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Biomedical subjects

H Eibl

Publications and source records attributed to H Eibl.

At least 73 records · Page 4Linked to original sources
PubMed1990

Cytotoxic activity of lysophosphatidylcholine analogues on human lymphoma Raji cells.

The cytotoxic activity of 21 lysophosphocholine analogues was tested on human lymphoma Raji cells. Structure-activity investigations revealed a more than 50-fold difference in the cytotoxicity between the different compounds. Whereas acyllysophosphocholines showed only borderline effects, the most pronounced toxic activity was observed with compounds which have an etherbond in the sn-1 position and a hydrogen, a methoxy or a methoxymethylgroup in position sn-2. Elongation of the phosphorous-nitrogen distance in the choline group markedly reduced the cytotoxicity of the compounds. From the results obtained it was concluded that a long chain fatty alcohol adjacent to a phosphocholine headgroup represents the minimal requirement for antineoplastic activity. Thus, a new group of antineoplastic compounds, the alkylphosphocholines, was developed in our laboratory, with in vitro cytotoxic activities just as effective as the most toxic alkyllysophosphocholines.

Antineoplastic Agents↗
PubMed1989

Effect of ether lipids on mouse granulocyte-macrophage progenitor cells.

In this study we determined the potential bone marrow toxicity of the ether lipid derivatives 1-0-octadecyl-2-0-methyl-rac-glycero-3-phosphocholine (OcMe-G-3-PC), 1-0-hexadecyl-propanediol-2-phosphocholine (He-Pr-2-PC), and hexadecylphosphocholine (He-PC). OcMe-G-3-PC inhibited the proliferation of mouse granulocyte-macrophage progenitor cells (GM-CFCs) at a dose of 1 micrograms/ml, whereas He-Pr-2-PC and He-PC started to inhibit the growth of hemopoietic precursors at 5 micrograms/ml. In contrast to this finding, NMRI mice given 10 mg/kg i.v. daily for 4 weeks and 20 or 30 mg/kg for 5 days showed no bone marrow toxicity. We conclude that the dose-dependent toxic effects observed in vitro are within the physiological tolerance in vivo.

Animals↗
PubMed1989

Hexadecylphosphocholine, a new ether lipid analogue. Studies on the antineoplastic activity in vitro and in vivo.

Hexadecylphosphocholine (He-PC) is a new compound synthesized according to the minimal structural requirements deducted from studies with other ether lipids. In vitro studies on He-PC revealed remarkable antineoplastic activity on HL60, U937, Raji and K562 leukemia cell lines. In addition, He-PC, applied orally, showed a superior effect in the treatment of dimethylbenzanthracene-induced rat mammary carcinomas when compared to intravenously administered cyclophosphamide. After oral application He-PC was well absorbed from the intestine and metabolized in the liver by phospholipases C and D. During a 5-week treatment no hematotoxic effects were detected. In a clinical pilot study on breast cancer patients with widespread skin involvement, topically applied He-PC showed skin tumor regressions without local or systemic side effects.

Animals↗
PubMed1988

Phospholipids and UDP-glucuronosyltransferase. Structure/function relationships.

The activation of delipidated microsomal UDP-glucuronosyltransferase from pig liver (GT2P type of enzyme) was studied as a function of several structural modifications of 1-palmitoyl-sn-glycero-3-phosphocholine, which is known to be a good activator of the enzyme. The following types of compounds were tested: substitution of H for OH at position 2; substitution of an ether for an acyl link at position 1; variation of the phosphorus-nitrogen or acyl ester-phosphate ester distances; removal of the glycerol backbone; optical isomers; and substitution of phosphoethanolamine for phosphocholine. Although there were variations in the extent to which these compounds activated delipidated enzyme, all the above types of lipids were effective in this regard. By contrast, lipids with a net negative charge did not activate the enzyme. They inhibited it reversibly. Positively charged lipids, even those lacking a phosphate group, were effective activators. These results indicate that GT2P is unlikely to interact with specific chemical groups of its phospholipid milieu. Effective activation appears instead to depend on the physical properties of the lipid environment.

Animals↗
PubMed1988

Substrate specificity of Staphylococcus aureus (TEN5) lipases with isomeric oleoyl-sn-glycerol ethers as substrates.

For the first time fully protected substrates with only one hydrolyzable ester bond have been used to analyze the substrate specificity of microbial lipases. In these substrates the ester is attached to the glycerol molecule in a precisely defined position. The use of three different substituents generates chirality and thus allows the analysis of positional specificities of individual lipases. Therefore, these new substrates have been used to study the enzymatic activities of two closely related lipases isolated from Staphylococcus aureus (TEN5) designated the 44 and 43 kDa lipase. The lipases, especially the 44 kDa molecule, show a high specificity for the hydrolysis of the ester in the sn-1 position (S-configuration), which is hydrolyzed by a factor of ten faster than that in the sn-3 position. In addition, the study demonstrates for the first time that the rate of hydrolysis of a fatty acid ester attached to the sn-2 position of glycerol by microbial lipases depends on the configuration of the substrate molecule.

Glyceryl Ethers↗
PubMed1988

1-O-methyl-rac-glycerol: a new agent for the cryopreservation of mononuclear cells.

1-O-methyl-rac-glycerol (1-O-MG), also known as 3-methoxy-1,2-propanediol is a lipophilic derivative of glycerol, and has been studied as a new cryoprotective agent (CPA) for mononuclear blood cells (MNC), a well-established experimental model in cryopreservation. The chemical modification of the glycerol molecule results in improved cryobiological properties, such as membrane permeability, thus allowing easier handling in the freeze/thaw process. The optimum preincubation period for MNC and 1-O-MG before freezing is 5 min at 4 degree C, resulting in 86% recovery of viable cells, whereas optimal recovery of glycerol-frozen MNC is only guaranteed after 30 min of preincubation at room temperature (74% viable recovery). The optimal concentration of 1-O-MG is 10% (v/v). Although this new agent offers no improvement in cryoprotective properties over dimethyl sulfoxide (Me2SO) there may be possible pharmacological advantages when used in humans. It is, however, obviously superior to glycerol with regard to its permeation kinetics. 1-O-MG might therefore also be of interest in the cryoprotection of other hematopoietic cells and biological tissues.

Blood Preservation↗
PubMed1988

Characterization of the antitumor activity of hexadecylphosphocholine (D 18506).

Hexadecylphosphocholine (HPC) differs from ether lipids with known antitumor activity by its lack of the glycerol part. In the experiments described here HPC revealed outstanding antitumor activity in dimethylbenzanthracene (DMBA)-induced rat mammary tumors. A dose-response relationship was seen after daily oral treatment with complete suppression of tumor growth at doses of 46.4 mg/kg/day. There was no schedule dependence and the therapeutic efficacy was independent of the tumor weight at the initiation of therapy. Another autochthonous tumor, the benzo[a]pyrene-induced sarcoma of the rat did not respond to HPC treatment, indicating a highly selective spectrum of activity of the test compound. In comparison to an optimal single dose of cyclophosphamide, a single high dose of HPC was considerably more active against the DMBA tumor. At therapeutic dose levels no major toxicity of HPC was observed. Bone marrow suppression was not encountered, on the contrary, at high doses leukocytosis became apparent. The available pharmacological and toxicological data suggest that HPC may be useful in the treatment of human cancer.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Conformation and packing properties of membrane lipids: the crystal structure of sodium dimyristoylphosphatidylglycerol.

The conformation and molecular packing of sodium 1,2-dimyristoyl-sn-glycero-phospho-rac-glycerol (DMPG) have been determined by single crystal analysis (R = 0.098). The lipid crystallizes in the monoclinic spacegroup P2(1) with the unit cell dimensions a = 10.4, b = 8.5, c = 45.5 A and beta = 95.2 degrees. There are two independent molecules (A and B) in the asymmetric unit which with respect to configuration and conformation of their glycerol headgroup are mirror images. The molecules pack tail to tail in a bilayer structure. The phosphoglycerol headgroups have a layer-parallel orientation giving the molecules an L-shape. At the bilayer surface the (-) phosphoglycerol groups are arranged in rows which are separated by rows of (+) sodium ions. Laterally the polar groups interact by an extensive network of hydrogen, ionic and coordination bonds. The packing cross-section per molecule is 44.0 A2. The hydrocarbon chains are tilted (29 degrees) and have opposite inclination in the two bilayer halves. In the chain matrix the chain planes are arranged according to a so far unknown hybride packing mode which combines the features of T parallel and O perpendicular subcells. The two fatty acid substituted glycerol oxygens have mutually a - synclinal rather than the more common + synclinal conformation. The conformation of the diacylglycerol part of molecule A and B is distinguished by an axial displacement of the two hydrocarbon chains by four methylene units. This results in a reorientation of the glycerol back bone and a change in the conformation and stacking of the hydrocarbon chains. In molecule A the beta-chain is straight and the gamma-chain is bent while in molecule B the chain conformation is reversed.

Hydrogen Bonding↗
PubMed1987

Brain uptake and CNS levels of 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)urea (HECNU).

The uptake of 14C-labeled 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)urea (HECNU) into the brain was investigated in the rat after intracarotid injection according to the method of OLDENDORF, as well as in cisternal cerebrospinal fluid obtained by suboccipital puncture after i.v. injection of the drug. The brain uptake index was 31.9 +/- 2.9%. Cerebrospinal fluid/blood quotients after i.v. injection were 0.82 at 10 min and 1.10 at 60 min. The results of both methods clearly show that HECNU, in spite of its hydrophilic property, easily penetrates the blood-brain barrier.

Animals↗
PubMed1987

Enzymatic acylation of ether and ester lysophospholipids in rat liver microsomes.

The 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.

Acylation↗
PubMed1987

A continuous assay for O-alkylglycerol monooxygenase (E.C. 1.14.16.5).

The antitumor activity of alkyl lysophospholipids has raised some questions concerning the degradation of O-alkyl bonds in naturally occurring ether lipids. In this report, we describe the first continuous assay for O-alkylglycerol monooxygenase (AGMO), the only enzyme known to cleave the O-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.

Animals↗
PubMed1987

Substrate specificity of O-alkylglycerol monooxygenase (E.C. 1.14.16.5), solubilized from rat liver microsomes.

Synthetic alkyl lysophospholipids (ALP) show antineoplastic activity. In the present discussion, the cytotoxicity of ALP is attributed to their accumulation in tumor cells. Some neoplastic cell species, in contrast to normal cells, cannot metabolize ALP because of a lack of O-alkylglycerol monooxygenase (AGMO) activity. To understand the metabolic fate of ether lipids and ether-linked phospholipids, AGMO substrate specificity studies were undertaken. Thirty-five different natural and synthetic ether lipids and their metabolites (including a thioether) were tested as substrates for AGMO. The study revealed that the potent cytostatic substance, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine is not a substrate for AGMO. Therefore, its selective toxicity to tumor cells cannot be based on the differences in direct detoxification of 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine by AGMO in normal and malignant cells. However, 1-O-octadecyl-2-O-methyl-rac-glycerol, which can be formed by phospholipase C hydrolysis, is a good substrate for AGMO.

Animals↗
PubMed1987

Metabolism of ether phospholipids and analogs in neoplastic cells.

The 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 was 3H-labeled in the methyl-choline groups, showed a formation of labeled (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.

Animals↗
PubMed1987

Effect of synthetic phospholipids on platelet aggregation and serotonin release.

1-O-Hexadecyl-2-O-acetyl-sn-glycero-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-octadecyl-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 of 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.

Blood Platelets↗
PubMed1987

Cytotoxic effects of ether lipids and derivatives in human nonneoplastic bone marrow cells and leukemic cells in vitro.

The effects of 2-lysophosphatidylcholine (2-LPC), the alkyl lysophospholipid derivatives (ALP) 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) and 1-O-hexadecyl-sn-glycero-3-phospho-trimethyl-ammonio-hexanol, the 2-acetamide analog of platelet-activating factor (PAF) 1-O-octadecyl-2-acetamide-sn-glycero-3-phosphocholine, the thioether lysophospholipid derivative (TLP) BM 41.440 and the ether-linked lipoidal amine CP-46,665 on tritiated thymidine uptake and trypan blue dye exclusion were tested in vitro in various freshly explanted cell samples from human nonneoplastic bone marrow and human leukemias. In both assay systems, a dose range of 1-20 micrograms/ml of the compounds was tested after 24, 48 and 72 hr of coincubation with the cells. The trypan blue dye exclusion revealed statistically significant preferential cytotoxicity in leukemic cells for three compounds with the order of quantitative selectiveness: ET-18-OCH3 greater than BM41.440 greater than 2-acetamide analog of PAF. CP-46,665 was the most toxic compound, but did not reveal significant differences between nonneoplastic bone marrow and leukemic cells when added in concentrations greater than 1 microgram/ml. The trimethyl-ammonio-hexanol compound showed only minor activity in the majority of tests, when added at concentrations less than 20 micrograms/ml. 2-LPC was rather ineffective. The tritiated thymidine uptake showed only preferential antiproliferative effects towards leukemic cells of ET-18-OCH3 and, sometimes, within the dose time frame tested of BM 41.440. All compounds tested except 2-LPC and the trimethyl-ammonio-hexanol compound were active also in this assay (inhibition of uptake greater than 50% of the controls).(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1987

Structure-cytotoxicity studies on alkyl lysophospholipids and some analogs in leukemic blasts of human origin in vitro.

Eleven 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.

Antineoplastic Agents↗
PubMed1987

Distribution and metabolism of hexadecylphosphocholine in mice.

Distribution and metabolic fate of radiolabeled hexadecylphosphocholine (He-PC) has been studied in mice. It is demonstrated that He-PC is well-absorbed from the intestinal tract, intravenous (IV) and oral administration lead to similar distributions throughout the body, the highest accumulation of radioactivity occurs in liver, lung and kidney, and the metabolic products are radioactive choline, phosphocholine and 1,2-diacylphosphatidylcholine. The occurrence of these metabolites indicates that phospholipases C and D may be involved in He-PC breakdown.

Administration, Oral↗