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Results for “Drug Collateral Sensitivity”

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PubMed1997

Characterisation of novel human lung carcinoma cell lines selected for resistance to anti-neoplastic analogues of staurosporine.

The staurosporine analogues CGP 41251, UCN-01 and Ro 31-8220 are specific inhibitors of protein kinase C (PKC). CGP 41251 and UCN-01 exert anti-neoplastic activity against human tumours grown in rodents, and CGP 41251 reverses multidrug resistance. The hypothesis was tested that these agents can induce drug resistance and alter cellular levels of target kinases. Human-derived A549 lung carcinoma cells were exposed for 6 months to CGP 41251, UCN-01 or Ro 31-8220 at gradually increasing concentrations. Cells acquired resistance against these agents, 4.3-fold against CGP 41251 (A549/CGP cells), 4.0-fold against UCN-01 (A549/UCN cells) and 14-fold against Ro 31-8220 (A549/Ro cells). Cells were neither collaterally cross-resistant towards the PKC inhibitors nor resistant against the growth-inhibitory properties of 12-O-tetradecanoylphorbol-13-acetate. However, cross-resistance was observed in A549/CGP cells against staurosporine (13-fold) and in A549/Ro cells against doxorubicin (26-fold). All 3 cell types expressed multidrug resistance-associated protein, and A549/Ro cells expressed P-glycoprotein, as adjudged by Western blot analysis. Phorbol ester-stimulated PKC activity in these cells was decreased by between 57% and 96% compared to wild-type A549 cells. Levels of the PKC isoenzymes alpha and theta in all 3 resistant cell types and of PKC-epsilon in A549/UCN cells were concomitantly reduced. Cells regained drug sensitivity after culture in the absence of drug for 6 (A549/Ro cells), 5 (A549/CGP cells) and 1 (A549/UCN cells) months. Our results suggest the following features of this type of anti-signalling drug: (i) they can induce drug resistance, (ii) they may be potentially useful in combination because of the lack of cross-resistance between them and (iii) they can down-regulate PKC, which may have pharmacological or toxicological consequences.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1992

Characterization of camptothecin-resistant Chinese hamster lung cells.

Three camptothecin-resistant sublines (V79r, IRS-1r and IRS-2r) of V79 cells and their irradiation-sensitive mutants, IRS-1 and IRS-2, were developed by stepwise, continuous exposure to camptothecin (CPT). The degree of resistance varied among these cells. Based on the biochemical characterizations of these resistant cell lines, the mechanisms which could be responsible for the resistance to CPT were proposed to be: (a) a decrease in the intracellular accumulation of CPT with or without alteration of DNA topoisomerase I, (b) a decrease in the amount of DNA topoisomerase I, or (c) a decrease in the sensitivity of DNA topoisomerase I to CPT. The resistant cells which exhibited down-regulation of DNA topoisomerase I were collaterally sensitive to etoposide (VP-16) and its analogue, 4'-demethy-4 beta-(4"-fluoroanilino)-4-desoxypodophyllotoxin, despite the fact that there were equal amounts of DNA topoisomerase II in the parental and in the resistant cell lines. Alternating the usage of CPT and VP-16 for the treatment of cancer is indicated.

Animals↗

PubMed2003

Increased sensitivity to halothane but decreased sensitivity to propofol in mice lacking the N-type Ca2+ channel.

Volatile anesthetics are known to depress excitatory synaptic transmission. Inhibition of voltage-dependent Ca2+ channels is speculated to underlie this mechanism, which remains to be clarified in vivo. We examined the sensitivity to halothane in mice lacking the N-type Ca2+ channel, a major contributor of presynaptic neurotransmitter release. Sensitivity to halothane was significantly increased in the knockout mice compared with the wild-type littermates. Halothane also depressed field excitatory postsynaptic potentials recorded from the Schaffer collateral-CA1 hippocampal synapses more greatly in the knockout mice. We further examined sleep time induced by injection of propofol, an intravenous anesthetic that mainly affects inhibitory synaptic transmission. In contrast, sensitivity to propofol was significantly decreased in the knockout mice. We suggest that inhibition of the N-type Ca2+ channel underlies mechanisms of halothane anesthesia but counteracts propofol anesthesia.

Anesthetics, Inhalation↗

PubMedDate not supplied

Cisplatin-resistant human small cell lung cancer cell line shows collateral sensitivity to vinca alkaloids.

A cisplatin-resistant cell line, SBC-3/CDDP, was established from a human small-cell lung cancer cell line, SBC-3. The SBC-3/CDDP cells were 13.1-fold more resistant to cisplatin than the parent SBC-3 cells. We investigated the cellular changes of this cell line with regard to the development of resistance to cisplatin. The SBC-3/CDDP cells showed various characteristics as follows: a) increased intracellular glutathione and glutathione S-transferase content b) decreased intracellular accumulation of cisplatin, c) increased topoisomerase I activity and the same topoisomerase II activity as the parent SBC-3 cells, and 4) strong cross-resistance to the platinum analogues and mitomycin C, moderate cross-resistance to 7-ethyl-10-hydroxy-camptothecin (SN-38), 4-hydroperoxy cyclophosphamide, etoposide, Adriamycin and methotrexate, and collateral sensitivity to vinca alkaloids and 5-fluorouracil. From these observations, the SBC-3/CDDP cells could be useful as a well characterized cisplatin-resistant cell line, and the resistance pattem in this cell line will give us much information for eradication of cisplatin-resistant tumor cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

The role of the bacitracin ABC transporter in bacitracin resistance and collateral detergent sensitivity.

The bacitracin resistance of Bacillus licheniformis, a producer of bacitracin, is mediated by the ABC transporter Bcr. Bacillus subtilis cells carrying bcr genes on high-copy number plasmids developed collateral detergent sensitivity, as did human cells with overexpressed multidrug resistance P-glycoprotein. Resistance against bacitracin and sensitivity of resistant cells to detergents were shown to be inseparable phenomena associated with the membrane part of Bcr transporter, namely protein BcrC. A fused protein, consisting of ATP-binding protein BcrA and membrane component BcrC was constructed. It resembled a half molecule of P-glycoprotein and was capable of providing a significant degree of antibiotic resistance and detergent sensitivity.

ATP-Binding Cassette Transporters↗

PubMed1984

Multidrug resistance.

Mutations resulting in a complex phenotype of cross-resistance and collateral-sensitivity are frequently observed in mammalian cell lines. A cell surface 170 000 dalton glycoprotein (P-glycoprotein) has been identified to be intimately associated with this multidrug resistance phenotype. We speculate that such mutations also occur in advanced cancers and play a major role in contributing to the non-response to combination chemotherapy. In this context, P-glycoprotein may be a useful molecular marker for diagnostic and therapeutic applications.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1985

Collateral sensitivity to cross-linking agents exhibited by cultured L1210 cells resistant to oxazaphosphorines.

The sensitivity of cultured L1210 and P388 cells, sensitive (L1210/0, P388/0) and resistant (L1210/CPA, P388/CPA) to cyclophosphamide in vivo, to five oxazaphosphorine and eight nonoxazaphosphorine cross-linking agents was determined. Each of the resistant sublines was cross-resistant to all of the oxazaphosphorines tested. The P388/CPA cell line was also cross-resistant to all of the nonoxazaphosphorines but, in most cases, not nearly to the same extent. The L1210/CPA cell line was collaterally sensitive to all but one of the nonoxazaphosphorines, in which case it was equisensitive. Changes in sensitivity could not be accounted for by changes in intracellular pH values, or by changes in intracellular inorganic phosphate or acid-soluble organic phosphate concentrations. Inasmuch as the L1210/CPA cell line was specifically resistant to the oxazaphosphorines, identification of the phenotypic basis for this resistance should serve to identify a potentially important determinant with regard to the basis for the oncotoxic specificity of this group of agents.

Animals↗

PubMed1996

Electrophysiological effects of aconitine in rat hippocampal slices.

The electrophysiological effects of aconitine were investigated in the rat hippocampal slice and compared with those of veratridine. Both alkaloids are known to bind at site 2 of sodium channels and to block its inactivation. Extracellular recordings revealed that aconitine and veratridine exert inhibitory effects on neuronal excitability. Aconitine slowly and reversibly decreased the population spike recorded in the CA1 pyramidal cell layer. The reduction of the spike amplitude was similar whether orthodromically or antidromically activated. The aconitine-induced inhibition did not differ from that of veratridine. However, following washout of aconitine, the amplitude of the antidromic spike was increased compared to the control amplitude. The veratridine-induced inhibition was only partially reversible. This inhibition was also observed during suppression of synaptic transmission by a low Ca2+/high Mg2+-medium, indicating an inhibition of axonal conductance. The results show that in the absence of synaptic transmission the antidromic (alvear) spike is more sensitive to the inhibitory action of aconitine than the presynaptic fiber spike elicited by stimulation of the Schaffer collaterals. Furthermore, it is shown that aconitine acts in an activity-dependent manner, in that the latency of onset of the inhibition is prolonged when the stimulation frequency is decreased. Field excitatory postsynaptic potentials were also suppressed by aconitine, whereas excitatory postsynaptic currents recorded by the patch clamp technique were not influenced by aconitine when cells were held at -60 mV.

Aconitine↗

PubMed1979

Prophylaxis of ventricular fibrillation after acute experimental coronary occlusion by chronic beta-adrenoceptor blockade with atenolol.

Acute occlusions of the left circumflex coronary artery were performed in open-chest dogs. A control group (n = 19) was compared with three groups (total n = 17) pretreated once daily with different doses of the cardioselective beta-blocking drug atenolol (ICI 66 082) given by mouth for 5 days. Only animals without coronary collateral vessels were examined, having a mortality rate of 100% in the control group. Arrhythmias and ventricular fibrillation during the first 30 min after coronary occlusion showed a biphasic distribution in time (phase 1a and 1b). A lower degree of beta-adrenoceptor blockade reduced the incidence of arrhythmias and ventricular fibrillation in phase 1a, but fibrillation occurred in all animals during phase 1b. A higher dose of the beta-blocking drug protected the animals from ventricular fibrillation, and arrhythmias in phase 1a were greatly reduced. At all times the ventricular fibrillation threshold in the group pretreated with atenolol was significantly higher than in the control group. In both groups a significant decrease in ventricular fibrillation threshold was found only during phase 1a. The greater sensitivity of phase 1a arrhythmias to beta-blockade and the lack of a decrease in ventricular fibrillation threshold during phase 1b might indicate differences in the genesis of arrhythmias and fibrillation in phases 1a and 1b.

Animals↗

PubMed2000

Screening of novel epilepsy-related genes and isolation and identification of cDNAs.

Twenty cDNA differential fragments were isolated from the hippocampus of rats in epileptic state using mRNA differential display technique. Four fragments were sequenced and compared with the known sequences in the Genebank, which showed that ERG8, ERG11, ERG12 had no significant identity to any known sequences; ERG14 had 64%-69% identity to microtubulin-associated protein of the rat. Because the differential expression of these genes was caused by epilepsy inducer coriaria lactone (CL) and anti-epilepsy drug MK-801 and ERG8 might be a novel candidate epilepsy gene; ERG11 and ERG12 might be novel candidate anti-epilepsy genes. Since the microtubulin-associated protein is closely associated with the collateral sprouting of mossy fibers in the hippocampus of seizured rat, the high expression of ERG14 in the early stage of epilepsy might predict the growth of axon and formation of synapse.

Animals↗

PubMedDate not supplied

Arsenic trioxide circumvents multidrug resistance based on different mechanisms in human leukemia cell lines.

To determine the antitumor effect of arsenic trioxide (As2O3) on multidrug-resistant cells, we applied 3 human leukemia cell lines: daunorubicin (DNR)-resistant cell line K562/D1-9, which overexpresses p-glycoprotein (Pgp); DNR and 1-beta-D-arabinofuranosylcytosine (Ara-C) double-resistant cell line HL60/AD, which overexpresses multidrug resistance-associated protein (MRP1); and Bcl-2-transfected pre-B lineage leukemia cell line 697/Bcl-2. Interestingly, K562/D1-9 showed collateral sensitivity. Only HL60/AD showed small cross resistance, but 697/Bcl-2 had no resistance to As2O3. An intracellular content of glutathione (GSH) played a critical role in sensitivity to As2O3. Buthionine-sulfoximine (BSO), which reduces the GSH content, not only increased the As2O3 sensitivity but also conquered the MRP1-related cross resistance in HL60/AD. In conclusion, As2O3 was effective in all 3 cell lines, suggesting that As2O3 may be a promising agent for the treatment of multidrug-resistant leukemia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1995

In vitro cytotoxicity of a novel antitumor antibiotic, spicamycin derivative, in human lung cancer cell lines.

Spicamycin (SPM), produced by Streptomyces alanosinicus, induces potent differentiation in a human leukemia cell line, HL60. One of the derivatives of SPM (SPM-D), KRN5500, has a wide range of antitumor activity against human cancer cell lines. We examined the cytotoxicity of SPM-D in small and non-small cell lung cancer cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony assays. SPM-D was active against a wide range of lung cancer cell lines. All three cisplatin (CDDP)-resistant cell lines established in our laboratory (PC-9/CDDP, PC-14/CDDP, and H69/CDDP) showed collateral sensitivity to SPM-D with relative resistance values of 0.43, 0.34, and 0.32, respectively. Intracellular SPM-D in PC-14/CDDP was 35% higher than that for PC-14 suggesting that intracellular accumulation can explain the collateral sensitivity to SPM-D at least in PC-14/CDDP. On the other hand, in PC-9/CDDP cells, no increase of intracellular SPM-D accumulation was observed, but the conversion ratio of a metabolite (the amino nucleoside moiety of spicamycin binding with glycine, SAN-G) from SPM-D evaluated by TLC was higher as compared with that of parental PC-9 cells (45.5% versus 37%; PC-9/CDDP versus PC-9). The increased intracellular metabolism of SPM-D could explain the mechanism of collateral sensitivity in PC-9/CDDP cisplatin-resistant cell lines. To elucidate the determinant of the SPM-D-induced cytotoxicity, we established SPM-D-resistant cell lines, PC-9/SPM-D, PC-14/SPM-D, and H69/SPM-D, by exposing cells to stepwise increases in SPM-D concentration. The relative resistances of these sublines were more than 5000, 46.6, and 37.8 times those of the parental cell lines, respectively. The intracellular concentration of the active metabolite, SAN-G, was found to be decreased in the SPM-D-resistant sublines. This result indicates that the intracellular metabolism of SPM-D to SAN-G is one of the determinants of cellular sensitivity to SPM-D in these SPM-D-resistant cell lines. In conclusion, both drug accumulation and metabolism may contribute to the sensitivity/resistance to SPM-D and both may merit investigation.

Adenocarcinoma↗

PubMed1992

Establishment and characterization of an etoposide-resistant human small cell lung cancer cell line.

An etoposide-resistant subline, SBC-3/ETP, from a human small cell lung cancer cell line, SBC-3, was developed by continuous exposure to increasing concentrations of etoposide in culture. The SBC-3/ETP was 52.1-fold more resistant to etoposide than the parent cell line. The SBC-3/ETP was highly cross-resistant to teniposide, adriamycin, vinca alkaloids, 4-hydroperoxycyclophosphamide, CPT-11 and mitomycin C, and marginally cross-resistant to cisplatin, while the subline showed a collateral sensitivity to bleomycin. Topoisomerase I activity in the SBC-3/ETP was reduced to an extent of one half and topoisomerase II activity to an extent of one eighth in comparison with those of the SBC-3. Intracellular accumulation of [3H]-etoposide in the SBC-3/ETP was significantly lower in comparison to the SBC-3. An overexpression of MDR1 mRNA, and the presence of its product, P-glycoprotein, were detected in the SBC-3/ETP by Northern blotting and flowcytometry using a monoclonal antibody of the protein, MRK16. These results indicate that a decreased activity of topoisomerase II is the major factor for the development of etoposide resistance, and that an overexpression of the MDR1 gene is responsible, in part, for the development of resistance to the drug and some structurally unrelated compounds such as adriamycin and vinca alkaloids.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Characterization of a BMS-181174-resistant human bladder cancer cell line.

This study was undertaken to elucidate the mechanism of cellular resistance to BMS-181174, a novel analogue of mitomycin C (MMC), in a human bladder cancer cell line. The BMS-181174-resistant variant (J82/BMS) was established by repeated continuous exposures of parental cells (J82) to increasing concentrations of BMS-181174 (9-40 nM) over a period of about 17 months. A 2.6-fold higher concentration of BMS-181174 was required to kill 50% of J82/BMS cell line compared with J82. The J82/BMS cell line exhibited collateral sensitivity to 5-fluorouracil (5-FU), but was significantly more cross-resistant to MMC, melphalan, taxol, doxorubicin and VP-16. NADPH cytochrome P450 reductase and DT-diaphorase activities, which have been implicated in bioreductive activation of MMC, were significantly lower in the J82/BMS cell line than in J82. The cytotoxicity of BMS-181174, however, was not affected in either cell line by pretreatment with dicoumarol, which is an inhibitor of DT-diaphorase activity. These results argue against a role of DT-diaphorase in cellular bioactivation of BMS-181174, a conclusion consistent with that of Rockwell et al (Biochem Pharmacol, 50: 1239-1243, 1995). BMS-181174-induced DNA interstrand cross-link (DNA-ISC) frequency was markedly lower in J82/BMS cell line than in J82 at every drug concentration tested. The results of the present study suggest that cellular resistance to BMS-181174 in J82/BMS cell line may be due to reduced DNA-ISC formation. However, the mechanism of relatively lower BMS-181174 induced DNA-ISC formation in J82/BMS cell line than in parental cells remains to be clarified.

Antineoplastic Agents, Alkylating↗

PubMed1995

Psychopharmacology of central serotonergic systems.

Serotonin neurons in the rostral and caudal brainstem raphe nuclear groups give rise to collateralized ascending and descending projections which provide modulatory input into most networks throughout the entire neuraxis. The rostral raphe system is interconnected with target forebrain areas through reciprocal limbic-midbrain loops, which suggests that serotonin has a role in the regulation of complex intelligent adaptive behavior. Serotonergic pathways sensitize brainstem and spinal cord central rhythmic pattern generators which organize repetitive autonomic and motor activities, e.g. oral-buccal and nutritive behaviors, facilitate tonically active motor neurons innervating antigravity muscles, and disfacilitate somatosensory information processing. Serotonin effects are mediated by multiple receptor subtypes with distinct pre- and postsynaptic localization and regional distribution pattern. They belong to the G protein superfamily, coupling to adenylate cyclase (5-HT1,4,5,6,7) or phospholipase C (5-HT2), and to the ligand-gated ion channel superfamily (5-HT3). Drugs acting at these receptors are known to modulate various aspects of cooperative social behavior and responding latency, i.e. impulsivity, in a variety of experimental models of anxiety and depression. The clinical efficacy of the so-called selective serotonin reuptake inhibitors (SSRIs) in disorders characterized by poor impulse control, e.g. bulimia nervosa, obsessive-compulsive disorder (OCD) and violent suicidal or homicidal behavior, may likewise be due to improved responding latency.

Brain↗

PubMed1976

Some physiological alteration associated with pleiotropic cross resistance and collateral sensitivity in Saccharomyces cerevisiae.

A mutant strain (2-20) isolated by growth on medium containing oligomycin and cycloheximide was also found to be cross resistant to antimyicn, cerulenin, chloramphenicol, tetracycline, triethyltin and triphenylmethylphosphonium bromide, but collaterally sensitive to dequalinium chloride, gentamycin, neomycin, paromomycin and thiolutin. Growth of 2-20, compared to the parental strain and 2 complete revertants, under a variety of environmental conditions revealed that strain 2-20 had an enhanced sensitivity to increased osmolality, elevated pH, and high temperature; in addition, strain 2-20 was unable to polymerize aminoimidazole ribotide at 37 degrees C as shown by the failure to develop a red colony in the presence of ade 2. Four complex solid media (glucose--KCI, galactose, ethanol, ethanol--KCI, Table 1) unable to sustain the growth of strain 2-20 were arbitrarily chosen to monitor cellular growth under different physiological conditions. Tetrad analysis indicated that the complex phenotype (cross resistance, collateral sensitivity, inablity to polymerize aminoimidazole ribotide, absence of growth under adverse physiological conditions) was inherited by an allele of a locus previously shown to result in a permeability barrier of the plasma membrane to chloramphenicol. 582 of 640 subclones used to isolate revertants of 2-20, under four different physiological conditions, were observed to produce a complete revertant of the complex phenotype. It is proposed that the pleiotropic phenotype could result from an alteration of the plasma membrane and mitochondrial inner membrane by a single nuclear gene mutation.

Alleles↗

PubMed1984

Kynurenic acid as an antagonist of hippocampal excitatory transmission.

Kynurenate, an endogenous tryptophan metabolite, was bath-applied to hippocampal slices while recording extracellular synaptic field potentials. Kynurenate antagonized the medial and lateral entorhinal projections to dentate granule cells, the Schaffer collateral projections to CA1 pyramidal cells, and inputs to the CA3 stratum radiatum of regio inferior with similar potencies. Concentration-response curves for these pathways paralleled theoretical antagonist curves with a Hill coefficient of 1, and the KdS were in the range of 130-400 microM. Projections to the stratum lucidum of regio inferior were much less sensitive to kynurenate. Inputs to CA3 pyramidal cells showed varying sensitivities to kynurenate, L-2-amino-4-phosphonobutanoic acid (L-APB), and (-)-baclofen depending on the placements of the stimulating and recording electrodes. When both electrodes were located in area CA3, outside the hilus of area dentata, all responses were insensitive to inhibition by L-APB. Under these conditions, responses recorded within the stratum radiatum were sensitive to inhibition by kynurenate and baclofen, while responses recorded within the stratum lucidum were insensitive to these drugs. When the stimulating electrode was placed within the hilus of area dentata, variable patterns of sensitivity to APB, baclofen, and kynurenate were observed from recording electrodes in area CA3. These results suggest that stimulation in the hilus, while recording in the stratum lucidum, produces responses that show composite effects resulting both from direct stimulation of mossy fibers and from stimulation of neuronal elements in the hilus which produce outputs to mossy fibers.

Action Potentials↗

PubMed1993

The differential induction of collateral resistance to 62.5 MeV (p-->Be+) neutrons and 4 MeV photons by exposure to cis-platinum.

PURPOSE: To determine the relative sensitivity to cis-platinum, 4 MeV photons and 62.5 MeV (p-->Be+) neutrons in five human tumor cell lines, and their cis-platinum resistant variants. METHODS AND MATERIALS: The degree of cross-resistance of five human in-vitro cell lines to photons or fast neutrons was analysed for both cisplatinum-sensitive and resistant variants. RESULTS: The development of acquired cis-platinum resistance conferred collateral resistance to 62.5 MeV (p--Be+) neutrons in all five cell lines, but did not consistently decrease the photon sensitivity of these same cells. CONCLUSION: The reduction in photon and neutron sensitivity following the development of acquired cis-platinum resistance may possibly be regulated by different mechanisms. The reduction in neutron sensitivity was primarily due to a 1.3-1.7 fold reduction in the magnitude of the initial slope (alpha), which was independent of the degree of platinum resistance induced, suggesting a non-stochiometric relationship between the mechanisms responsible for acquired cis-platinum, and 62.5 MeV (p-->Be+) neutron resistance.

Cell Survival↗