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Biomedical subjects

C Unger

Publications and source records attributed to C Unger.

At least 127 records · Page 7Linked to original sources
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↗
PubMed1988

[Treatment of unstable thoracolumbar spinal injuries--determination of its present status and a preliminary report on transpedicular stabilization].

Follow-up checks were made on 19 patients with instabile injuries of the thoracolumbar spine. Poor late results were recorded from eleven of them who had undergone conservative or inadequate surgical treatment. Axial malposition of severe clinical disorders were among the findings. Transpedicular osteosynthesis of instable fractures of thoracic or lumbar regions of the spine has been practised by the authors since 1986, with plate fixation of only two vertebral segments. Pathoneurological disorders are handled by laminectomy or hemilaminectomy followed by H-shaped interspine bone grafting. Posterior rim fragments, burst off the spine, are either reduced or removed. Intraoperative perimyelography is possible. Therapeutic exercises are initiated immediately after the operation. After wound healing, the patient is allowed to get out of bed, supported by a plaster corset. Eleven patients have so far undergone the above surgical treatment. Four of them have resumed their original jobs, whereas three patients with paraplegia have been transferred to a rehabilitation centre.

Bone Plates↗
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

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↗
PubMed1987

Alkyl phosphocholines: toxicity and anticancer properties.

The study reports on the investigation of acute and subacute toxicity and on antineoplastic activity of hexadecylphosphocholine (HPC), the first compound of a new class of antineoplastic chemotherapeutics. In rats, the LD50 of HPC was 606 mumol/kg; the maximum tolerable dose over four weeks was 39 mumol/kg. Symptoms of toxicity were enteritis, spider cell activation in the liver, hemosiderosis in the spleen and reversible transaminase increase. The best therapeutic effect was observed on methylnitrosourea (MNU)-induced mammary carcinoma in the rat. Two transplantable mammary carcinomas in the rat and autochthonous benzo(a)pyrene-induced sarcomas exhibited low-grade sensitivity to HPC. The MXT mammary carcinoma of the mouse, the Walker 256 carcinosarcoma of the rat, and autochthonous acetoxymethylmethylnitrosamine-induced colonic tumors of the rat were not chemosensitive to HPC.

Animals↗
PubMed1987

Sensitivity of leukemia cell lines to cytotoxic alkyl-lysophospholipids in relation to O-alkyl cleavage enzyme activities.

The human leukemia cell lines K562, HL60, and Raji and the mouse leukemia cell line L1210 showed a differential susceptibility to the action of the alkyl-lysophospholipid (ALP) 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3). After 48 hours, the 50% growth-inhibition doses (ID50) of ET-18-OCH3 were found to be 0.78 microgram/ml (HL60), 1.53 microgram/ml (Raji), 4.41 micrograms/ml (K562), and 5.05 micrograms/ml (L1210), as determined by [3H]thymidine incorporation. At the same time, cell viability was determined by trypan blue exclusion and revealed median lethal doses (LD50) of 3.5 micrograms/ml (HL60), 15 micrograms/ml (Raji), 24 micrograms/ml (L1210), and 38 micrograms/ml (K562). Since O-alkyl cleavage enzyme previously was suggested as being important in the detoxification of cytotoxic ALPs, the enzyme activity was compared with the susceptibility to ET-18-OCH3 in the distinct cell lines. In comparison to an approximate sevenfold to elevenfold (ID50 and LD50, respectively) difference in the susceptibility of the above leukemia cell lines to ET-18-OCH3, no significant difference in the specific activities (0.13-0.21 nmol/min/mg) of the O-alkyl cleavage enzyme was found in the above leukemia cell lines. Therefore, the differential sensitivity of the above lines investigated cannot be explained by differences in O-alkyl cleavage enzyme activity. Experiments with radiolabeled ET-18-OCH3 in Raji cells suggest, rather, a critical role for phospholipases C and/or D in ALP metabolism.

Animals↗
PubMed1986

Aminoglutethimide. Penetration of the blood brain barrier.

The uptake of 14C-labeled aminoglutethimide 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 of aminoglutethimide after intracarotid injection was 30.7 + 2.4%. Cerebrospinal fluid/blood quotients after i.v. drug injection were 0.53 at 10 min and 0.26 at 60 min. The results of both methods clearly show that aminoglutethimide easily penetrates the blood brain barrier.

Aminoglutethimide↗
PubMed1986

Ether lipid derivatives: antineoplastic activity in vitro and the structure-activity relationship.

The antineoplastic activity of two ether lipid derivatives, the alkyl-lysophospholipid derivative (ALP) ET-18-OCH3 and the ether-linked lipoidal amine CP-46,665 was tested in a human tumor clonogenic assay (HTCA) in vitro. CP-46,665 suppressed the colony formation of various human tumors with a slight dose response relation after 1 hr incubation and with a clear optimum (85% response rate) after continuous exposure in the higher dose range tested (10 micrograms/ml). ET-18-OCH3 did not have substantial activity after 1 hr of incubation. However, when continuous exposure to the compound was used, ET-18-OCH3 seemed to have a modest dose response effect and yielded a response in about 60% of the tumor cell samples tested in the higher dose range (10 micrograms/ml). Thus, both compounds have in vitro antitumor activity in the HTCA within a dose range of 1-10 micrograms/ml, especially during continuous exposure. The tumor specific type activity was found in breast cancer, ovarian cancer, lung cancer and mesothelioma. Both compounds caused decreases in colony formation down to the 0%, 2% and 4% levels. In a comparison of specimens in which both compounds were used, only one of five times showed a discordance in sensitivity or resistance; therefore the compounds appear similar in their in vitro activity. In a second set of experiments we tested the structure-activity relationship among a variety of ALP in the [3H]thymidine incorporation assay after incubation with HL-60 leukemic blasts and other neoplastic cells from human origin.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗