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PubMed2001

Analysis of electron spin resonance spectra of alkyl spin labels in excised guinea pig dorsal skin, its stratum corneum, delipidized skin and stratum corneum model lipid liposomes.

The electron spin resonance (ESR) spectra of alkyl spin labels were observed in the excised guinea pig dorsal skin, its stratum corneum, delipidized skin and stratum corneum model lipid liposomes. The spectrum of 5-doxylstearic acid (5-NS) in the stratum corneum and order parameter obtained from the spectrum, indicated that the spin label was present in highly ordered lipid lamella. On the other hand, the spectrum of methyl ester of 5-NS (5-NMS) and its apparent rotational correlation time calculated from the spectrum, showed only a weakly immobilized component in the stratum corneum as well as in the whole excised skin. The ester spin label seemed to be scarcely present in the rigid lipid lamella, but mainly in the relatively fluid environment. On the other hand, cationic alkyl spin labels showed quite different spectra depending on their alkyl chain lengths. Long-chain 4-(N,N-dimethyl-N,-pentadecyl)ammonium-2,2,6,6-tetramethylpiperidine-1-oxyl (CAT-15) seemed to be present in the protein region of the stratum corneum as we recently reported, whereas hydrophilic quaternary ammonium spin label 4-trimethylammonium-2,2,6,6-tetramethylpiperidine-1-oxyl (CAT-1) seemed to be present in the bulk water of the skin, even in delipidized skin. These findings indicated that the different interaction and different localization of the alkyl spin labels depended on their electronic charge as well as their alkyl chain lengths.

Animals↗
PubMed1976

On the biosynthesis of plasmalogens during myelination in the rat. VIII[1]. Incorporation of 1-[1-14C] alkyl-2-acyl-3-sn-glycerophosphoethanolamine with different fatty acids.

The uptake of 14C labelled alkyl chains into the alkenyl chains of plasmalogens was estimated 12, 24, 48 and 72 h after intracerebral administration of different substrates to 14 day-old rats We used as substrates 1-[1-14C] alkyl-3-sn-glycerophosphoethanolamines, containing in the 2-position of the glycerol residue a stearoyl (substrate I), an oleoyl (II), an archidonoyl (III), a 4, 7, 10, 13, 16, 19-docosahexaenoyl (IV) or no acyl residue (substrate V, so-called lysoether phosphatide). 1) If the fatty acid in the 2-position of the substrate is a saturated one (as in experiment I), the recovery of radioactive alkyl chains is relatively high, but their desaturation is very slow and seems not to reach its maximum even after 72 h. 2) If a substrate with an unsaturated fatty acid in the 2-position is applied, the number of radioactive chains (alkyl plus alkenyl) depends on the chain length and/or the number of double bonds in the fatty acids. The desaturation of the alkyl chains, however, reaches its maximum about 48 h after application (except for substrate IV). 3) Not only is the recovery of radioactivity in the glycerophosphoethanolamine lipids by far the highest in experiment V at any time, but also the total activity of the alkenyl chains has already reached a maximum 24 h after application.

Animals↗
PubMedDate not supplied

Suppression of radical-induced lipid peroxidation in a model system by alkyl esters of cinnamate quaternary ammonium salts.

Three new groups of phenolic antioxidants, quaternary ammonium salts with a phenol ring and alkyl chains of different length (pyrrolidine ethyl esters of 3,5-di-t-butyl-4-hydroxydihydrocinnamic acid n-alkoxymethylchlorides (PYE-n) or n-alkylbromides (PYA-n) and 2-dimethylaminoethyl ester n-alkylbromides (PPA-n), were synthesized. Some of them were previously found to efficiently protect yeast cells against oxidants and to inhibit the production of thiobarbituric acid-reactive substances in whole yeast cells and in isolated membrane lipids. The new antioxidants (at 1-100 microM) abolished or diminished peroxidation of olive oil emulsions caused by the OH*-producing Fe2+ and RO* and ROO*-producing tert-butylhydroperoxide (TBHP) and the azo compounds 2,2'-azobis-(amidinopropane)dihydronitrile (AAPH) and 1,1'-azobis-(1-cyclohexanecarbonitrile) (ACHN): all present at 10 mM. The efficiency of individual both antioxidants was examined in relation to the type of lipid peroxidation inducer, the site of antioxidant incorporation into the emulsion lipid phase, the length of the alkyl chain, and the maximum concentration of effective antioxidant monomers given by its critical micelle concentration. PYA-n class compounds were highly efficient against all peroxidation inducers and their efficiency did not depend on the position of their molecules in the lipid phase and/or on the aliphatic chain length. In contrast, the efficiency of PYE-n and PPA-n class compounds depended both on the type of oxidant and on the length of their aliphatic chain. Their potency against Fe2+ and ACHN increased with increasing alkyl chain length whereas with AAPH it dropped with increasing alkyl chain length. A similar pattern was found with the action of PYE-n against TBHP whereas in the PPA-n group an extending alkyl chain reduced the anti-TBHP efficiency. These relationships may not be entirely straightforward and other factors (chemical nature of each compound, its possible interaction with fluorescent probes used for diagnostics, etc.) may play a considerable and not yet quite clear role. PPA-n class antioxidants have the lowest critical micelle concentration, which may limit their efficiency. Nevertheless, these phenolic antioxidants can be conveniently employed as highly efficient inhibitors of lipid peroxidation.

Antioxidants↗
PubMed1983

Blood pressure and heart rate effects of alkyl ether phospholipids in conscious renal, spontaneously hypertensive, and normotensive rats.

The blood pressure and heart rate effects of a synthetic alkyl ether phospholipid and similar lipids derived from beef heart and egg yolk were studied in normotensive, renal, and spontaneously hypertensive rats. Each agent (1.25 to 10 micrograms/kg) produced a dose-related decrease in blood pressure and increase in heart rate in each model after rapid IV injection. The degree of blood pressure lowering was dependent upon the pretreatment blood pressure. Alkyl ether phospholipid was infused at 10 to 30 micrograms/kg/min to SHR and to platelet depleted SHR; comparable effects (blood pressure decreases and heart rate increases) were noted in both models. Reversal of the epinephrine pressor response was seen in all rats. When administered orally in ascending doses on three consecutive days, 50 and 150 micrograms/kg b.i.d. doses (Day 1 and 2) were inactive whereas 500 micrograms/kg b.i.d. (Day 3) decreased blood pressure by 25 +/- 8 and 21 +/- 8 mm Hg in renal and spontaneously hypertensive rats, respectively. Side effects (by all routes) included limp, cyanotic hind limbs and sedation and were similar in SHR and platelet depleted SHR. Significant, sustained blood pressure lowering was not achieved by any of the alkyl ether phospholipids in the conscious rat models at doses devoid of limiting side effects. The results of these studies show: 1) the BP, HR, and toxic profiles of all three alkyl ether phospholipids were qualitatively similar, 2) at doses causing significant BP lowering there was epinephrine reversal suggesting an alpha-adrenergic blocking component of action, 3) the BP, HR, and toxic effect profiles of alkyl ether phospholipid were comparable in normal and platelet depleted SHR and apparently not platelet-dependent, 4) sustained antihypertensive activity could be achieved by the oral route; however the effects were modest (12 +/- 4% decrease) and associated with limiting side effects.

Animals↗
PubMed1978

Anti-riboflavin activity of 8N-alkyl analogues of roseoflavin in some Gram-positive bacteria.

Three new 8N-alkyl analogues of roseoflavin (MM), i.e., 8-ethylamino- (EH), 8-methylethylamino- (ME), 8-diethylamino-8-demethyl-D-riboflavin (EE), their tetraacetates, and 8-amino-8-demethyl-D-riboflavin (HH) tetraacetate, were synthesized. A relation between the anti-riboflavin activity and the chemical structure of 8N-alkyl analogues (8N-methyl, ethyl) was studied by a restoration by riboflavin (RF) of inhibitory effect of the analogues on a growth of Gram-positive bacteria, i.e., Sarcina lutea, Bacillus cereus, and Staphylococcus aureus. The inhibitory effect of most of the analogues was restored by RF. But in some cases, i.e., 8-methylamino-8-demethyl-D-riboflavin (MH) in Sar. lutea and MM in Staph. aureus, the effect was not completely restored. Apparently, the inhibition in early phase of growth was restored, but the maximum growth was still suppressed. The non-alkylated amino analogue (HH) showed only unrestorable suppression of maximum growth in Sar. lutea. Of restorable effect by RF of N-alkyl analogues, approximate decreasing orders of anti-RF activity were as follows. Dialkylated analogue greater than monoalkylated. HH showed insignificant anti-RF activity. In each group, methylated analogue greater than ethylated. In B. cereus monoalkylated analogues, and in Staph. aureus monoalkylated and EE showed no significant inhibitory effect. Redox potentials of the N-alkyl analogues were measured, and a definite relation between the chemical structure and the potential was found (RF = EE greater than ME greater than MM greater than HH greater than EH greater than MH). But the anti-RF activity of the analogues was not completely explained by the difference of the redox potential from RF.

Anti-Bacterial Agents↗
PubMed1997

Cladinose analogues of sixteen-membered macrolide antibiotics. III. Efficient synthesis of 4-O-alkyl-L-cladinose analogues: improved antibacterial activities compatible with pharmacokinetics.

The synthesis and biological evaluation of sixteen-membered macrolides possessing a 4-O-alkyl-alpha-L-cladinosyl moiety as a neutral sugar are described. These potent novel derivatives have been efficiently synthesized avoiding glycosylations. Two hydroxyl groups in mycarose of the tri-(tert-butyldimethylsilyl) ether intermediate were successively alkylated. Sequential deprotections of silyl groups afforded 4-O-alkyl-L-cladinose analogues and 3,4-di-O-alkyl-L-mycarose analogues of leucomycin V. Some 4-O-alkyl-L-cladinose analogues exhibited potent antibacterial activities. The most active derivative, 3"-O-methyl-4"-O-(3-methylbutyl)leucomycin V, showed improved metabolic stability in rat plasma in vitro and extremely high concentrations in serum after oral administrations in mice and in hamsters.

Animals↗
PubMed2003

Physico-chemical properties and spectrophotometric determination of biologically active 1-alkyl-2-(2-pyridyl)pyridinium bromides.

Physico-chemical properties of compounds prepared from 2,2'-bipyridine, 1-alkyl-2-(2-pyridyl)pyridinium bromides, were investigated by DC polarography and by GC-MS. Their ionization potentials were calculated. Additionally, the formation of associates with bromothymol blue and methyl orange during the spectrophotometric determination was measured. It was determined that 1-alkyl-2-(2-pyridyl)pyridinium ions are reduced by 2 one-electron steps in a DC polarography system. The reduction potentials are not related to the ionization potential values calculated for the substances investigated. The carcinogenic potential (tg alpha) of the parent compound 2,2'-bipyridine and of a series of 1-alkyl derivatives was very low indicating that the compounds are not carcinogenic. The MS fragmentation patterns indicate the low stability of the 1-alkyl substituents. It was shown that 2,2'-bipyridine is either fragmented to two pyridine ions or the--N=CH--fragments are removed. Additionally, spectrophotometric determinations of colored associates of 1-alkyl-2-(2-pyridyl)pyridinium bromides with bromothymol blue and methyl orange were investigated and the optimal condiditions for these determinations are reported.

2,2'-Dipyridyl↗
PubMed1992

Conversion of 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine to 1-O-alk-1'-enyl-2-acyl-sn-glycero-3-phosphoethanolamine. A novel pathway for the metabolism of ether-linked phosphoglycerides.

Madin Darby canine kidney (MDCK) cells convert 1-O-[3H]alkyl-2-acyl-sn-glycero-3-phosphocholine [( 3H]alkylacylGPC) to a product tentatively identified as an ethanolamine-containing phosphoglyceride (PE) (Daniel, L. W., Waite, B. M., and Wykle, R. L. (1986) J. Biol. Chem. 261, 9128-9132). In the present study, analysis of the radiolabeled phosphoglycerides as diradylglycerobenzoate derivatives indicated that [3H] alkylacylGPC was initially converted to 1-O-[3H]alkyl-2-acyl-sn-glycero-3-phosphoethanolamine [( 3H]alkylacylGPE) which was subsequently desaturated to 1-O-[3H]alk-1'-enyl-2-acyl-sn-glycero-3-phosphoethanolamine [( 3H]alkenylacylGPE). The conversion of [3H]/[32P]alkyl-lysoGPC to [3H]alkenylacylGPE indicated that base exchange enzymes were not involved in this pathway. A phosphono analog of alkyl-lysoGPC, resistant to phospholipase D hydrolysis and radiolabeled in the 1-O-alkyl chain was readily incorporated, acylated, and subsequently metabolized to [3H]alkylacylGPC and [3H]alkenylacylGPE. Therefore, the involvement of phospholipase D in the conversion pathway was ruled out. The conversion of [3H]alkylacylGPC or its phosphono analog to [3H]alkenylacylGPE was significantly enhanced by the addition of 100 microM ethanolamine to the culture media, suggesting that [3H]alkylacylglycerol is an intermediate in the cytidine-dependent pathway of PE synthesis. MDCK cell cytosol and microsomes contained no detectable phospholipase C activity. However, incubation of microsomes with CMP resulted in the degradation of [3H]alkylacylGPC and accumulation of [3H]alkylacylglycerol. Furthermore, the addition of CDP-ethanolamine to microsomes following preincubation with CMP, resulted in a decrease in [3H]alkylacylglycerol with a concomitant increase in [3H]alkenylacylGPE. Overall, these results suggest that the reverse reaction of choline phosphotransferase may be responsible for the conversion of alkylacylGPC to alkylacylGPE.

Animals↗
PubMed1992

Nonresponsiveness of the rat liver to alkylating carcinogens given by gavage.

Carcinogenic alkylating agents administered orally are metabolized in the liver and alkylate DNA in liver cells of rats and hamsters. They frequently, but not always, induce liver tumors, in addition to tumors of other organs. Directly acting alkylating agents, such as alkylnitrosoureas and alkylnitrosocarbamates, rarely induce liver tumors, although they alkylate DNA in liver cells. The methylating agents nitrosodimethylamine and azoxymethane induce high incidences of liver tumors in rats when given in drinking water, but few or no liver tumors when given by gavage, although the total dose and the weekly dose were the same in either regimen. In contrast, methylnitrosoethylamine and nitrosodiethylamine give rise to liver tumors in rats in high incidences whether given by gavage or in drinking water. Sharp differences are also observed with other nitrosamines, such as those containing a propyl group with an oxygen substituent in the 2-position. These discrepancies indicate that, in addition to alkylation of DNA, pharmacokinetics of dosing and distribution and other reactions of the carcinogen are the dominant factors in determining the development of tumors in the liver.

Administration, Oral↗
PubMed1991

Lonidamine as a modulator of alkylating agent activity in vitro and in vivo.

We are searching for relatively nontoxic compounds that can positively modulate the efficacy of antitumor alkylating agents. Lonidamine inhibits cellular energy metabolism and could potentially increase damage by alkylating agents if cellular defenses are energy requiring. Exposure of cells to lonidamine (500 microM) for 2 h under hypoxic conditions followed by 1-h exposures to lonidamine plus alkylating agents under normally oxygenated conditions in vitro significantly increased the cell kill achieved by cis-diamminedichloroplatinum(II) (CDDP) approximately 5-fold and by D-tetraplatin approximately 10-fold at 90% inhibitory concentration in MCF-7/CDDP (CDDP-resistant) cells. Carboplatin cytotoxicity, however, was little changed. In the MCF-7 parent cell line, treatment with lonidamine increased CDDP cytotoxicity by approximately 10-fold, D-tetraplatin by approximately 10-fold, and carboplatin by approximately 8-fold at the 90% inhibitory concentration. For L-phenylalanine mustard (melphalan), N,N',N"-triethylenethiophosphoramide (thiotepa), and N,N'-bis(2-chloroethyl)-N-nitrosourea, little resistance was evident in the MCF-7/CDDP lines compared with the parent line. Treatment with lonidamine increased the cytotoxicity of each drug by 1.5- to 3-fold in both cell lines. When exposure to lonidamine was extended to 24 h before and 12 h after drug exposure in MCF-7 normally oxygenated cultures, CDDP (250 microM) cytotoxicity was increased by approximately 100-fold, but melphalan cytotoxicity was increased only 2- to 3-fold over the concentration range tested. In the FSaIIC murine fibrosarcoma tumor system, five i.p. injections of 50 mg/kg of lonidamine over 36 h increased the tumor cell kill by CDDP and carboplatin approximately 2- to 3-fold over the dose range tested when the platinum complexes were given i.p. immediately after the third lonidamine injection. When cyclophosphamide and thiotepa were given in the same schedule, 10-fold increases in tumor cell killing were evident on tumor excision assay over the dosage ranges. The increase in bone marrow toxicity caused by lonidamine in addition to the alkylating agents was less than for tumor cells. Finally, in the EMT6 murine mammary carcinoma, use of lonidamine at 500 mg/kg twice daily along with CDDP, carboplatin, thiotepa, and cyclophosphamide significantly increased tumor growth delays by approximately 1.6- to 3.0-fold. The results suggest that lonidamine can positively modulate antitumor alkylating agent cytotoxicity and may be a clinically useful adjunctive therapy with these drugs.

Animals↗
PubMedDate not supplied

[Reaction ability and alkylation kinetics of sulfhydride groups of soluble succinate dehydrogenase].

Inhibition kinetics of succinate--an acceptor of oxidoreductase activity of soluble succinate dehydrogenase by N-ethylmaleimide is studied. The alkylation reaction is described by the kinetic equation of the first order, its stechiometric coefficient being 1. The binding of enzyme sulphhydride groups by p-chloromercuriumbenzoate blocks the enzyme alkylation and its inhibition by oxaloacetate. Succinate protects succinate dehydrogenase from the inhibitory effect of N-ethylmaleimide. The reaction of the enzyme with an alkylating agent in the presence of different substrate concentrations corresponds kinetically to the model, according to which a sulphhydride group acts in the active site of the enzyme. pKa of this group is 7.0 at 20degreesC. The dependency of the maximal substrate oxidation reaction rate and that of the enzyme alkylation rate on pH coinside at the pH range 5.8--7.8. The presence of anions in the alkylation medium decreases the reaction ability of the active site with respect to N-ethylmaleimide. A mechanism of the initial stage of succinate oxidation with the cooperation of the sulphhydride group of the enzyme active site is postulated.

Binding Sites↗
PubMed1988

Modification of cell surface carbohydrates and invasive behavior by an alkyl lysophospholipid.

The effect of the alkyl lysophospholipid racemic-1-O-octadecyl-2-O-methyl glycero-3-phosphocholine on the expression of cell surface carbohydrates of four matched pairs of normal and malignant cells was studied using chromatographic techniques. After treatment with alkyl lysophospholipid, glycopeptides proteolytically derived from normal and malignant cells displayed a shift in the size distribution profiles obtained by gel filtration. These drug-induced changes in molecular weight distribution were expressed most strongly in untransformed cells and resembled the carbohydrate alterations found after their malignant transformation. Desialylation abolished the effect of alkyl lysophospholipid, thus suggesting an increased amount of sialic acid in the surface carbohydrates of drug-treated cells. Chromatography of glycopeptides on concanavalin A-Sepharose, Ricinus communis agglutinin I-agarose, and Bio-Gel P-4 columns excluded a higher degree of branching but suggested addition of extra terminal sialic acid residues as the major cause of the observed alterations. Alkyl lysophospholipid stimulated glycoprotein sialylation of normal cells to the level observed in malignant cells, thus inducing a "malignant-like" surface phenotype. The drug-induced carbohydrate changes in normal chick heart tissue prevented its being invaded by tumor cells when tested in an organotypic assay. The alkyl lysophospholipid thus appears to modulate in a nontoxic fashion the expression of surface molecules implicated in various cellular interactions including invasiveness.

Animals↗
PubMedDate not supplied

Difference in effects of alkyl-lysophospholipids and verapamil on vincristine transport in vincristine-sensitive and -resistant human myelogenous leukemia K562.

Several kinds of alkyl-lysophospholipids enhanced the accumulation of vincristine (VCR) in both drug-sensitive and -resistant K562 cells. The drugs also augmented the efflux of VCR from the tumor cells. It is assumed that alkyl-lysophospholipids made tumor cells permeable to both the influx and efflux of VCR. The alkyl-lysophospholipids produced nonspecific effects of almost equal intensity in both sensitive and resistant tumor cells. These effects were compared with those of verapamil, a calcium channel blocker. Verapamil, as reported previously, specifically inhibited the efflux of drugs from tumor cells, especially drug-resistant tumor cells, thereby enhancing the accumulation of antitumor agents in the cells. Thus the actions of alkyl-lysophospholipids and verapamil in tumor cells were obviously different. Furthermore, the combined effects of alkyl-lysophospholipids and verapamil were additive or synergistic, indicating that their sites of action may be different.

Cell Line↗
PubMed1986

A novel nontoxic alkyl-phospholipid with selective antitumor activity, plasmanyl-(N-acyl)-ethanolamine (PNAE), isolated from degenerating chick embryonal tissues and from an anticancer biopreparation cACPL.

A novel alkyl-phospholipid with selective antitumor activity was isolated from an anticancer biopreparation cACPL (crude anticancer phospholipids) and from tissues of degenerating chick embryos. The alkyl-phospholipid was isolated and purified by chromatographic methods using silicic acid column chromatography and thin layer chromatography. The chemical structure of the alkyl-phospholipid was characterized by thin-layer chromatographic analysis of the degradation products after enzymatic digestion with phospholipase C from Bacillus cereus and with phospholipase D, by two-dimensional thin-layer chromatography, infrared spectrum, and mass spectrometric analysis. The alkyl-phospholipid was identified as 1-O-alkyl-2-acyl-sn-glycero-3-phospho-(N-acyl)-ethanolamine, i.e. plasmanyl-(N-acyl)-ethanolamine (PNAE), the main molecular species being 1-O-octadecyl-2-oleoyl-sn-glycero-3-phospho-(N-palmitoyl)-ethanol-amine. PNAE exhibits a selective cytolytic effect on human tumor cells HEp-2, HeLa and T24 in tissue cultures at the concentration of 25 micrograms PNAE per ml and 66-98% inhibition of DNA synthesis in the human tumor cells at concentration as low as 2.5 micrograms/ml, but it does not inhibit at a 50-fold higher concentration the DNA synthesis and normal growth of human fibroblasts (cell line LEP). PNAE represents the main biologically active antitumor component of the cACPL biopreparation and exhibits a significant antitumor effect in vivo in B10/An mice bearing Mc11 fibrosarcoma. Possible molecular mechanism of the selective antitumor activity of PNAE is discussed, involving the selective disturbance of phospholipid metabolism in tumor cells, leading to progressive destruction of tumor cell membranes. The fact that PNAE is nontoxic and selectively active against tumor cells at nanomolar concentrations in vitro as well as in vivo, indicates the possibility of its clinical use. PNAE and cACPL biopreparation might provide a very useful new tool for human anticancer chemotherapy.

Animals↗
PubMed1985

Effects of new N-alkyl analogues of adriamycin on in vitro survival and cell cycle progression of L1210 cells.

The effects of N-benzyladriamycin-14-valerate (AD198) and N,N-dimethyladriamycin-14-valerate (AD199), two novel lipophilic N-alkyl derivatives of Adriamycin (ADR), on cell growth and cell cycle distribution were investigated in L1210 cells grown in suspension. Following a 1-h exposure to the drug levels selected, growth inhibition was noticeable in all cultures for most or all of the observation period of 96 h. With flow cytometry, an asynchronous cell population was measured with respect to cellular DNA, RNA, and light scatter (size) properties following a 1-h incubation with the various ADR analogues. In addition, flow cytometric techniques were utilized to determine whether drug treatment altered the sensitivity of DNA in situ to acid-induced denaturation or to binding by small DNA-intercalating dyes. Unlike the parent compound ADR or its DNA-nonbinding derivative N-trifluoroacetyladriamycin-14-O-hemiadipate (AD143), the N-alkyl derivatives AD198 and AD199 only slightly affected L1210 cell cycle traverse over the first 5 h posttreatment. However, by 24 h, AD199 (0.62 micrograms/ml) caused an S- and G2 + M-phase accumulation which became more dramatic at 48 and 72 h. AD198 (3.27 micrograms/ml) also caused an accumulation of cells predominantly in G2 + M phase at longer culture times (48 to 96 h). The two half-substituted congeners N-benzyladriamycin (AD288) and N,N-dimethyladriamycin (AD280) affected L1210 cell cycle traverse over a similar time scale at concentrations of 12.3 and 4.17 micrograms/ml, respectively. AD280 blocked cells in G1 and G2 + M whereas AD288 caused predominantly a G2 + M accumulation. While neither ADR nor AD143 interfered appreciably with binding and fluorescence of the intercalating dye acridine orange, all of the N-alkyl analogues tested reduced the fluorescence signal of acridine orange-stained L1210 cells by 26 to 60%. This effect lasted, with decreasing intensity, for at least 48 h following a 1-h exposure to the drugs. In addition, while ADR appeared to stabilize DNA in situ against acid-induced denaturation, all N-alkyl derivatives, to varying degrees, tended to increase DNA denaturability. Thus alkylation at the glycoside amine combined with the lipophilic 14-valerate side chain function accounts for several new biochemical and biological properties of AD198 and AD199, relative to ADR.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1979

Disturbance of phospholipid metabolism during the selective destruction of tumor cells induced by alkyl-lysophospholipids.

Alkyl-lysophospholipids inhibit the growth of Meth A sarcoma cells in vitro. In contrast, murine bone marrow macrophages are not sensitive to the destructive effect of these substances. Since alkyl-lysophospholipids are antimetabolites in the synthesis of 3-sn-phosphatidylcholine, tumor cell destruction can be correlated with the disturbance of this metabolism. A decreased synthesis of 3-sn-phosphatidylcholine is accompanied by an increased degradation of cellular 3-sn-phosphatidylcholine in the presence of alkyl-lysophospholipids. As a consequence, endogeneously formed lysophospholipid accumulates, although the lysophospholipase is found to be stimulated. This accumulation of endogeneous lysophospholipids might be due to the fact that a high percentage of these compounds contain an alkyl bond which cannot be split by a lysophospholipase. On the other hand, the reacylation of the formed lysophospholipids is partially blocked as the lysophosphatidylcholine acyltransferase is inhibited by the added alkyllysophospholipids. An accumulation of potentially cytotoxic lysophospholipids in tumor cells might be an additional factor in the tumor cell destruction by alkyl-lysophospholipids.

Animals↗
PubMed1983

Interaction of ultrasonic hyperthermia with two alkylating agents in a murine bladder tumor.

Fischer rats bearing s.c. implants of TCT-4909 bladder tumor were treated either with ultrasonic hyperthermia (US) (44.2 degrees, 20 min) or either of two alkylating agents, thiotepa or Cytoxan (CTX) or in combinations of chemotherapeutic agent and heat at specific time intervals. Applying US 20 hr before either agent (thiotepa, 2 mg/kg i.p.; or CTX, 50 mg/kg i.p.) had a less than additive effect upon tumor growth. CTX, administered 20 hr before US, resulted in a significantly increased tumor volume-doubling time compared to CTX only. This was not true for thiotepa. With both agents, a synergistic effect was obtained when US and the agent were applied within 1 hr of each other, but the maximum was observed when the US had been applied 30 min before injection of agent. The intratumor temperature had decayed to normal at the time of injection. Radiolabeled alkylating agents injected at different times after US showed decreased uptake of label up to 20 hr after heating. Tritiated thymidine uptake was also reduced over the same period. Nuclear morphometry indicated increased nuclear condensation in parallel with the reduced uptakes described above. The data suggest that the synergism was not due to increased uptake of agent into heated tissue nor to the direct activation of alkylating activity by heat. It was demonstrated that heat had a rapid and marked inhibitory action upon DNA synthesis. This could have augmented the delayed but prolonged DNA inhibition caused by the alkylating agents to produce a synergistic effect. The apparent prolongation of the growth-inhibitory effect of CTX or thiotepa by heat may be due to the thermal inhibition of the enzymes responsible for the recovery of DNA after alkylation. The precise mechanism for the synergy may vary with the agent, the dose, the equilibrium temperature and its dwell time, and the interval between modalities. The influence of each of these parameters will require further investigation.

Animals↗
PubMedDate not supplied

[Microorganisms that break down alkyl sulfates].

The following bacteria assimilating alkyl sulphates as a sole source of carbon and energy were isolated from various substrates: Pseudomonas, Achromobacter, Flavobacterium, Citrobacter, Enterobacter. The bacteria decomposed sodium dodecyl sulphate at a high rate, and some of them, industrial preparations of alkyl sulphates. The ability to assimilate alkyl sulphates was tested in 257 collection cultures belonging to different taxonomic groups. Alkyl sulphates were found to be decomposed by heterotrophous gram-negative rod-like bacteria belonging to different families and genera. The frequency of bacteria destroying alkyl sulphates at a high rate was found most often in the Pseudomonas genus.

Bacteria↗