Effect of alkoxyglycerols on the frequency of injuries following radiation therapy for carcinoma of the uterine cervix
Acta Obstet Gynecol Scand; 56(4):441-448 1977
he occurrence of complications of intracavitary and external radiotherapy of cervical carcinoma was studied in 657 patients given radium only (controls), 595 patients treated prophylactically with shark liver oil alkoxyglycerols (preparation AT-18: 0.6 g/day, po) before (for 7 days), during, and after (for 1-3 mo) radiotherapy, and 523 patients given a 'non-prophylactic' course of alkoxyglycerols during and after radiotherapy. The follow-up period was greater than 5 yr in 1,496 patients (including all controls) and 3.5 yr in 279 patients. Radiation damage to the bladder, ureters, intestine, and rectum and complex damage caused by tumor growth, with or without radiation injury, were studied. High-dose radium (intrauterine, greater than 100 mg; vaginal application, greater than 90 mg) caused an unexpectedly large number of radiation injuries, but this was greatly reduced by alkoxyglycerol therapy, especially prophylactic therapy. In all groups studied, prophylactic and non-prophylactic therapy greatly reduced radiation injuries. Only prophylactic therapy reduced complex damage (by about 60% in the high-dose radium group, about 67% in the total group). The data suggested that prophylactic alkoxyglycerol therapy could transform complex damage to a radiation injury by inhibiting the tumor-growth component of complex injuries. Since about 99% of the patients with complex injuries died within 5 yr, such prophylactic therapy could increase the 5-yr survival rate
In vivo radioprotective activity of Panax ginseng and diethyldithiocarbamate..
In Vivo; 7(5):467-70 1993
Studies were performed to determine whether the water fraction and the alkaloid fraction of Panax ginseng protect against radiation damage to jejunal crypts of N:GP(s) mice and induction of micronuclei (MN) in cytokinesis-blocked (CB) lymphocytes of C57BL/6 mice after in vivo irradiation with 60Co gamma-rays. The radioprotective effect of ginseng was compared with the effect of diethyldithiocarbamate (DDC). Jejunum was protected by the water fraction (2 mg/ml of drinking water) (P < 0.001) and the alkaloid fraction (5.4 mg/day, P.O.) (P < 0.005), both pre-and post-treatment, and by DDC (1000 mg/kg B.W., single I.P., 30 minutes before 15 Gy irradiation) (P < 0.001). The frequency of radiation (3 Gy)-induced micronuclei in spleen lymphocytes was also reduced by pretreatment of water fraction, alkaloid fraction of ginseng (P < 0.025) and DDC (P < 0.001). The data suggested that the water fraction and alkaloid fraction of Panax ginseng may reduce cell damage caused by gamma-rays, especially damage to DNA molecules, and play a role in the repair or regeneration process of damaged cells.
A new class of antihypertensive neutral lipid: 1-alkyl-2-acetyl-sn-glycerols, a precursor of platelet activating factor
BIOCHEM. BIOPHYS. RES. COMMUN. (USA), 1984, 118/1 (344-350)
A new type of neutral lipid is described that possesses hypotensive activity in genetic hypertensive (SHR) and normotensive (WKY) rats. 1-Alkyl-2-acetyl-sn-glycerols and 1-alkyl-2-propionyl-sn-glycerols are both equally effective in eliciting the hypotensive response. Requirement for the 1-alkyl and 2-acetyl or 2-propionyl structure of the active isomer was documented by the negative responses obtained with closely related neutral lipid analogs (1-alkyl-2-acyl-, 1-alkyl-3-acetyl-, 1-acyl-2-acetyl-, 1-alkyl-2,3-diacetyl-, and 1-alkyl-glycerols). Although less potent than PAF (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine), the 1-alkyl-2-acetyl-sn -glycerols produce a response of significantly longer duration and may have fewer immediate side effects than PAF. The mechanism for the biological activity is unknown; however, we have demonstrated previously that the enzymatic synthesis of 1-alkyl-2-acetyl-sn-glycerols to PAF occurs via a specific cholinephosphotransferase and therefore the observed blood pressure response might be due to the conversion of the neutral lipid precursor to PAF in vivo.
Metabolism of 1-O-alkyl-2-acetyl-sn-glycerol by washed rabbit platelets: Formation of platelet activating factor
ARCH. BIOCHEM. BIOPHYS. (USA), 1984, 234/1 (318-321)
A new type of neutral lipid, 1-O-alkyl-2-acetyl-sn-glycerol (AAG), induced a delayed aggregation pattern on interaction with washed rabbit platelets. Although far less potent on a molar basis than platelet activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), AGEPC, nevertheless this compound caused an aggregation, albeit delayed in time, remarkably similar to that exhibited by AGEPC. In view of the possible formation of AGEPC in this reaction, AAG was incubated with washed rabbit platelets, and a lipid corresponding in chromatographic behavior to AGEPC was isolated and identified as such by a combined gas-liquid chromatography/mass spectrometry technique coupled with selected ion monitoring.
Conversion of 1-alkyl-2-acetyl-sn-glycerols to platelet activating factor and related phospholipids by rabbit platelets
BIOCHEM. BIOPHYS. RES. COMMUN. (USA), 1984, 124/1 (156-163)
The metabolic pathway for 1-alkyl-2-acetyl-sn-glycerols, a recently discovered biologically active neutral lipid class, was elucidated in experiments conducted with rabbit platelets. The total lipid extract obtained from platelets incubated with 1-(1,2-sup 3H) alkyl-2-acetyl-sn-glycerols or 1-alkyl-2-(sup 3H)acetyl-sn-glycerols contained at least six metabolic products. The six metabolites, identified on the basis on chemical and enzymatic reactions combined with thin-layer or high-performance liquid chromatographic analyses, corresponded to 1-alkyl-sn-glycerols, 1-alkyl-2-acetyl-sn-glycero-3-phosphates, 1-alkyl-2-acetyl(long-chain)-sn-glycero-3 -phosphoethanolamines, 1-alkyl-2-acetyl-sn-glycero-3-phosphoethanolamines, 1-alkyl-2-acetyl(long-chain)-sn-glycero-3-phosphocholines, and 1-alkyl-2-acetyl-sn-glycero-3-phosphocholines (platelet activating factor). These results indicate that the metabolic pathway for alkylacetylglycols involves reaction steps catalyzed by the following enzymatic activities, choline- and ethanolamine-phosphotransferases, acetyl-hydrolase, an acyltransferase, and a phosphotransferase. The step responsible for the biosynthesis of platelet activation factor would appear to be the most important reaction in this pathway and this product could explain the hypotensive activities previously described for alkylacetyl-(or propionyl)-glycerols. Of articular interest was the preference exhibited for the utilization of the 1-hexadecyl-2-acetyl-sn-glycerol species in the formation of platelet activating factor.
Anti-neoplastic action of peritoneal macrophages following oral administration of ether analogues of lysophospholipids
EUR. J. CANCER PART A GEN. TOP. (United Kingdom), 1992, 28/10 (1637-1642)
Inflamed lesions of normal and cancerous tissues induce activation of phospholipase A in plasma membranes resulting in the release of various decomposed products of membranous lipids. Oral administration in mice of dodecylglycerol (DDG), a synthetic alkylglycerol, and an alkyl ether analogue of lysophospholipids, 1-0-octadecyl-2-0-methyl-rac-glycero-3-phosp hocholine (ET-18-OCH3-choline) efficiently activated peritoneal macrophages for enhanced Fc-mediated (fragment crystallisable) ingestion of red blood cells and direct cytotoxic action on retinoblastoma tumour cells. The activated macrophages not only inhibited tumour cell growth, but also markedly induced cytolysis of tumour cells. The antitumour capability of the macrophages was substantiated by luminol-enhanced chemiluminescence. These findings suggest that dodecylglycerol and ET-18-OCH3-choline administered orally retain their ability to induce a high level of macrophage activation and tumour cytotoxicity, just as occurs with intraperitoneal administration. Thus, these compounds have potential practical application in chemotherapy and immunotherapy of the tumour, which could be accomplished by simple oral rather than parenteral administration.
Activation of mouse macrophages by alkylglycerols, inflammation products of cancerous tissues.
Cancer Research, 1988 Nov 1, 48(21):6044-9.
Alkylglycerols, inflammation products of lipids in cancerous tissues, are potent macrophage stimulating agents. Administration of small amounts (10-100 ng) of alkylglycerols to mice greatly enhanced macrophage activation for Fc-mediated ingestion activity at the 5th day posttreatment. Dose effect analysis revealed that dodecylglycerol (DDG), one of the alkylglycerols, stimulates macrophages most effectively at the dose of 100 ng/mouse. Administration of lower concentrations of a longer carbon chained alkylglycerol, sn-3-octadecylglycerol (batyl alcohol), to mice produced a similar activation of macrophages. In vitro incubation of mouse peritoneal cells with 50 ng DDG/ml efficiently stimulated macrophages for Fc-mediated ingestion activity. However, in vitro treatment of macrophages alone with DDG was unable to stimulate ingestion activity. When a mixture of macrophages and nonadherent (B and T) cells was treated with DDG, a greatly enhanced Fc-mediated ingestion was observed at about 3 h posttreatment, suggesting that nonadherent cells contributed to the activation of macrophages. Since coincubation of these cells with DDG is required for macrophage activation, stepwise stimulation processes by exchanging signaling factor(s) among these cell types were considered for the developmental mechanism of ingestion capacity of macrophages. When a conditioned medium of DDG-treated B- or T-cells was admixed with macrophages and incubated for 3 h, no significantly enhanced ingestion activity of macrophages was observed. Thus, exchange of signaling factor(s) among B- and T-cells was analyzed by transferring conditioned media of DDG-treated B- or T-cells to untreated T- or B-cells. When the resultant (treated B-cells----untreated T-cells conditioned medium was admixed with untreated macrophages and incubated for 3 h, a markedly enhanced Fc-mediated ingestion was observed. However, no significant increase in ingestion activity was found in macrophages incubated with the treated T-cell----untreated B-cell conditioned medium. Therefore, we concluded that DDG-treated B-cells initiated macrophage activation processes by releasing and transmitting a signaling factor(s) to T-cells, and in turn the T-cells modified the factor or produced a new factor(s) capable of the ultimate stimulation of macrophages for ingestion capability.
Activation of mouse peritoneal macrophages by lysophospholipids and ether derivatives of neutral lipids and phospholipids.
Cancer Research, 1987 Apr 15, 47(8):2008-13.
Cellular damage and inflammatory processes cause activation of phospholipase A in plasma membranes resulting in the production of various lysophospholipids. Treatment of mice with L-alpha-lysophosphatidylcholine, a decomposition product of phosphatidylcholine, greatly stimulates mouse peritoneal macrophages to ingest target cells via the Fc receptors. Similarly, treatment of mice with L-alpha-lysophosphatidylethanolamine and L-alpha-lysophosphatidyl-L-serine resulted in an enhanced ingestion activity of macrophages. Cancer cell membranes contain alkyl ether derivatives of phospholipids and neutral lipids. Inflamed cancer cells release decomposition products of alkyl ether phospholipids and neutral lipids, alkyl-lysophospholipids and alkylglycerols, respectively. Administration of alkyl ether analogues of lysophospholipids into mice were able to induce stimulation of macrophages for ingestion with Fc receptor preference. Two synthetic alkylglycerols, dodecylglycerol and tridecylglycerol, were tested. Dodecylglycerol induced an efficient stimulation of macrophages for Fc-mediated ingestion whereas tridecylglycerol induced a minimal level of activation. Therefore, in vivo effect of dodecylglycerol on macrophage stimulation is similar to that of lysophospholipids and their alkyl analogues. These in vivo stimulations of macrophages for Fc receptor-mediated ingestion activity were reproduced in in vitro activation of macrophages by treatment of peritoneal cells with the alkyl lipid derivatives. Among these compounds, dodecylglycerol was found to be the most potent agent for macrophage stimulation. Since macrophages are antigen-presenting cells, the degradation products of cancer cell membrane lipids may have immune potentiating capacity.
Activation of macrophages by ether analogues of lysophospholipids.
Cancer Immunology, Immunotherapy, 1987, 25(3):185-92
Inflammation processes cause activation of phospholipase A in plasma membranes resulting in the production of various lysophospholipids. Treatment of mice with L-alpha-lysophosphatidyl-DL-glycerol (lyso-Pg) resulted in an enhanced ingestion activity of peritoneal macrophages as did other lysophospholipids. However, lyso-Pg is rather toxic as indicated by a rapid decrease in macrophage activity 3 days after treatment while macrophage activity of lysophosphatidylcholine-treated mice continued to increase at least up to the 6th day after treatment. Alkyl-lysophospholipid derivatives, racemic 1-0-octadecyl-2-methylglycero-3-phosphocholine and -phosphoethanolamine stimulated mouse macrophages for Fc-mediated ingestion. Decomposed products of alkyl-lysophospholipids, alkyl-glycerols, were also found to be excellent activators of macrophages not only for ingestion of IgG-coated target cells but also antibody-mediated tumoricidal activity. Macrophages from mice treated with alkylglycerols developed superoxide generating capacity. Furthermore, alkyl-glycerols were found to be tumoricidal by direct contact with retinoblastoma cells. Therefore, the advantage of the potential application of alkylglycerols as chemotherapeutic agents is that they have dual beneficial effects: potentiation of macrophage activity and cytotoxicity to malignant cells.
Interactions between alkylglycerols and human neutrophil granulocytes.
Scandinavian Journal of Clinical and Laboratory Investigation, 1990 Jun, 50(4):363-70
We evaluated whether various alkylglycerols would initiate a functional response of human neutrophils or modify responses induced by a formyl peptide (fMLP) in vitro. We found that platelet activating factor (PAF) was the most potent with regard to the ability to produce an oxidative response (assessed by cytochrome c reduction and/or chemiluminescence), followed by ET-16-OCH3. Lyso-PAF, ET-18-OCH3, batyl- and chimyl alcohols exhibited only a weak activity. PAF was also the most efficient lipid conferring a rise of intracellular calcium concentrations ([Ca2+]i). ET-16-OCH3, ET-18-OCH3 and lysoPAF were less potent, although maximal [Ca2+]i levels were similar to that of 0.1 mumol/l fMLP. The kinetics of the calcium responses were highly specific for each ether lipid. When neutrophils had been treated with PAF or ET-18-OCH3 and were subsequently stimulated by fMLP, enhancement of the oxidative response was noted. Thus, this study shows that there was an association between the ability of an alkylglycerol to initiate oxidative and calcium responses, indicating strict structure-activity relationships for these lipids.