to symptomatic coronary artery disease patients otherwise inoperable by classical revascularisation methods. Perfusion improvement after TMLR is considered as one possible mechanism causing alleviation of symptoms in a significant percentage of operated patiens. The goal of this work was to assess the history f myocardial perfusion during the first 6 month after sole TMLR operation. METHODS: TMLR was performed by using high-power (800 W) CO(2) laser. Tc-99m-Sestamibi single photon emission computed tomography (SPECT), both in rest and stress, was performed 4 times: before TMLR [SPECT-0], very early (mean: 3 weeks) after TMLR [SPECT-I], 3 months after TMLR [SPECT-II] and 6 months after TMLR [SPECT-III] in every patient. The group consisted of 25 patients, including 21 patients with previous myocardial infarctions. The patients subjected to the operation were those suffering from angina in spite of pharmacological therapy, with diffuse changes in the peripheral parts of coronary arteries, with left ventricle (LV) ejection fraction not lower than 0.30 and with at least one transient or small persistent defect in preoperative SPECT. Perfusion was assessed in 13 of 17 segments of the LV (after exclusion of 4 septal segments). Only a history of transient or small persistent perfusion defects ('viable' segments) detected in SPECT-0 is discussed. RESULTS: In comparison to SPECT-0: in SPECT-I perfusion did not change in 52% of segments, improved--in 31%, and deteriorated--in 17%: in SPECT-II perfusion did not change in 48% of segments, improved--in 34%, and deteriorated--in 18%; in SPECT-III perfusion did not change in 52%, improved--in 25%, and deteriorated--in 22% of segments. No significant difference in the number of segments with perfusion preservation, improvement or deterioration in comparison to SPECT-0 was found in SPECT-I,-II or III. In SPECT-II in comparison to SPECT-I, no changes in perfusion were found in 66% of segments, perfusion improved in 20% and deteriorated in 14%. In SPECT-III in comparison to SPECT-II, no changes in perfusion were found in 79% of segments, perfusion improved in 5% and deteriorated in 15%. CONCLUSIONS: Our evaluation of the history of segments with preoperatively transient or small persistent ('viable') defects indicates that during the first 6 months after TMLR: 1) perfusion is better than before the operation in about one third of the segments, and 20 in some of these segments there are dynamic perfusion changes (improvement or deterioration) from one to the next postoperative moment of observation.

[Does the universal "signal transduction pathway of differentiation" exist? Comparison of different cell differentiation experimental models with differentiation of HL-60 cells in response to 1,25-dihydroxyvitamin D3]. / Czy istnieje uniwersalny "szlak róznicowania"? Porównanie róznicowania in vitro róznych linii komórkowych ze szczególnym uwzglednieniem róznicowania komórek bialaczki HL-60 pod wplywem 1,25-dihydroksywitaminy D3.

The comparison of distinct cell-differentiation models can help to answer the question whether there are common signalling pathways activated in the cells during the differentiation process or not. The differentiation of PC12 pheochromocytoma cells in response to NGF, the differentiation of melanoma B16 cells triggered by alpha-MSH, the formation of myotubes by L6E9 skeletal muscle myoblasts deprived of FCS or differentiation of HL-60 cells in response to steroid hormone 1,25-dihydroxyvitamin D3 share some similarities in the activation of signal transduction pathways. Differentiation-inducing agents stimulate sustained activation and nuclear translocation of MAP kinases (ERK1 and ERK2). Some of differentiation-inducing agents activate PI3-kinase as well, and the inhibition of the PI3K/p70S6K pathway blocks the process of differentiation in the cells.

Synthesis, and cytotoxic activity of some novel indolo[2,3-b]quinoline derivatives: DNA topoisomerase II inhibitors.

A series of new 5H-indolo[2,3-b]quinoline derivatives bearing methoxy and methyl groups at C-2 and C-9 was synthesized (according to the modified Graebe-Ullmann reaction). These compounds were evaluated for their antimicrobial and cytotoxic activity and tested as inhibitors of DNA topoisomerase II. Lipophilic and calf thymus DNA binding properties of these compounds were also established. In the SAR studies we used quantum-mechanical methodology to analyze the molecular properties of the drugs. All of the 5H-indolo[2,3-b]quinolines tested were found to inhibit the growth of gram-positive bacteria and pathogenic fungi at MIC ranging between 2.0 and 6.0 microM. They showed also cytotoxic activity in vitro against several human cancer cell lines of different origin (ID50 varied from 0.6 to 1.4 microM), and stimulated the formation of topoisomerase-II-mediated pSP65 DNA cleavage at concentration between 0.2 and 0.5 microM. The most active indolo[2,3-b]quinolines which had the greatest contribution to the increase in the Tm of DNA displayed also the highest DNA binding constants and the highest cytotoxic activity. The differences in DNA binding properties and cytotoxic activity seem to be more related to steric than electrostatic effects.

Antiproliferative activity in vitro of side-chain analogues of calcitriol against various human normal and cancer cell lines.

The antiproliferative in vitro activity of side-chain modified analogues of 1,25-dihydroxyvitamin D3 was examined in order to select compounds with potential antitumour activity. Analogues PRI-1906, PRI-1907, PRI-1909, PRI-2191, PRI-2192, PRI-2193 and PRI-2194 were examined for their antiproliferative activity in vitro against a spectrum of various human cancer cell lines using the MTT technique. In addition, analogues PRI-1906 and PRI-2191 were screened against cells of human leukaemia HL-60 line and against normal human skin fibroblasts. Calcitriol and these two analogues revealed strong antiproliferative activity against these two targets with maximal growth inhibition of 68% for HL-60 cells and of 60% for fibroblasts, and this effect was dose dependent. All analogues tested, except PRI-1909, revealed antiproliferative activity against human carcinoma cell lines of breast origin applied, namely against T47D and MCF-7. The maximal growth inhibition of 49% for T47D cell line and 39% for MCF-7 line was observed, and this effect was dose dependent. The inhibitory doses of the analogues tested were compared with the indices for calcitriol. Analogue PRI-1906 revealed the strongest antiproliferative activity against these four target cell lines (HL-60, fibroblasts, MCF-7, and T47D). The novel analogues of calcitriol, similarly to calcitriol, appeared to be not active against other human cancer cell lines tested (including those originated from lung, colon, prostate, urinary bladder, ovary, pancreas, stomach and kidney) revealing an antiproliferative activity not exceeding 20%. The mechanism of the observed antiproliferative effect of calcitriol and its analogues in vitro remains unclear, however, it may be related to their effect on cell differentiation. The appearance of antigen CD14 and CD11b expression after exposure to calcitriol and its new analogues confirmed their effect on cell differentiation.

[Radionuclide diagnosis of tricuspid regurgitation as a method of estimating the significance of tricuspid insufficiency with concurrent mitral valve disease]. / Diagnostyka radioizotopowa wielkosci fali zwrotnej trójdzielnej jako metoda okreslania istotnosci niedomykalnosci trójdzielnej towarzyszacej wadzie mitralnej.

UNLABELLED: A mitral valve replacement without simultaneous correction of a concomitant tricuspid regurgitation aggravates remote postoperative results. Nowadays diagnostics of a degree of tricuspid regurgitation bases on semi-quantitative methods, which are not unequivocal criteria of a significant tricuspid insufficiency. The aim of the study was to investigate diagnostic usefulness of a radioisotopic method of determination significant tricuspid insufficiency. The study group consisted of 35 patients with rheumatic mitral valve disease and tricuspid regurgitation (30 females, 5 males) at a mean age of 55 years qualified for operative treatment. Physical and noninvasive examinations were performed in all patients: chest X-ray (relative heart volume--RHV) and echocardiographicy (tricuspid regurgitation and right ventricle pressure). Final determination of a significant tricuspid insufficiency based on intraoperative diagnosis. The radioisotopic method relies on first pass technique with a determination of a tricuspid regurgitation index (TRI) and a right ventricular ejection fraction. Intraoperatively the patients were divided into two groups: with significant tricuspid regurgitation--21 patients and without--14 patients. Statistically significant differences, considering clinical and echocardiographic assessment between the two groups were noticed. The TRI index did not differentiate two groups. Noninvasive parameters that could affect diagnosis of significant tricuspid regurgitation were proved by a logistic regression analysis. Among them the TRI Index could have a separate value. CONCLUSIONS: Presented radioisotopic method of determination a degree of tricuspid regurgitation with the new TRI Index is of value in diagnosing significant tricuspid insufficiency when assessed with other noninvasive parameters. Estimation of a clinical usefulness of the method needs further investigation and bigger study group.

Microbial conversion of methyl- and methoxy- substituted derivatives of 5H-indolo[2,3-b]quinoline as a method of developing novel cytotoxic agents.

In furtherance of our structure-activity relationship studies on the antitumor activity of indolo[2,3-b]quinolines, novel cytotoxic derivatives bearing methyl groups at N-5, C-11, C-2 and/or C-9, as well as methoxy-groups at C-2 and/or C-9, were synthesized by the modified Graebe-Ullmann reaction. To elucidate the metabolic pathways of these compounds, zygomycete fungus Cunninghamella elegans ATCC 9245 (which is known to produce drug metabolites that are also formed in mammals) was used as a mimetic organism. Simultaneously, biotransformation of the same substrates was carried out with a microsomal fraction of rat liver. Three forms of microbial conversion were observed: hydroxylation of the aromatic ring or hydroxylation of the methyl group, and O-demethylation. The reaction proceeded regioselectively, and only positions C-2 and C-9 were affected in the indolo[2,3-b]quinoline system. The products formed were found to be identical with the metabolites generated by rat liver microsomes. The metabolites obtained displayed a cytotoxic activity in vitro against colon adenocarcinoma SW-707 and lung carcinoma A-549 (ID50 in the range 0.27-3.04 microM), which was as strong as that of the substrates. In the course of the further metabolic pathway study of indolo[2,3-b]quinolines we found that metabolites with a hydroxyl group in the aromatic system were transformed to non-cytotoxic polymeric products by multicopper oxidases: human ceruloplasmin or fungal laccase (used as mimetic enzyme), whereas metabolites with a hydroxymethyl group did not undergo such bioconversion. The last mentioned compounds can be regarded as a novel type of cytotoxic indolo[2,3-b]quinoline derivatives formed in metabolic processes.

Evidence that phosphatidylinositol 3-kinase and p70S6K protein are involved in differentiation of HL-60 cells induced by calcitriol.

1,25-dihydroxyvitamin D3 (calcitriol) is not only an antirachitic agent, but also a well known regulator of cell differentiation. HL-60 promyelocytic leukemia cells differentiate to monocytes upon treatment with calcitriol. We describe here, that PI3-K inhibitors are able to block the differentiation induced by calcitriol in HL-60 cells. Also the downstream effector of PI3-K, p70S6K ribosomal protein kinase seems to be involved in HL-60 cell differentiation. PKC alpha and PKC delta are activated and translocated to the nucleus upon exposure of cells to calcitriol. However in our experiments the inhibition of PKC did not result in an inhibition of calcitriol induced differentiation of HL-60 cells. On the contrary, the use of thapsigargin, caused the differentiation process to stop.

Cell differentiating and anti-proliferative activity of side-chain modified analogues of 1,25-dihydroxyvitamin D3.

Besides its calcium mobilizing activity in vivo, 1,25-dihydroxyvitamin D3 has the ability to induce differentiation of human promyelocytic leukemia cells in vitro. We studied the cell differentiating activity of four novel analogues of 1,25-dihydroxyvitamin D3, using the HL60 cell line as a model. We also analyzed the influence of these compounds on the proliferation of HL60 cells, normal human keratinocytes, normal fibroblasts from human skin and human keratinocytes transfected with human papillomavirus type 16. Two of the four analogues, i.e. those with extended side-chain, were found to display similar cell differentiating and anti-proliferative activities as 1,25-dihydroxyvitamin D3. The other two analogues, with a shortened side-chain which included an additional hydroxyl, showed a substantially lower activity than that of 1,25-dihydroxyvitamin D3. We observed distinct differences in sensitivity to the anti-proliferative activity of either 1,25-dihydroxyvitamin D3 or its analogues between cells of different origin.

Methoxy- and methyl-, methoxy-5,6,11-trimethyl-6H-indolo [2,3-b]quinolinium derivatives as novel cytotoxic agents and DNA topoisomerase II inhibitors.

New members of the cytotoxic indolo[2,3-b]quinoline family, with a methyl groups at N-5, N-6 (their presence stabilizes the positive charge of the molecule), were prepared using a modified Graebe-Ullmann reaction. The derivatives obtained were well soluble in water in a non-pH-dependent manner. They displayed strong antimicrobial activity against Gram-positive bacteria and pathogenic fungi (the MIC values fall between 0.0025 and 0.12 mM) and highly selective cytotoxicity in vitro against different human cancer cell lines: colon adenocarcinoma SW 707, lung carcinoma A 549, transitional cell carcinoma Hu 1703, and oral epidermoid carcinoma KB, in the range of 0.01 to 3.0 microM. They also stimulated the formation of topoisomerase-II-mediated DNA cleavage at concentration from 0.04 to 0.5 microM. These observations correspond well with the ability of the tested compounds to increase the melting temperature of calf thymus DNA (delta Tm being between 13 degrees C and 22 degrees C).

The new sensitizing agents for photodynamic therapy: 21-selenaporphyrin and 21-thiaporphyrin.

BACKGROUND: Photodynamic therapy may be a promising treatment for patients with tumors. The mechanism of its action is poorly understood and different from the cytotoxic effects induced by antitumor drugs. MATERIALS AND METHODS: New sensitizers, termed as 21-selenaporphyrin (SEP) and 21-thiaporphyrin (STSP) were studied for their photocytotoxicity in vitro against selected human cancer cell lines. This study was followed by in vivo screening of the effect of SEP using an animal tumor model. The activity of the new agents was compared with that of a known photosensitizer, namely chlorin e6. In our selection of the cell lines applied for in vitro study, the possible accessibility and effectiveness of photodynamic therapy (PDT) for treatment of colon and urinary bladder cancers, was considered. RESULTS: New compounds appeared to be not toxic for tested cells in culture, without exposure to light. The STSP exerted in vitro effects comparable with chlorin e6 photocytotoxicity, while SEP appeared to be ineffective. However, in vivo experiments performed in a BFS1 fibrosarcoma tumor model in mice showed that the SEP was at least as much effective as chlorin e6 in the induction of tumor necrosis. In contrast to chlorin e6, SEP-PDT induced no skin sensitization. CONCLUSIONS: Both new sensitizers can be applied in PDT at no risk of skin damage. The mechanism of the action of these two compounds is probably different, i.e. the 21-thiaporphyrin possibly acts directly on tumor cells and the 21-selenaporphyrin via endothelial cells of newly formed tumor vasculature.

1,25-Dihydroxyvitamin D3 induced activation and subsequent nuclear translocation of MAPK is upstream regulated by PKC in HL-60 cells.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) in addition to its classical role in calcium homeostasis regulates cell differentiation. The mechanisms involved in mediating numerous functions of 1,25(OH)2D3 are not clearly understood. In addition to genomic actions involving nuclear vitamin D receptor (VDR), some rapid nongenomic responses have been observed, but the full signalling pathway activated by 1,25(OH)2D3 has still not been described. Our recent data allow for better understanding of nongenomic effects evoked by 1,25(OH)2D3. In this paper we show that mitogen activated protein kinase (MAPK) is activated in HL-60 promyelocytic leukemia cells and in normal human keratinocytes under exposure to differentiation inducing concentrations of 1,25(OH)2D3. The MAPK is then transported to the cell nucleus in active form, which is different from the activation evoked by fetal calf serum. Experiments utilising tyrosine kinase inhibitor suggested that the postulated putative membrane vitamin D receptor, if it exists, does not have tyrosine kinase activity. Usage of protein kinase C (PKC) inhibitor allowed to state that PKC is an upstream element in the MAPK signalling pathway.

5,20-bis(4-sulphophenyl)-10,15-bis (2-methoxy-4-sulphophenyl)-21-thiaporphyrin as a new potent sensitizer in photodynamic therapy.

The main purpose of the study was to investigate the effectiveness of a new photosensitizer for photodynamic therapy. 5,20-bis(4-sulphophenyl)-10,15-bis (2-methoxy-4-sulphophenyl)-21-thiaporphyrin (21-thiaporphyrin) was compared to chlorin e6 and tetra(m-hydroxyphenyl)porphyrin (m-THPP) for its ability to sensitize tumors and skin to light. Chlorin e6 and m-THPP induced a strong tumor and skin photosensitization. In contrast, the same doses of 21-thiaporphyrin produced no skin sensitization and gave approximately 10 mm tumor necrosis after light exposure, in comparison to the 5-6 mm necrosis induced by chlorin e6 or m-THPP under identical conditions. 21-Thiaporphyrin, tested as a potential photosensitizer, induced no skin sensitization even at doses as high as 7.5 mg/kg body weight. 21-Thiaporphyrin presents a high potency in tumor sensitizing, i.e. a feature required for an efficient photosensitizer in photodynamic therapy applications.

[99mTc-Cardiolite and Tl-201 in the evaluation of myocardial blood flow. Comparison of their diagnostic usefulness]. / Technet-99m cardiolite i tal-201 w ocenie ukrwienia miesnia sercowego. Porównanie przydatnosci diagnostycznej.

The aim of this study was to compare regional perfusion of myocardium measured with Tl-201 and Tc-99m CARDIOLITE in 35 patients with coronary artery disease. All the patients were examined three times. Investigations with Tc-99m CARDIOLITE at stress and rest were performed after twice done injection of dose. Tl-201 was given within 7 days from investigations with Tc-99m CARDIOLITE. All the patients were stress tested according to Bruce's protocol. The radiopharmaceutic was injected at maximal ergometric stress level and then stress was continued for at least one minute. The results of regional perfusion scintigraphy--separately with Tl-201 and Tc-99m CARDIOLITE--were compared in 19 patients with contrast coronarography. Similar sensitivity, specificity and accuracy were obtained for both tracers, 67%, 80%, 71% respectively for Tl-201 and 69%, 86%, 73% for Tc-99m CARDIOLITE. Entire accuracy was obtained in 80% comparisons in segment to segment correlation. Tc-99m CARDIOLITE showed smaller perfusion defect in 9% comparisons and greater in 11%. This findings suggest that both tracers can be used interchangeably.

[Functional scintigraphy of radioactive cardiac blood pool: amplitude and phase analysis and conventional parameters of left-ventricular wall motion at rest]. / Czynnosciowa scyntygrafia zbioru radioaktywnej krwi serca: analiza amplitudowo-fazowa i konwencjonalne parametry ruchomosci scian lewej komory w spoczynku.

Authors performed quantitative assessment of 13 global and regional, left ventricular wall motion parameters obtained from 52 radioactive blood pool cardiac scintigrams. Of these performed in 1986 examinations, authors selected 3 equipotent patients' groups (myocardial infarction, cardiac aneurysm, cardiomyopathy) thus the contractility disorders were located in inferior wall segments. 13 examinations of the same material, without contractility disorders were selected (standard). Using time-activity curve authors measured following global parameters: ejection fraction (EFg1), mean ejection rate (MER), peak ejection rate (PER), peak filling rate (PFR), time from the end-systole to peak filling rate (tPFR) and regional parameters such as: regional and local ejection fraction (EFr and EF1), time from the beginning of the cycle to the end-diastole (ED) and to the end-systole (ES), contractility (KURCZ), amplitude of contractions. (AMPL) and of phase (PHASE) as well as standardized variables of amplitude distribution (SDU). The most significant quantitative parameter was EFgl. Dyskinesis symptom was the most important for cardiac eneurysm diagnosis. Phase shift served a confirmation of aneurysm earlier diagnosed using a cinematic display.