bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concept maps: Experiments on dynamic thinking
Authors: Derbentseva Natalia , Safayeni Frank , Cañas Alberto, J. 
Published: December 2006

AbstractThree experiments were conducted to examine the effects of map structure, concept quantification, and focus question on dynamic thinking during a Concept Map (CMap) construction task. The first experiment compared cyclic and hierarchical structures. The second experiment examined the impact of the quantification of the header concept in the map. The third experiment explored the effect of the focus question on the map. For all three experiments, the content of the CMaps was assessed for the number of dynamic propositions and the number of quantified concepts. The results show that the cyclic structure, the quantification of the header concept, and the focus question “How” significantly increased dynamic thinking. The studies, the theoretical background, and the implications of the findings are discussed. © 2006 Wiley Periodicals, Inc. J Res Sci Teach 44: 448–465, 2007
Enzymatic acylation of ether and ester lysophospholipids in rat liver microsomes
Authors: Neumüller W. , Fleer E. A. M. , Unger C. , Eibl H. 
Published: December 2006

AbstractThe acylation of lysophospholipids by rat liver acyltransferases was studied. A comparison between ester and ether lysophospholipids as substrates revealed large differences in substrate properties. For instance, oleic acid from oleoyl‐CoA and arachidonic acid from arachidonoyl‐CoA were not incorporated into 1‐O‐octadecyl‐sn‐glycero‐3‐phosphocholine under experimental conditions that allowed an optimal transfer of oleic acid and arachidonic acid to 1‐O‐palmitoyl‐sn‐glycero‐3‐phosphocholine. However, we observed an acyl‐CoA‐independent transfer of arachidonic acid from 1‐O‐stearoyl‐2‐O‐arachidonoyl‐sn‐glycero‐3‐phosphoinositol to 1‐O‐octadecyl‐sn‐glycero‐3‐phosphocholine.
A continuous assay forO‐alkylglycerol monooxygenase (E.C. 1.14.16.5)
Authors: Koetting Jochem , Unger Clemens , Eibl Hansjoerg 
Published: December 2006

AbstractThe antitumor activity of alkyl lysophospholipids has raised some questions concerning the degradation ofO‐alkyl bonds in naturally occurring ether lipids. In this report, we describe the first continuous assay forO‐alkylglycerol monooxygenase (AGMO), the only enzyme known to cleave theO‐alkyl bond in saturated ether lipids and ether phospholipids. AGMO activity was monitored at 340 nm by coupling the NADH redox reaction to the tetrahydropteridine cofactor of the rat liver microsomal enzyme. Turnover rates as low as 0.6 nmol/min could be measured. Using radiolabeled substrates, the products were identified with a TLC‐Linear‐Analyzer. The only interference with this assay can arise from other reducing agents, e.g. dithiothreitol. The assay was used to develop protocols for the solubilization of AGMO from membrane preparations in the presence of detergents.
Differential effects of ether lipids on the activity and secretion of interleukin‐1 and interleukin‐2
Authors: Andreesen Reinhard , Giese Veronika 
Published: December 2006

AbstractAlkyl lysophospholipids (ALP) are synthetic analogues of lysophosphatidylcholine and represent a new generation of antitumor drugs currently being tested in phase‐I trials in patients with cancer. The present study reports the differential modulation of human immunocompetent cells in vitro by ALP. Serum‐bound ALP effectively blocked the response of growth factor‐dependent cells to interleukin‐2 (IL‐2), inhibited the cellular production and release of IL‐2 and suppressed the comitogenic effect of interleukin‐1 (IL‐1) on mouse thymocytes. In contrast, ALP‐primed, monocyte‐derived macrophages (MO) lost their ability to release IL‐1 in response to stimuli like lipopolysaccharides (LPS) during terminal maturation from monocytes. Supernatants from ALP‐primed, LPS‐induced MO possessed costimulatory as well as direct mitogenic activity. Neither ALP alone nor ALP‐conditioned MO supernatants stimulated mouse thymocytes. Priming of MO by ET‐18‐OH, an ALP molecule not substituted in thesn‐2 position, occurred at concentrations 4‐ to 16‐fold higher than the most active compounds ET‐18‐OCH, and the thioether analogue BM 41.440. ALP also primed MO for subsequent activation of tumor cytotoxicity by LPS and interferon‐gamma.IL‐1 has multiple biological activities in common with ALP, and it may mediate antitumor activity and other ALP effects in vivo. The ability of ALP to induce differential immunomodulation, as demonstrated in this study, may make ALP worthy of study for the therapy of both autoimmune and neoplastic disease.
A metabolite of an antineoplastic ether phospholipid may inhibit transmembrane signalling via protein kinase C
Authors: van Blitterswijk Wim J. , van der Bend Rob L. , Kramer Ïjsbrand M. , Verhoeven Arthur J. , Hilkmann Henk , de Widt John 
Published: December 2006

AbstractIn our search for the mechanisms by which the drug 1‐O‐alkyl‐2‐O‐methylglycero‐3‐phosphocholine (AMG‐PC) inhibits tumor growth and metastasis, we have detected a metabolite, 1‐O‐alkyl‐2‐O‐methylglycerol (AMG), in membranes of MO4 mouse fibrosarcoma cells grown in the presence of the drug. Synthetic AMG inhibited the activation of highly purified human protein kinase C by diacylglycerol in the presence of phosphatidylserine. Furthermore, AMG also inhibited the receptor‐specific binding of3H‐phorbol‐12,13‐dibutyrate to human HL‐60 promyeloid leukemia cells in a dose‐dependent fashion. AMG‐PC was not effective or much less so in these assays. We suggest that interaction of the metabolite AMG with protein kinase C may inhibit stimulus‐response coupling in tumor cells and may thus potentially contribute to the mechanism by which AMG‐PC exerts its anticancer activities.
Effect of lipid derivatives on invasion in vitro and on surface glycoproteins of three rodent cell types
Authors: Storme Guy A. , Bruyneel Erik A. , Schallier Denis C. , Bolscher Jan G. , Berdel Wolfgang E. , Mareel Marc M. 
Published: December 2006

AbstractThe antiinvasive activity on MO4 mouse cells of the following lipid derivatives was tested in vitro: an alkyllysophospholipid derivative (BM 41.440), an alkyl‐linked lipoidal amine (CP‐46,665) and a naturally occurring ester‐linked phospholipid (2‐LPC). In this test, BM 41.440 had the same antiinvasive potency as ET‐18‐OCH3, whereas CP‐46,665 and 2‐LPC had no effect on invasion. Comparison of the antiinvasive effect of ET‐18‐OCH3 on three types of cells showed the following ranking: 12R1C‐RK rat kidney adenovirus type 12 transfected cells>MO4 mouse cells>LLC‐H61 Lewis lung carcinoma cells. This ranking was not reflected in ET‐18‐OCH3‐induced changes of cell surface exposed glycopeptides derived from the three types of cells metabolically labeled with radioactive fucose. The present and previous experiments suggested that changes in invasion caused by lipid derivatives depended upon relative cell surface fucosylglycopeptide alterations in both the invasive cells and the normal tissue.
Metabolism of ether phospholipids and analogs in neoplastic cells
Authors: Fleer E. A. M. , Unger C. , Kim D. ‐J. , Eibl H. 
Published: December 2006

AbstractThe ether phospholipid 1‐O‐octadecyl‐2‐O‐methyl‐rac‐glycero‐3‐phosphocholine (OM‐GPC) is known to be a potent inhibitor of cell growth. Metabolic studies in both Raji and L1210 leukemic cells on OM‐GPC,3H‐labeled in the methyl groups of the choline moiety, showed a (diacyl)‐phosphatidylcholine as the only labeled metabolite. Since the formation of radiolabeled (diacyl)‐phosphatidylcholine showed a direct correlation with cell death, we tested other lipid analogs. One of these compounds, hexadecylphosphocholine (He‐PC), which was3H‐labeled in the methyl‐choline groups, showed a formation of labaled (diacyl)‐phosphatidylcholine similar to that found with OM‐GPC. Again, there was a direct linear correlation between the formation of the labeled product and cell death. He‐PC was found to be a potent cell toxin in in vitro experiments on cell cultures. However, analogs with an elongated phosphor to trimethylammonium distance showed no toxicity towards the cells in in vitro experiments. From the data, we conclude that the ether phospholipids are substrates for a phospholipase C or related enzyme. This substrate property may be responsible for the toxicity of the compounds in neoplastic cells.
Effect of synthetic phospholipids on platelet aggregation and serotonin release
Authors: Söling Ulrike , Eibl Hansjörg , Nagel Gerd A. , Unger Clemens 
Published: December 2006

Abstract1‐O‐Hexadecyl‐2‐O‐acetyl‐sn‐glycerol‐3‐phosphocholine (platelet‐activating factor, PAF) is known to stimulate platelet aggregation and serotonin release in concentrations ranging from 10−10–10−5 M. Since a variety of synthetic PAF analogues are potent antineoplastic agents in vitro and in vivo, it was the aim of this study to examine the PAF‐like activity of 15 analogues, including 1‐O‐actadecyl‐2‐O‐methyl‐rac‐glycero‐3‐phosphocholine (ET‐18‐OCH3) and a thioether analogue. In platelet‐rich plasma from human blood, platelet aggregation and serotonin release were studied to compare the effects on PAF and the analogues. Platelet function was controlled by testing their response to adenosine diphosphate, arachidonic acid, collagen and epinephrine. Our results show that only PAF was able to induce platelet aggregation and serotonin release in concentrations from 10−9 to 10−5 M, whereas all the tested analogues up to a concentration of 10−3 M failed to induce these effects.
Immunomodulatory and therapeutic properties of alkyl lysophospholipids in mice
Authors: Talmadge James E. , Schneider Mark , Lenz Barbara , Phillips Hamblin , Long Cedric 
Published: December 2006

AbstractThis paper describes the immunomodulatory and therapeutic properties of the alkyl lysophospholipids [ALP; 1‐O‐octadecyl‐2‐O‐rac‐glycero‐3‐phosphocholine (ET‐18‐OCH3)]. ALP was able to activate macrophages both in vitro and in vivo as well as to act as an immunoadjuvant for syngeneic tumor vaccines. However, ALP appeared to be transferred, at least in part, to the macrophage membrane, and some of the tumoricidal macrophage‐activating properties seem to be associated with the direct cytotoxic effect of membrane‐released ALP. ALP also had some therapeutic activity for experimental and spontaneous metastases, requiring administration three but not two times weekly at near‐toxic doses; this suggests that at least some of its therapeutic activity is due to direct cytotoxicity.
Antitumor activity of SRI 62‐834, a cyclic ether analog of ET‐18‐OCH3
Authors: Houlihan William J. , Lee Mark L. , Munder Paul G. , Nemecek Georgina M. , Handley Dean A. , Winslow Christine M. , Happy John , Jaeggi Christian 
Published: December 2006

AbstractSRI 62‐834, an analog of the antitumor agent ET‐18‐OCH3 in which the oxygen atom at carbon atom 2 has been incorporated into a five‐membered heterocycle, has been prepared and evaluated as an antitumor agent. The compound exhibited good cytotoxicity in vitro against a variety of tumor cell lines and was as effective as ET‐18‐OCH3 given orally in the mouse Meth A sarcoma model. SRI 62‐834 was shown to be an inhibitor of platelet‐derived growth factor (PDGF), possibly at the receptor level, and platelet‐activating factor (PAF) at the receptor level.
Liposomes in chemo‐ and immunotherapy of cancer
Authors: Scherphof Gerrit L. , Daemen Toos , Spanjer Halbe H. , Roerdink Frits H. 
Published: December 2006

AbstractIn this paper, we report on the in vivo behavior of liposomes as a function of their size and composition. It is emphasized that by varying these parameters we can influence not only the rate of blood elimination but also the intrahepatic destination of the liposomes. Thus, we show that small liposomes with diameters well below 100 nm can reach and be internalized by the parenchymal cells of the liver, i.e. the hepatocytes. The rate and the extent at which this occurs depends on the liposomal composition. With respect to the application of liposomes as a drug carrier system in anticancer therapy, we put emphasis on the liver macrophage, i.e. the Kupffer cell, as a target cell. Large liposomes with diameters well over 100 nm exclusively are taken up by these cells as far as hepatic uptake is concerned. By encapsulation within liposomes, a drug may be delivered specifically to these macrophages; this will prevent its rapid excretion from the body and/or undesired accumulation in other cell types. Two examples of the way in which this condition may be exploited are presented. First, we demonstrate the formation of intracellular depots in the macrophages of the cytostatic drug 5‐fluorodeoxyuridine (FUdR), thus preventing the rapid metabolism of the drug by the hepatocytes and allowing its sustained release from the macrophages and subsequent uptake by adjacent metastatic tumor cells. Second, we show that the liposome‐encapsulated immunomodulator muramyl dipeptide is capable of activating liver macrophages both in vitro and in vivo to a tumor‐specific cytotoxic state, and this can result in substantial reduction of metastatic growth in the livers of mice inoculated in the spleen with colon adenocarcinoma cells.
Structure‐cytotoxicity studies on alkyl lysophospholipids and some analogs in leukemic blasts of human origin in vitro
Authors: Danhauser Susanne , Berdel Wolfgang E. , Schick Hans D. , Fromm Michael , Reichert Anneliese , Fink Ulrich , Busch Raymonde , Eibl Hansjörg , Rastetter Johann 
Published: December 2006

AbstractEleven lipids have been tested for cytotoxic (trypan blue dye exclusion) activity in cells from eight freshly explanted human leukemias in vitro. 4‐Aminomethyl‐1‐[2,3‐(di‐N‐decyloxy)N‐propyl]‐4‐phenylpiperidine (CP‐46,665), 1‐mercapto‐hexadecyl‐2‐methoxymethyl‐rac‐glycero‐3‐phosphocholine (BM 41.440), the 2‐acetamide analog of platelet‐activating factor (PAF) and 1‐O‐octadecyl‐2‐O‐methyl‐rac‐glycero‐3‐phosphocholine (ET‐18‐OCH3) were found among the most active compounds. 2‐Lysophosphatidylcholine (2‐LPC) showed the lowest activity. However, in addition there was variation among the results regarding the activity of the 1‐octadecyl‐rac‐glycero‐3‐phosphocholine (ET‐18‐OH) and its D‐ and L‐forms, but a significantly higher cytotoxic activity of D‐ET‐18‐OH compared with L‐ET‐18‐OH on the basis of 2‐LPC as control after an incubation time of 48 hr. We conclude that with the limited number of structures available, this type of study is not sufficient to yield further information about the mode of the accumulation and toxicity of this type of lipids.
Experimental studies on the role of alkyl lysophospholipids in autologous bone marrow transplatation
Authors: Vogler William R. , Olson Anita C. , Okamoto Shinichiro , Somberg Lewis B. , Glasser Lewis 
Published: December 2006

AbstractThe selective cytocidal effect of alkyl lysophospholipids against neoplastic cells while sparing normal cells make these ideal candidates for purging leukemic cells from bone marrows obtained during remission. To test the feasibility of such an approach, a murine model and an in vitro human cell model were developed. In the murine system a mixture of normal bone marrow cells and WEHI IIIB myelomonocytic leukemic cells was incubated with varying doses of 1‐O‐octadecyl‐2‐O‐methyl‐rac‐glycero‐3‐phosphocholine (ET‐Me) for 24 hr before being injected into tail veins of lethally irradiated Balb/c mice. At doses of 20 and 100 μg/ml, long‐term survivors were noted. The additional steps of freezing and thawing following incubation resulted in significantly longer survival with doses of 10 to 50 μg/ml, but were toxic to marrow stem cells at 100 μg/ml.In the in vitro model, normal marrow progenitor cells and leukemic cells (the promyelocytic cell line HL60) were exposed to varying concentrations of ET‐Me for 1 and 4 hr alone or mixed, and clonogenicity was assayed by colony formation in semisolid medium during 7–14 days’ incubation. At doses up to 100 μg/ml exposed for 4 hr normal progenitor cells were spared and HL60 colonies eliminated. Other phospholipids analogues were less effective in eliminating leukemic cells, but spared normal progenitor cells.A survey of fresh leukemic cells found varying degrees of sensitivity to ET‐Me, indicating the need for testing a variety of compounds.These studies clearly indicated the potential usefulness of alkyl lysophospholipid compounds in selectively purging leukemic cells from remission marrows for autologous bone marrow transplantation.
Therapeutic activity of ET‐18‐OCH3 and hexadecylphosphocholine against mammary tumors in BD‐VI rats
Authors: Scherf H. R. , Schuler B. , Berger M. R. , Schmähl D. 
Published: December 2006

AbstractThe present therapy experiments with two different transplantable mammary tumors were performed to compare the therapeutic efficacy in BD‐VI rats of 1‐O‐octadecyl‐2‐O‐methyl‐rac‐glycero‐3‐phosphocholine (ET‐18‐OCH3) and hexadecylphosphocholine (HPC). Both compounds were administered orally, subcutaneously or intracutaneously at equimolar doses ranging from 4.8 to 88 μmol/kg/day five times per week for two weeks. Under the experimental conditions, both transplanted mammary carcinomas were moderately sensitive to the therapy with either HPC or ET‐18‐OCH3. Comparing both tumors, TMA2 was more sensitive than TMA1. The activity and toxicity of both compounds were dose‐related in both tumor lines. Females seemed to be less sensitive with respect to antineoplastic activity and toxicity. Like ET‐18‐OCH3, HPC was active also at low, probably noncytotoxic doses associated with no detectable toxicity according to body weight development. This suggests that there are at least two different mechanisms of action that lead to tumor growth inhibition.
Antineoplastic activity of conjugates of lipids and 1‐β‐d‐arabinofuranosylcytosine
Authors: Berdel Wolfgang E. , Danhauser Susanne , Schick Hans D. , Hong Chung , West Charles R. , Fromm Michael , Fink Ulrich , Reichen Anneliese , Rastetter Johann 
Published: December 2006

AbstractFive different lipid conjugates of 1‐β‐D‐arabinofuranosylcytosine (ARA‐C) were tested in comparison with ARA‐C, the ether lipid ET‐18‐OCH3 (1‐O‐octadecyl‐2‐O‐methyl‐rac‐glycero‐3‐phosphocholine) and their equimolar mixtures. The compounds were tested in vitro for cytotoxicity in the trypan blue dye exclusion test with cells from six different leukemias, one glioblastoma and two bronchogenic carcinomas of human origin. The compounds were given in vivo to assess their therapeutic activity against 3‐Lewis lung carcinoma (3‐LL) of syngeneic C57Bl6 mice. Although some of the conjugates have shown cytotoxic activity in vitro against the cell samples tested, they have not revealed higher cytotoxicity than ET‐18‐OCH3, ARA‐C or their equimolar mixtures. In these experiments, ARA‐CDP‐D,L‐MBA was the conjugate with the highest cytotoxicity. Some of the conjugates significantly inhibited tumor growth and also increased survival of C57Bl6 mice with intraperitoneally (ip) implanted 3‐LL. In these experiments, ARA‐CDP‐D,L‐PTBA, ARA‐CDP‐D,L‐PBA, ARA‐CDP‐L‐dipalmitin and ARA‐CDP‐D,L‐PCA were more active than either the parent compounds ARA‐C and ET‐18‐OCH3 alone or their equimolar mixtures. Furthermore, when the conjugates were injected as adjuvant chemotherapy shortly after the surgical removal of the primary 3‐LL, they inhibited the metastasis of 3‐LL to the lungs of the animals, demonstrated by an increase of the survival time and the number of surviving animals. The mode of action of these new antineoplastic compounds still is speculative.
Cytotoxic activity of the thioether phospholipid analogue BM 41.440 in primary human tumor cultures
Authors: Herrmann Dieter B. J. , Neumann Herbert A. 
Published: December 2006

AbstractThe inhibitory effect of the new thioether alkyl lysophospholipid analogue 1‐hexadecylmercapto‐2‐methoxymethyl‐rac‐glycero‐3‐phosphocholine (BM 41.440, Ilmofosine) on colony formation of different spontaneous human tumors was studied in vitro using a methyl cellulose monolayer assay. The most sensitive tumors were lung (small cell, squamous cell and adenocarcinomas), gastrointestinal and ovarian cancers and hyernephromas. On the basis of the current difinition of sensitivity by the National Cancer Institute, Bethesda, MD, i.e. more than 70% inhibition of colony formation at an arbitrary concentration of 10 μg/ml, 34 out of 64 malignancies tested were susceptible to BM 41.440.
Phase I trial of the thioether phospholipid analogue BM 41.440 in cancer patients
Authors: Herrmann Dieter B. J. , Neumann Herbert A. , Berdel Wolfgang E. , Heim Manfred E. , Fromm Michael , Boerner Dietmar , Bicker Uwe 
Published: December 2006

AbstractBM 41.440 (1‐hexadecylmercapto‐2‐methoxymethyl‐rac‐glycero‐3‐phosphocholine) is a new thioether phospholipid, which has been shown to possess antineoplastic, antimetastatic, anti‐invasive and immunomodulating properties in serveral tumor models. The mechanism whereby this compound exerts its direct antineoplastic effect is thought to be related to specific interference with the normal phospholipid metabolism, preferentially of neoplastic cells. BM 41.440 was evaluated in a multicenter phase I study in patients (pts) with refractory cancers. In phase I A, 34 pts were orally treated with doses ranging from 0.5 to 7.0 mg/kg body weight (bw). Three different formulations were tested. The maximum‐tolerated dose (MTD) was ca. 5 mg/kg bw. The limiting side effects were nausea and vomiting. There was no evidence for systemic toxicities like myelosuppression, nephro‐, neuro‐, hepatotoxicity or hematological side effects. The current phase I B is designed to determine the MTD of BM 41.440 administered orally on a daily schedule for at least eight weeks. So far, 19 pts have entered this trial at dose levels ranging from 1.0 to 5.0 mg/kg bw/day. Some pts receiving 1.0 and 2.5 mg/kg bw/day, respectively, have been treated, up to now, for more than nine months. Clinical progress was followed with at‐least‐weekly blood counts, chemistry profiles, urine analysis, liver function tests and recordings of side effects. Tumor parameters were evaluated at eight‐week intervals. In parallel, pharmacokinetic investigations were performed in some pts in phase I A and IB. First results on tolerability and therapeutic efficacy of the long‐term BM 41.440 treatment are reported in this intermediate evaluation.
Clinical phase I pilot study of the alkyl lysophospholipid derivative ET‐18‐OCH3
Authors: Berdel Wolfgang E. , Fink Ulrich , Rastetter Johann 
Published: December 2006

AbstractSixteen patients suffering from widespread malignant disease, the majority pretreated and found in poor general health, were treated in a phase I pilot study with the alkyl lysophospholipid derivative 1‐O‐octadecyl‐2‐O‐methyl‐rac‐glycero‐3‐phosphocholine (E‐18‐OCH3). Eleven patients were treated intravenously, and five were given oral therapy. Prolonged IV administration of 15–20 mg/kg/day at a concentration of 5 mg ET‐18‐OCH3 per 1 ml 20% human serum albumin could be continued safely. The maximum‐tolerated dose was either 50 mg/kg as a single injection or 20 mg/kg during daily dispensions. Grade 2–4 toxicity, as pulmonary edema and impairment of hepatic function, then occurred during daily treatment. Toxicity was reversible. Mitogen stimulation and mixed lymphocyte culture studies revealed possible immunosuppressive effects of higher doses of ET‐18‐OCH3. There were no chromosomal changes in cytogenetic studies. Frequent post‐mortem examinations revealed no further toxicity. IV and oral treatment showed few encouraging response data since there were two partial remissions in non‐small cell lung cancers and a reduction of leukemic blasts to less than 10% in an acute myelomonocytic leukemia.