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E J Modest

Publications and source records attributed to E J Modest.

At least 19 recordsLinked to original sources
PubMed1995

Fate of 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET18-OME) in malignant cells, normal cells, and isolated and perfused rat liver.

Ether lipids show high specific cytotoxicity in vitro on a wide variety of experimental tumors, but only moderate activity in vivo. One reason for this lack of activity in the whole animal might be a high degree of metabolic degradation. We therefore studied the biotransformation of 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine ([3H]ET18-OMe) labeled in position 9-10 of the 1-alkyl chain, in rat plasma and erythrocytes, HL60 and K562 leukemic cells, HT29 adenocarcinoma cells, and cultured hepatocytes at 37 degrees C, and in a system of isolated and perfused rat liver. ET18-OMe and its metabolites were identified and quantified after lipid extraction and TLC separation. In tumor cells, 98% of ET18-OMe remained almost unmodified in vitro after 24-hr incubation. Plasma and erythrocytes from rats metabolized only 4-5% of the original compound in 3 hr. In cultured hepatocytes, 35% and 58.3%, respectively, of ET18-OMe was present after 6 and 24 hr as the metabolites 1-O-alkyl-2-O-methylglycerol (AMG), 1-O-alkyl-2-O-methylphosphatidic acid (AMPA), and stearyl alcohol (SA) (products of direct hydrolysis by phospholipases C and D and alkylhydrolase); phospholipids (phosphatidylcholine and phosphatidylethanolamine); and neutral lipids (products of secondary metabolism). In perfused rat liver, approximately 15% of the total radioactivity incorporated after 3 hr was distributed in metabolites as follows: 5.9% of AMPA, 5.0% of AMG, and 3.1% of SA. We conclude that the metabolism of ET18-OMe in normal tissues occurring through the same enzymes that metabolize natural lipids may partly explain the lack of effect in vivo.

Animals↗
PubMed1995

Animal cell mutants unable to take up biologically active glycerophospholipids.

We have isolated two mutant strains from the murine, macrophage-like cell line, RAW 264.7, that are resistant to the cytotoxic effects of the antineoplastic, platelet activating factor analogue, 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OMe). The mutants were isolated using a single round of selection to ensure that resistance was due to a single gene defect. These mutants, RAW.R1 and RAW.R23, are approximately 20 times more resistant to ET-18-OMe (ID50 = 15-17 microM) than the parent strain (ID50 = 0.7-1.0 microM). Resistance to ET-18-OMe was due to a 90-95% reduction in the ability to take up and accumulate this compound. The uptake of other choline glycerophospholipids (e.g., platelet activating factor and 1-acyl-2-lyso-sn-glycero-3-phosphocholine) was also severely affected. This defect was not limited to choline glycerophospholipids; the uptake of an ethanolamine glycerophospholipid (1-alkyl-2-lyso-sn-glycero-3-phosphoethanolamine) was reduced by 80%. The uptake of palmitic acid, an amphipathic molecule bearing no phosphate-containing head group, was unaffected in the mutants. There was little metabolism of ET-18-OMe by either the wild-type or mutant cells. Binding of ET-18-OMe appeared to be normal in the mutants, but internalization of pre-bound ET-18-OMe was reduced. Uptake of non-lipid ligands such as horseradish peroxidase, lucifer yellow, and transferrin was normal in the mutants demonstrating that fluid-phase and receptor-mediated endocytosis is functional. The ability to generate mutants displaying a lesion that affects the uptake of both choline and ethanolamine phospholipids demonstrates that these species are internalized by RAW cells through one common primary route or through pathways that share a common factor. These mutants, and this approach to their isolation, offer a system with which to study and define the mechanisms of glycerophospholipid uptake into macrophages as well as other cell types.

Animals↗
PubMed1994

The induction of apoptosis is a common feature of the cytotoxic action of ether-linked glycerophospholipids in human leukemic cells.

The ability of 2 recent ether-lipid derivatives, aza-phospholipids BN52205 and BN52211, to induce apoptosis in different leukemia cell lines was investigated using I-octadecyl-2-methyl-rac-glycero-3- phosphocholine (ET-18-OCH3) as a positive control. HL60, K562, Molt-4 and U937 cells were exposed for 24 hr to 20 microM of drug. The 2 aza-derivatives were as cytotoxic as ET-18-OCH3: BN52205 and BN52211 selectively induced apoptotic death in HL60, Molt-4 and U937 cells, but not in the K562-resistant cell line. Around 50% of DNA was fragmented in HL60 cells after exposure to the aza-derivatives, and 34% and 20% of DNA was fragmented in Molt-4 and U937 cells respectively. Similar results were obtained when cells were exposed to ET-18-OCH3. Our data confirm that ether lipids induce apoptosis in a variety of human leukemic cells, providing a possible explanation for their selectivity and mechanism of action.

Antineoplastic Agents↗
PubMed1994

Relationship of cell survival, drug dose, and drug uptake after 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine treatment.

The mechanisms that govern the activity and the factors that control the anticancer activity of synthetic ether lipids have not been fully elucidated. In this study, three factors were studied in relationship to cell survival after treatment with 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3): (1) exposure dose, (2) drug uptake, and (3) cell density and cell-cycle distribution. In BG-1 human ovarian carcinoma cells, cell survival was an exponential function of exposure dose and was dependent on drug concentration. Drug uptake was dependent on the concentration of ET-18-OCH3, whereas the reduction in cell survival was directly related to the uptake of drug only in the first decade of cell kill. When the quantity of cells per flask was tripled from 4 to 12 x 10(6) cells, ET-18-OCH3 failed to induce a G2 block. Furthermore, the cell kill induced by a 72-h exposure to 2 microM ET-18-OCH3 was decreased by a factor of 2 when the cell density increased. Therefore, exposure dose and cell density are important parameters in determining the cell kill induced by ET-18-OCH3.

Antineoplastic Agents↗
PubMed1994

Superoxide production by macrophages stimulated in vivo with synthetic ether lipids.

The anticancer activity of synthetic ether lipids may depend in part upon their ability to activate cells of the monocyte/macrophage lineage. In the present study, we have sought to determine whether 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OMe) and related ether lipids enhance superoxide production by mouse peritoneal macrophages. Ether lipids were administered intraperitoneally to C57BL/6 mice 4 d after injection with thioglycollate broth. Elicited peritoneal macrophages were harvested and purified one day later, and superoxide production was detected by measuring the superoxide dismutase inhibitable reduction of cytochrome c. Low levels of superoxide were secreted by macrophages in the absence of phorbol 12-myristate 13-acetate (PMA). When PMA was added in vitro to macrophages from ET-18-OMe-treated mice, these cells secreted 194.2 nmol superoxide/mg protein in comparison to 53.5 nmol superoxide/mg protein for PMA-treated control cells. The in vitro treatment of the macrophages with ET-18-OMe was not effective in stimulating superoxide secretion. Macrophages harvested from mice treated with a series of ether lipids (with and without phosphorus) were examined, and superoxide secretion was found to vary with structure. AM-18-OEt and CP-7 were the most effective compounds, secreting 8.6 and 11.9 times more superoxide, respectively, than PMA-stimulated control cells. Moreover, direct cytotoxicity of the compounds for HL60 human promyelocytic leukemic cells did not necessarily correlate with the ability of each drug to increase macrophage superoxide production.

Animals↗
PubMed1993

Inhibition of the signalling enzyme phosphatidylinositol-3-kinase by antitumor ether lipid analogues.

Phosphatidylinositol-3-kinase (PtdIns-3-kinase) is an enzyme found associated with many growth factor receptor protein tyrosine kinases and oncogene protein tyrosine kinases. PtdIns-3-kinase appears to be important for mitogenesis and the malignant transformation of cells. The antitumor ether lipid analogue, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3), was found to be an inhibitor of Swiss mouse 3T3 fibroblast and bovine brain PtdIns-3-kinases. The concentration of ET-18-OCH3 causing 50% inhibition (IC50) was 35 microM. The inhibition of PtdIns-3-kinase by ET-18-OCH3 was noncompetitive with ATP. Other antitumor ether lipid analogues also inhibited PtdIns-3-kinase. The cyclic ether lipid analogue (+/-)-2-(hydroxy[tetrahydro-2-(octadecyloxy)methylfuran-2- yl]methoxyl)phosphinyloxy,N,N,N-trimethyethaniminium hydroxide inhibited with an IC50 of 42 microM and hexadexylphosphocholine with an IC50 of 48 microM. 1-O-Octadecyl-2-O-methyl-rac-3-glycerophospho-myo- inositol was a weaker inhibitor of PtdIns-3-kinase, with an IC50 of 96 microM and was itself phosphorylated by the enzyme. Lipid extracted from cells grown with ET-18-OCH3 for 18 h showed inhibition of PtdIns-3-kinase with endogenous PtdIns as substrate, with an ET-18-OCH3 IC50 of 18 microM. ET-18-OCH3 inhibited platelet-derived growth factor-stimulated phosphatidylinositol-3-phosphate formation by v-sis NIH 3T3 cells with an IC50 of 12.5 microM. The results of the study suggest that inhibition of PtdIns-3-kinase might contribute to the antiproliferative activity of the antitumor ether lipid analogues.

3T3 Cells↗
PubMed1993

Synthesis of phosphocholine and quaternary amine ether lipids and evaluation of in vitro antineoplastic activity.

The in vitro antineoplastic activity of many phosphorus-containing (e.g., phosphocholines) and non-phosphorus-containing (e.g., quaternary ammonium salts) ether lipids has been evaluated in the HL-60 promyelocytic cell line. These compounds are analogues of ET-18-OMe (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine). Structural modification of 1-(alkylamido)-, -(alkylthio)-, and -(alkyloxy)propyl backbones has provided further insight into the structure-activity relationships of these lipids. In this study, a long saturated C-1 chain and a three-carbon backbone with a single short C-2 substituent were preferred. At the positively charged nitrogen of phosphocholines, fewer than three substituents caused a significant loss of activity, and substituents larger than methyl decreased activity slightly. In the nonphosphorus compounds, many nitrogen heterocycles and also a sulfonium moiety were incorporated without changing the degree of activity; however, a thiazolium group decreased activity. The most active compound, 29 [N-[3-(hexadecyloxy)-2-methoxypropyl]-3-(hydroxymethyl)pyridinium bromide], was approximately twice as active as the reference standard, ET-18-OMe, in a trypan blue dye exclusion assay.

Antineoplastic Agents↗
PubMed1993

Unidirectional membrane uptake of the ether lipid antineoplastic agent edelfosine by L1210 cells.

We have studied the cellular uptake of edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine; ET-18-OCH3), a membrane active anticancer drug of the ether lipid family, by L1210 murine leukemia cells. Initial unidirectional linear uptake velocity was 1.1 nmol/min per 2 x 10(6) cells; at about 30 min it reached a steady-state phase of accumulation of approximately 5 nmol/2 x 10(6) cells. Concentration studies indicated no saturation kinetics from 0 to 40 microM. Studies with metabolic inhibitors displayed no energy dependence. There was no effect of chloroquine, monensin or cytochalasin B, which are known inhibitors of endocytosis. The inhibitory effect of lower temperature on uptake was moderate in extent and compatible with passive diffusion. There was no efflux of drug from preloaded cells which indicates intense binding of incorporated drug to cells. In human serum, edelfosine bound to several protein components, primarily high density lipoprotein and albumin, and this may explain why cellular uptake was slowed considerably by the presence of serum or albumin in the incubation medium. We conclude that the lipophilic ether lipid derivative edelfosine is taken up by passive diffusion by the L1210 cell. It is tightly bound to cellular structures, probably by insertion into the membrane lipid bilayer.

Animals↗
PubMed1993

Induction of apoptosis in human leukemic cells by the ether lipid 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine. A possible basis for its selective action.

Ether-linked glycerophospholipids (ether lipids, EL) are membrane-interactive drugs selectively cytotoxic toward neoplastic cells compared with normal cells. No conclusive explanation has yet been provided for this selectivity. We now present data indicating that the drug 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OMe) induces apoptosis, or programmed cell death, in human leukemic cells. Apoptotic death is induced selectively by ET-18-OMe in HL60 cells, which are sensitive to the drug's cytotoxic action, but not in the resistant K562 cell line. Enrichment of HL60 cells with cholesterol (HL60-CHOL cells) significantly protects the cells from the cytotoxic effect and from the induction of apoptosis by ET-18-OMe; the percentage of fragmented DNA is only 17% for HL60-CHOL, compared with 50% in native HL60 cells after exposure to 20 microns ET-18-OMe for 24 hr. Our study provides a possible explanation for differences in sensitivity to EL among different cell types and illustrates an indirect interaction of EL with cellular DNA.

Antineoplastic Agents↗
PubMed1993

The effect of culture medium composition on ether lipid cytotoxic activity.

The effect of a serum-free medium (TNB-100), compared to RPMI 1640 containing 10% fetal bovine serum (FBS), on the lipid composition of HL60 and K562 leukemic cells was investigated. The 10% FBS RPMI medium contained approximately three times more phospholipids (PL), about three times more protein and eight times more cholesterol (CHOL) than did the TNB-100 medium. Cells cultured in TNB-100 medium, referred to as HL60-TNB and K562-TNB cells, were significantly lower in PL and CHOL than 10% FBS RPMI cells, with about a threefold higher PL-to-CHOL ratio; however, these cells were significantly higher in protein content. Cells grown in TNB-100 were also significantly more fluid than 10% FBS RPMI cells and were more sensitive to the fluidizing action of the ether lipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine. The 50% inhibitory dose of the drug was about 50% lower in TNB-grown cells than in 10% FBS RPMI cells.

Cholesterol↗
PubMed1992

Membrane lipid modification and sensitivity of leukemic cells to the thioether lipid analogue BM 41.440.

Since the ether lipid anticancer drugs are membrane targeted, we examined the effect of membrane lipid structural alteration on their cytotoxicity. Enrichment with docosahexaenoic acid increased the sensitivity to the thioether lipid BM 41.440, compared to control cells enriched with oleic acid. The effect was dependent upon drug concentration, time, and the extent of cellular fatty acid enrichment. Other polyunsaturated fatty acids had a similar effect, which was proportional to the degree of unsaturation of the molecule inserted. Depletion of cellular glutathione with buthionine sulfoximine increased the sensitivity to ether lipid, but prooxidants such as Fe2+ and antioxidants such as vitamin E had little effect. The addition of serum to the incubation medium markedly diminished the cytotoxicity of ether lipids for cells modified with both docosahexaenoic acid and oleic acid, probably due to binding of the drug to serum components. The toxicity of another ether lipid, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, was not affected appreciably by membrane alteration. Drug uptake studies with a radiolabeled BM 41.440 analogue, 1-[3H]hexadecylthio-2-ethyl-rac- glycero-3-phosphocholine, demonstrated no difference in transport at early time points and no difference in accumulation up to 60 min. We conclude that increases in cellular and/or membrane fatty acid polyunsaturation heighten the cytotoxic effect of a membrane-active ether lipid. The effect is not due to a change in drug transport or accumulation. It may be related to a change in oxidative events. These observations provide further confirmation of the membrane being the target of ether lipid action, using biochemical rather than morphological techniques. Most importantly, this observation offers a potential innovative approach to therapy.

Animals↗
PubMed1992

Selective inhibition of phosphatidylinositol phospholipase C by cytotoxic ether lipid analogues.

The ether lipid analogue 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) has been shown to be a direct inhibitor of Swiss 3T3 fibroblast and BG1 ovarian adenocarcinoma cell cytosolic phosphoinositide selective phospholipase C (PIPLC) using [3H]-phosphatidylinositol-(4, 5)-bisphosphate ([3H]PIP2) as the substrate. The inhibition occurred when ET-18-OCH3 was incorporated into the [3H]PIP2 substrate micelles, with 50% inhibition (IC50) occurring at a ET-18-OCH3: [3H]PIP2 ratio of 0.04, or an assay concentration of 0.4 microM, and when ET-18-OCH3 was added directly to the incubation, with an IC50 of 9.6 microM. Lipid prepared from cells exposed to cytotoxic concentrations of ET-18-OCH3 for 18 h also inhibited PIPLC with an IC50 less than 1 microM. The noncytotoxic analogue 1-O-alkyl-2-hydroxy-sn-glycero-3-phosphocholine inhibited PIPLC when incorporated into the [3H]PIP2 substrate micelles, but lipid from cells grown with 5 microM 1-O-alkyl-2-hydroxy-sn-glycero-3-phosphocholine did not inhibit PIPLC. BG1 cells, which were more sensitive than Swiss 3T3 fibroblasts to growth inhibition by ET-18-OCH3, had a cytosolic PIPLC activity one-third that of Swiss 3T3 cells. NIH 3T3 cells exhibited the same sensitivity to growth inhibition by ET-18-OCH3 as Swiss 3T3 cells and had a similar level of PIPLC. v-sis NIH 3T3 cells were relatively resistant (greater than 3-fold) to growth inhibition by ET-18-OCH3 and had a cytosolic PIPLC activity more than twice that of the wild type cells. ET-18-OCH3 was a weak inhibitor, IC50 greater than 100 microM, of phospholipase D activity in NIH 3T3 cell membranes. In intact NIH 3T3 cells ET-18-OCH3 at cytotoxic concentrations did not inhibit phospholipase D or phosphatidylcholine-selective phospholipase C activity. The results show that the ether lipid analogues at cytotoxic concentrations are selective inhibitors of PIPLC and that the inhibition of PIPLC may be related to the growth inhibitory activity of the ether lipid analogues.

3T3 Cells↗
PubMed1992

Modulation of ATPase activity by cholesterol and synthetic ether lipids in leukemic cells.

Synthetic ether lipids (EL) exert their antiproliferative action on leukemic cells through localization in the plasma membrane with subsequent biochemical effects which are still being elucidated. In the present study, the modulation of membrane-linked ATPase activity was investigated in relation to changes in membrane fluidity of HL60 and K562 human leukemic cells. Incubation of HL60 and K562 cells with EL under non-cytotoxic conditions caused significant membrane fluidization which was related to the membrane cholesterol (CHOL) levels. HL60 cells, which are sensitive to the cytotoxic action of EL, had a lower basal CHOL content. When HL60 cells were loaded with CHOL, Na+, K(+)-ATPase activity was reduced significantly compared to that of untreated cells. In contrast, CHOL-deprived K562 cells had twice the Na+,K(+)-ATPase activity of unmodified K562 cells. Na+K(+)- and Mg(2+)-ATPase activities were stimulated significantly in both cell lines by EL at concentrations lower than 20 microM. This stimulation was greater in cells richer in CHOL, such as K562 cells and CHOL-enriched HL60 cells. In contrast, Na+,K(+)-ATPase in both cell lines was inhibited by EL above 20 microM regardless of the CHOL content. Mg(2+)-ATPase activity was not related to cell CHOL content and was not inhibited by EL above 20 microM.

Bone Marrow↗
PubMed1991

Increased ether lipid cytotoxicity by reducing membrane cholesterol content.

Ether-linked glycerophospholipids (ether lipids, EL) are selectively toxic and anti-proliferative agents against cancer cells in vitro. The reason for such selectivity is not completely clear. Their mechanism of action is mediated through an interaction with the plasma membrane and the membrane lipid composition may modulate it. As a continuation of previous reports, we now present data showing that cholesterol concentration modulates EL toxicity in the K562, U937 and MOLT4 leukemic cell lines in vitro. Cells become sensitive to otherwise ineffective doses of EL when their cholesterol content is lowered. Cell cholesterol levels were reduced by exposure to an egg lipid mixture (neutral glycerides, phosphatidylcholine and phosphatidylethanolamine, AL721). The data contribute to an understanding of the EL mechanism of action on membranes and suggest that the cellular cholesterol concentration must be considered a major factor in modulating the cytotoxic effects of EL.

Cholesterol↗
PubMed1990

Role of cell cholesterol in modulating antineoplastic ether lipid uptake, membrane effects and cytotoxicity.

Membrane-interactive ether lipids (EL) exert toxic and antiproliferative effects on cancer cells in vitro. They appear to be selectively more toxic to cancer cells than to normal cells and thus they are ideal candidates for bone-marrow purging procedures. However, no conclusive explanation has yet been provided for this property. We now present some data indicating that the cholesterol concentration in the incubation medium modulates EL toxicity against the HL60 leukemic cell line in vitro. Furthermore, model membranes richer in cholesterol take up EL more slowly, and cell cholesterol enrichment of HL60 cells counteracts EL biophysical membrane interaction, but not toxicity, in our experimental model. However, the K562 cell line, a leukemia line less sensitive to EL toxic action, has higher levels of cell cholesterol. Our data provide evidence to explain differences in sensitivity to EL among different cell types and contribute to the understanding of the mechanism of action of EL.

Antineoplastic Agents↗
PubMed1990

Inhibition of growth factor-dependent inositol phosphate Ca2+ signaling by antitumor ether lipid analogues.

Cytotoxic ether lipid analogues have been studied for their ability to inhibit growth factor-dependent [Ca2+]i signaling in Swiss 3T3 fibroblasts. 1-Octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) inhibited 45Ca2+ uptake and inositol(1,4,5)trisphosphate-induced 45Ca2+ release in saponin permeabilized cells with concentration producing 50% inhibition values of 55 and 360 microM, respectively. When cells were exposed to ET-18-OCH3 for 18 h before permeabilization there was selective inhibition of inositol(1,4,5)trisphosphate-induced 45Ca2+ release with a concentration producing 50% inhibition value of 20 microM, but no effect on 45Ca2+ uptake, or on 45Ca2+ release by arachidonic acid. The concentration of ET-18-OCH3 with continuous exposure to inhibit cell growth 50% was 19 microM. The ether lipid analogues 1-hexadecylthio-2-ethyl-rac-glycero-3- phosphocholine and 1-S-octadecyl-2-O-methylthiopropyl-3-N,N-dimethyl-gamma-hydroxy pro pyl ammonium iodide had effects similar to those of ET-18-OCH3 but the noncytotoxic analogue 1-alkyl-2-hydroxy-sn-glycero-3- phosphocholine was without effect. Exposure of cells to 10 microM ET-18-OCH3 produced 81% inhibition of platelet-derived growth factor-stimulated inositol phosphate formation and 66% inhibition of fluoroaluminate anion-stimulated inositol phosphate formation. Addition of ET-18-OCH3 to cells in medium with 10% fetal calf serum gave a transient increase in [Ca2+]i without causing an increase in resting [Ca2+]i, while the addition of ET-18-OCH3 to cells in medium without serum gave a sustained increase in resting [Ca2+]i. Cells exposed to 5 microM ET-18-OCH3 for 18 h showed no increase in resting [Ca2+]i but there was 95% inhibition of the [Ca2+]i response to platelet-derived growth factor, 63% inhibition of the response to bradykinin, and 55% inhibition of the response to vasopressin. The block by ether lipid analogues of inositol phosphate-mediated [Ca2+]i signaling suggests a mechanism for preventing the action of growth factors that could contribute to the inhibition of cell proliferation by the agents.

Animals↗
PubMed1990

Cross-resistance pattern of cell lines selected for resistance towards different cytotoxic drugs to membrane-toxic phospholipids in vitro.

The synthetic ether lipids ET-18-OCH3 and BM41.440 and a derivative, hexadecylphosphocholine, were tested for inhibition of [3H]-thymidine uptake into a Chinese hamster ovarian cell line (AUXBl) and its multidrug-resistant subline selected for colchicine resistance (CHRC5). The activity of all three compounds against the multidrug-resistant subline was equal to or higher than that against the parent line. The same result was found for their activity against a human leukemic lymphoblastic cell line (CEM/O) and its methotrexate-resistant subline (CEM/MTX). In contrast, two multidrug-resistant cell lines selected for resistance to Adriamycin, the mouse leukemia cell line P388/ADR and the murine sarcoma cell line S180/ADR, expressed modest cross-resistance to the lipids as measured by thymidine uptake. Experiments performed using the trypan-blue dye-exclusion assay yielded comparable results, although this system revealed a slightly different sensitivity in showing the cytotoxicity of the drugs. By this assay, modest cross-resistance for ET-18-OCH3 and BM41.440 to Adriamycin was found only after 24 h incubation and decreased after 48 h incubation, with almost equal sensitivity to both drugs being shown by the parental (P388/W) and resistant lines (P388/ADR). Furthermore, findings from a human tumor-cloning assay were in accordance with these data, although they did not indicate cross-resistance for the P388/ADR cell line. These results suggest that certain ether lipids and derivatives might represent valuable anticancer drugs warranting further study in the setting of resistant disease.

Animals↗