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At least 19 recordsLinked to original sources
PubMedDate not supplied

Cytotoxic activity of synthetic aza alkyl lysophospholipids against drug sensitive and drug resistant human tumor cell lines.

The anti-tumor cytotoxic activity of four newly synthesized aza alkyl lysophospholipids (AALP), namely BN 52205, BN 52207, BN 52208 and BN 52211, was investigated. Using the 51Cr release assay, the four compounds were endowed with cytotoxic activity, in a concentration-dependent fashion, against various human tumor cell lines of different histological origin. Two different mechanisms appear to be involved in the AALP-mediated cytotoxicity. A rapid membrane damaging effect was observed in less than one hour's incubation of tumor cells with AALP and cytotoxicity was temperature-independent when AALP were used at greater than or equal to 200 micrograms/ml. A slower cytotoxic mechanism was observed after 18 hours incubation at 37 degrees C when AALP were used at concentrations of 30-100 micrograms/ml. The pattern and magnitube of the cytotoxic activity achieved with all the 4 AALP compounds tested were similar and the cytotoxicity mediated by combination of two compounds was additive. In addition to the cytotoxic effect, the AALP compounds also exerted a cytostatic anti-tumor effect, as assessed by inhibition of 3H TdR incorporation. Using a variety of human tumor cell lines as targets, the cytotoxic effect observed with the AALP was noted with tumor cells that were either sensitive or resistant to TNF-alpha and/or chemotherapeutic drugs such as mitomycin C, adriamycin and cis-platinum. The LD50 toxicity in mice was 100-125 mg/kg. The present findings demonstrate that AALP are cytotoxic to a variety of human tumor cell lines and do not appear to discriminate between drug/cytokine sensitive or resistant cells. Thus the present study suggests that some aza alkyl lysophospholipids may be considered as potential anticancer agents.

Drug Screening Assays, Antitumor↗
PubMed1992

Different distribution of daunomycin in plasma membranes from drug-sensitive and drug-resistant P388 leukemia cells.

When the anthracycline daunomycin (DNM) is incorporated into isolated plasma membranes from P388 murine leukemia cells, the drug partitions between 'deep' and 'surface' membrane domains. Such domains have been characterized on the basis of: (1) fluorescence resonance energy transfer between 1,6-diphenylhexa-1,3,5-triene or 1-[4-(trimethylamino)phenyl]-6-phenylhexa-1,3,5-triene as energy donors, which are well known in their positioning within the membrane, and daunomycin as the energy acceptor, and (2) quenching of the fluorescence of the membrane-associated drug by the water-soluble quencher iodide. The distribution of DNM between the two plasma membrane domains is different depending on the cellular phenotype. Thus, in membranes from drug-sensitive cells, DNM is preferentially confined to 'surface' domains, while in membranes from drug-resistant cells, the drug distributes more homogeneously between 'surface' and 'deep' domains. Experiments using artificial lipid vesicles suggest that differences in the relative levels of certain lipids in the plasma membranes from drug-sensitive and drug-resistant cells, namely phosphatidylserine and cholesterol, are partly responsible for the observed differences in the distribution of DNM. Since drug-membrane interactions are important in anthracycline cytotoxicity, it is possible that our observations on a different membrane distribution of daunomycin, may be related to the different sensitivity to the drug exhibited by these cells.

Animals↗
PubMed1990

Information from combined 1H and 31P NMR studies of cell extracts: differences in metabolism between drug-sensitive and drug-resistant MCF-7 human breast cancer cells.

Combined analysis of both 1H and 31P NMR spectra of extracts of drug-sensitive and multidrug-resistant MCF-7 human breast cancer cells enabled quantitative comparisons between the concentrations of major metabolites, as well as of their precursors. In resistant cells high energy phosphorus compounds, phosphocreatine and ATP, and also their precursors, creatine and ADP, were elevated compared to the sensitive cells. In phospholipid metabolism, the sensitive cells showed higher phosphocholine and phosphoethanolamine concentrations than the resistant cells, but choline levels were similar. These results delineated the differences in control of metabolic pathways between drug-sensitive and drug-resistant cells.

Breast Neoplasms↗
PubMed1991

Enhancement of antitumour activity of etoposide by dihydropyridines on drug-sensitive and drug-resistant leukaemia in mice.

We recently reported that six 1,4-dihydropyridine derivatives out of 57 screened effectively over-came vincristine (VCR)-resistance in VCR-resistant (P388/VCR) leukaemia-bearing mice when the dihydropyridines and VCR were administered intraperitoneally (i.p.). Furthermore, among the six dihydropyridine derivatives, two compounds, NK-250 and NK-252, most effectively overcame VCR-resistance while exhibiting relatively low calcium antagonistic activity and toxicity. In this study, we examined whether NK-250 and NK-252 could potentiate the antitumour activities of etoposide in mice with drug-sensitive (P388/S) or VCR-resistant (P388/VCR) leukaemia cells when the anticancer agents and tumour cells were administered by various routes. In both groups of mice inoculated i.p. with P388/S- and P388/VCR-leukaemia cells, the oral (p.o.) administration of NK-250 combined with i.p. or intravenously (i.v.) administration of etoposide (ip-po-ip trials and ip-po-iv trials) dramatically potentiated the antitumour activity of etoposide. Although etoposide alone was less effective in treating mice inoculated i.v. with P388/S- and P388/VCR-leukaemia cells, p.o. administration of NK-250 combined with i.p. or i.v. administration of etoposide (iv-po-ip trials and iv-po-iv trials) potentiated the antitumour activity of etoposide to similar levels as in treating mice inoculated i.p. with leukaemia cells. These 1,4-dihydropyridines were therefore highly effective in potentiating anticancer drugs against both drug-sensitive and drug-resistant tumours.

Administration, Oral↗
PubMed1975

An autoradiographic study of the binding of 3-H-chlorambucil to cells of a drug-sensitive and drug-resistant strain of the Yoshida ascites sarcoma.

The binding of chlorambucil to drug-sensitive and drug-resistant. Yoshida sarcoma cells has been investigated by an autoradiographic technique. The cells were treated with the drug at various concentrations both in vitro and in vivo. Using both light and electron microscope techniques, and by counting grains on various areas of the cell, the following conclusions were reached. (1) At all drug concentrations there was general cytoplasmic and nuclear uptake by both cell lines. There was no evidence of a specific localization in one site only or for specific exclusion of any one site. (2) At high dose levels (equivalent to 2 mM) the binding was approximately equal in both cell lines, although a few damaged cells bound much greater amounts of drug. (3) At low dose levels (equivalent to 3 mu-M) there was a higher uptake by the nucleus of the sensitive cells compared with the nucleus of the resistant cells; the cytoplasmic binding was similar.

Animals↗
PubMed1992

Rapid kinetics of the interaction between daunomycin and drug-sensitive or drug-resistant P388 leukemia cells.

The initial stages of the interaction of daunomycin (DNM) with drug-sensitive (P388/S) and drug-resistant (P388/100) cells have been defined by a rapid kinetics stopped-flow procedure. The process can be described by two kinetic components. The faster component accounts for rapid occupation of cell surface sites by DNM, as supported by experiments with liposomes with different surface charge. On the other hand, the effect of verapamil in the assays, suggests that the slower component is involved in the transport of the drug into the cells. Our observations are consistent with a loss in the control of the passive permeability to the drugs in the drug-resistant tumor cells.

Animals↗
PubMed1990

The effect of hyperthermia in combination with melphalan on drug-sensitive and drug-resistant CHO cells in vitro.

The effect of temperature on the cytotoxicity of melphalan in a pleiotropic drug-resistant mutant CHO cell line (CHR C5) and in its drug-sensitive parent (Aux B1) was studied in vitro using a clonogenic assay. The cytotoxicity of melphalan was significantly enhanced at elevated but non-lethal temperatures (39-41 degrees C) and hyperthermia potentiated the effect of melphalan in the lethal temperature range (43-44 degrees C) in both cell lines. The effect of temperature on membrane permeability to melphalan was studied to determine whether the increase in cytotoxicity was associated with increased intracellular drug levels. The uptake of 14C-labelled melphalan during 5 min increased with increasing temperature. Drug efflux, however, also increased at elevated temperatures. Intracellular drug levels at equilibrium were increased at elevated temperatures but the magnitude of this effect was small in comparison with the much larger increases in cytotoxicity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Secretion of lysosomal enzymes by drug-sensitive and multiple drug-resistant cells.

The multiple drug-resistant human lymphoblastic leukemic cell, CEM/VLB100, in which P-glycoprotein (P-170) is overexpressed, has a lowered content of lysosomal enzymes, such as N-acetylglucosaminidase and beta-galactosidase, and the relative rates of secretion of these enzymes are significantly greater than those of its drug-sensitive counterpart, CEM. The ability of CEM/VLB100 cells to accumulate [3H]vinblastine ([3H]-VLB) is also greatly reduced. Multiple drug-resistant cells whose mode of resistance is not associated with P-170 do not have reduced enzyme content, and their rate of secretion is the same as that of their drug-sensitive parents. Linkage of drug and enzyme elimination is suggested by the observation that verapamil inhibits both the efflux of [3H]VLB and the secretion of lysosomal enzymes in CEM/VLB100 cells; the content of both [3H]VLB and enzyme increases in these cells when chronically exposed to verapamil. Further, both secretion of N-acetylglucosaminidase and efflux of [3H]VLB by CEM/VLB100 cells are enhanced by the addition of NaCl to the suspending, sucrose-containing medium. When cells have taken up [3H]VLB and are then fractionated by means of a Percoll centrifugation gradient, the distribution of drug among the various populations of vesicles is similar to that of N-acetylglucosaminidase. Losses of both enzyme and drug take place from these vesicular populations to varying degrees, when CEM/VLB100 cells are induced to secrete. It is proposed that, in a multiple drug-resistant cell such as CEM/VLB100, the presence of P-170 in the plasma membrane may, in some indirect manner, lead to increased exocytosis of lysosomal enzyme, ultimately resulting in a significant depletion of enzyme. Further, a toxic, cationic drug such as vinblastine, accumulating in lysosomes and acidic vesicles, is also eliminated from the cell by exocytosis. This pathway may supplement the known, major mode of efflux directly involving P-170.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

The effect of isometamidium chloride on insect forms of drug-sensitive and drug-resistant stocks of Trypanosoma vivax: studies in vitro and in tsetse flies.

Isometamidium chloride-resistant and -sensitive Trypanosoma vivax insect forms were continuously propagated in vitro without feeder-layer cells in a semi-defined liquid medium at 27 degrees C. The effect of isometamidium chloride (Samorin) on T. vivax was assessed by monitoring the viability of epimastigotes and the production of metacyclic forms. Populations of insect forms of T. vivax stock IL 1392 and clone IL 3185 showed reduced growth and died after 10 days when cultivated in the presence of 1 ng/ml isometamidium chloride and after 6 days in the presence of 10 ng/ml. In contrast, populations of the isometamidium-resistant T. vivax stocks CP 2171 and CP 2331 continued to grow for 17 days in the presence of 1 ng/ml isometamidium chloride. The production of metacyclics was inhibited in cultures of T. vivax IL 1392 after incubation in medium containing 1 or 10 ng/ml isometamidium chloride. Epimastigotes of T. vivax CP 2171 and CP 2331 produced metacyclic forms in the presence of 1 ng/ml isometamidium chloride but not 10 ng/ml. When tsetse infected with drug-sensitive T. vivax IL 1392 were fed on a Boran steer that had previously been treated with 1 mg/kg isometamidium chloride, trypanosome infection rates were greatly reduced. In contrast, infection rates in Glossina morsitans centralis infected with drug-resistant T. vivax CP 2171 were not affected when these flies were fed on the same drug-treated animal.

Animals↗
PubMed1990

Increased drug sensitivity in the drug discrimination procedure afforded by drug versus drug training.

Rats were trained to discriminate norfenfluramine (NF) 1.4 mg/kg from its vehicle or amphetamine (AMPH) 0.8 mg/kg or pentobarbital (PB) 6.0 mg/kg in order to determine the role that drug combination training plays in the rate of learning and sensitivity to lower drug doses. The results suggest that drug versus drug training can increase the rate of drug discrimination learning for some drugs that are learned slowly when trained in a drug versus vehicle training procedure, whereas drug versus drug training does not increase the rate of learning for other drugs that are learned rapidly. Drug versus drug training does, however, appear to increase the level of stimulus control of the training drug for all drugs examined in this study.

Amphetamine↗
PubMed1992

Effects of v-src oncogene activation on radiation sensitivity in drug-sensitive and in multidrug-resistant rat fibroblasts.

Recent work has implicated the activated ras oncogene, whose gene product is a G-protein located in the plasma membrane, as well as the activated raf oncogene, whose gene product is a membrane-associated protein kinase, in contributing to radioresistance. Another transforming oncogene whose gene product is localized to the plasma membrane is v-src. We have examined a rat fibroblast line (RAT-1) infected with an avian sarcoma virus carrying a temperature-sensitive mutation in the v-src tyrosine kinase domain (LA-24). At 40 degrees C, LA-24 cells have a flat morphology and grow as a contact-inhibited monolayer, while at 35 degrees C, LA-24 cells have a transformed morphology, lose contact inhibition, grow in soft agar, and exhibit 3.5-fold higher tyrosine kinase activity. The parental RAT-1 line, not infected by the virus, grows at both temperatures as a contact-inhibited monolayer. This well-characterized system represents a good model for examining the effect of v-src transformation on radiosensitivity. RAT-1 and LA-24 cells grown at 35 and 40 degrees C were irradiated with graded doses of radiation, and clonogenic survival was assayed. For LA-24 cells grown at 35 and 40 degrees C, and for RAT-1 cells grown at 35 and 40 degrees C, calculated D0, n, alpha, and beta values did not differ significantly. To determine whether there might be differences in radiation damage repair capacity too subtle to detect by comparing radiation survival curves, sublethal damage repair capacity was assessed. There was no difference in sublethal damage repair capacity for LA-24 cells grown at 35 or 40 degrees C. Other studies have associated multidrug resistance with radioresistance. We have examined the radiation sensitivity of two colchicine-resistant LA-24 clones with four- to fivefold amplification of the P-glycoprotein gene, which are four-to fivefold more resistant to colchicine than the parental LA-24 line. In these multidrug-resistant clones, v-src activation does appear to increase radiation resistance. This did not appear to be due to alteration in cell cycle kinetics. We conclude that oncogene activation, or even protein kinase activity per se, does not necessarily lead to radiation resistance. Rather, radiation resistance following oncogene activation depends upon the oncogene and cell line studied, and perhaps upon specific protein phosphorylation.

Animals↗
PubMed1990

Effects of 2-deoxyglucose on drug-sensitive and drug-resistant human breast cancer cells: toxicity and magnetic resonance spectroscopy studies of metabolism.

The glycolytic inhibitor 2-deoxyglucose (2-DG) was tested as a potential chemotherapeutic agent for drug-resistant cancer cells. Previously it was found that Adriamycin-resistant human MCF-7 breast cancer cells (ADR) exhibit an enhanced rate of glycolysis compared to their parent wild-type (WT) cell line (R. C. Lyon et al., Cancer Res., 48: 870-877, 1987). We now describe a specific toxic effect of 2-DG on the ADR cells, which is more than 15-fold greater than for WT cells. Using 31P magnetic resonance spectroscopy of perfused MCF7 cells we continuously monitored the accumulation of 2-deoxyglucose 6-phosphate together with concomitant changes in other phosphate-containing metabolites. Kinetic measurements demonstrated that ADR cells accumulated 2-deoxyglucose 6-phosphate faster and to a greater extent than WT cells, while their depletion of high energy compounds (ATP, phosphocreatine) was more pronounced and became irreversible earlier. The phosphorylation of 2-DG could be followed more effectively by the use of 13C magnetic resonance spectroscopy of 2-DG enriched with 13C at C-6, since the signals of 2-DG and 2-deoxyglucose 6-phosphate are clearly resolved and, unlike 31P magnetic resonance spectroscopy, there are no other interfering signals. With the use of this technique with ADR and WT cells the rate of phosphorylation of 2-DG was found to be 11.2 x 10(-4) and 6.5 x 10(-4) mmol/min/mg protein, respectively. The results of these studies indicate that differences in the biochemistry of energy metabolism of resistant cells may make them targets for energy antimetabolites.

Antineoplastic Agents↗
PubMed1977

Host heme catabolism in drug-sensitive and drug-resistant malaria.

Chloroquine resistance has arisen in both human and murine forms of malaria. CR Plasmodium berghei in mice does not produce the malaria pigment which is characteristic of the CS form. Determinations of carbon monoxide production (i.e., host heme catabolism) by individual mice revealed that those infected with CS P. berghei produce only one fourth as much carbon monoxide as do CR infected mice at all levels of infection. These observations confirm the idea that malaria pigment is composed of precipitated host cell hemoglobin and suggest that drug resistance is accompanied by a basic alteration in parasite-mediated hemoglobin catabolism.

Animals↗
PubMed1991

[Drug sensitivity panel of human cancers transplanted in nude mice].

Drug sensitivities of 76 human tumor lines/nude mice to 9 anti-cancer drugs were tested. Human tumor lines include pancreas cancers, brain tumors, neuroblastomas and etc. Tested anti-cancer drugs include MMC, 5-FU, and etc. When clinically equivalent dose of anti-cancer drugs were administered, drug sensitivities of these carcinomas were well correlated with clinical one, although blood brain barrier must be considered when brain tumors were tested. Our drug sensitivity panel revealed that cancers originated from the same organ showed the same tendency of drug sensitivity. Therefore, our drug sensitivity panel is thought to be useful to know the anti-cancer spectrum of newly developed anti-cancer drugs. Our panel is also useful to study the chemotherapy of rare cancers, because clinical studies of rare cancers are difficult. Expression of P-glycoprotein is correlated with drug resistance when treated with CED, but is not correlated with those when treated with MTD (maximum tolerate dose). That is human tumor lines with P-glycoprotein detected by C219 monoclonal antibody showed resistance to ADR, VCR and VLB when treated by CED, but the relationship was not observed when treated with MTD.

Animals↗
PubMedDate not supplied

Heat sensitization to cisplatin in two cell lines with different drug sensitivities.

Heat sensitization to cisplatin was studied in drug-sensitive Chinese hamster fibroblast (CH) and inherently drug-resistant hamster kidney (HaK) cells. Under normothermic conditions the slopes of the survival curves differed by a factor of 3.6, while the cellular uptake was higher in CH cells by a factor of 3. When heat and drug treatment were given simultaneously, both effects were increased in CH and HaK cells: thermal enhancement factors at 43 degrees C were 5.5 (CH) and 2.9 (HaK) for cytotoxic drug action and 3.9 and 2.2 for the increase in cellular drug content. Increase in cell sensitization was also obtained if the cells were heat pretreated (42.5-44 degrees C for various times) followed by drug exposure at 37 degrees C. It is concluded that thermal enhancement depends on the efficiency of cisplatin cytotoxicity, which in turn correlates with cellular drug uptake in both the sensitive and resistant cell line.

Animals↗