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PubMed2000

Magnetic resonance spectroscopy of cellular lipid extracts from sensitive, resistant and reverting K562 cells and flow cytometry for investigating the P-glycoprotein function in resistance reversion.

The proton NMR spectra of K562 cells contain resonances of lipids. When these cells acquire multidrug resistance phenotype, the NMR lipid signals are modified and partially recovered when the resistance is reversed. The goals of the present study are to elucidate the mechanism of the resistance phenotype reversion and to investigate the possible origin of lipid signals detected in whole cells with proton NMR spectroscopy. Therefore, the K562 drug-sensitive cell line, its adriamycin resistant counterpart and two reverting derivates, obtained by verapamil treatment and long term culture in drug-free medium, were used in this study. The P-glycoprotein (P-gp) pump function was measured by flow cytometry and lipids were extracted to be analysed by proton and phosphorus spectroscopy. The phenotype reversion is due to the decrease of the P-gp function and an increased entrance of anthracycline drug when compared with the resistant cells. The spectra obtained on extracts showed no modification of the fatty acid composition and of the ratio of total cholesterol to fatty acid content. A different phospholipid composition in sensitive and resistant cells was found, but the reversion of resistance did not produce a recovery of these lipids. Thus, the lipid NMR spectra of extracts could not explain the spectral modifications observed on whole cells, in relation to acquiring and reverting drug resistance. These results are in favour of a different lipid organization or of localization within the cell.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Evaluation of cross-resistance between responses to cisplatin, hyperthermia, and radiation in human glioma cells and eight clones selected for cisplatin resistance.

Human glioma cells were exposed to stepwise increasing concentrations of cisplatin and given a final, acute, high concentration treatment of cisplatin. From the surviving cells, eight cisplatin resistant clones were selected. These clones demonstrated a range of cisplatin sensitivities that were retained in the absence of cisplatin when cells were continually passaged. These cells were tested for cross-resistance to radiation and hyperthermia at 42 and 45 degrees C. The data showed that seven of the eight clones were also more radioresistant than the parental line, while one was more radiosensitive. The degree of cisplatin resistance was not related to the degree of radiation resistance. For hyperthermia at 42 and 45 degrees C, some of the clones were slightly more resistant than the parental line, while one clone was much more sensitive. This was not the same clone that was radiosensitive. In conclusion, there was no direct correlation between cisplatin resistance, radiation resistance, and hyperthermia response, although some of the clones were resistant to all three treatments.

Antineoplastic Agents↗
PubMed2000

Gabapentin for drug-resistant partial epilepsy.

BACKGROUND: The majority of epileptic patients have a good prognosis and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with partial seizures. In this review we summarise the current evidence regarding a new antiepileptic drug, gabapentin, when used as an add-on treatment for drug-resistant partial epilepsy OBJECTIVES: To evaluate the efficacy and tolerability of gabapentin when used as an add-on treatment for patients with drug-resistant partial epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trial register, the Cochrane Controlled Trials Register of The Cochrane Library Issue 4, 1998. In addition, we contacted Parke Davis (manufacturers of gabapentin) and experts in the field to seek any ongoing studies or unpublished studies. SELECTION CRITERIA: Randomized placebo controlled double blind add-on trials of gabapentin in patients with drug-resistant partial epilepsy. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted the relevant data. The following outcomes were assessed: (a) 50% or greater reduction in seizure frequency; (b) treatment withdrawal (any reason); (c) side effects. Primary analyses were intention to treat. Sensitivity best and worst case analyses were also undertaken. Summary odds ratios were estimated for each outcome. Dose response was evaluated in regression models, and Number Needed to Treat (NNTs) were calculated for individual doses. MAIN RESULTS: Four trials were included representing 750 randomized patients. EFFICACY: Overall odds ratio (OR) (95% Confidence Interval (CI)) for 50% or greater reduction in seizure frequency compared to placebo 2.22 (1.49 - 3.32). Dose regression analysis shows increasing efficacy with increasing dose, with 28.5% (21.5 - 36.7) of patients responding to 1800mg of gabapentin compared to placebo, NNT 6.7 (3.0 - 10.5). Global effectiveness: treatment withdrawal OR (95% CI) compared to placebo 1.40 (0.76 - 2.55); Side effects: OR (99% CI) compared to placebo. dizziness 2.26 (1.28 - 3.99); fatigue 2.29 (1.11 - 4.74); somnolence 2.04 (1.21 - 3.45) were significanty associated with gabapentin. REVIEWER'S CONCLUSIONS: Gabapentin has efficacy as an add-on treatment in patients with drug-resistant partial epilepsy. However, trials reviewed were of relatively short duration, and provide no evidence for the long term efficacy of gabapentin. Results cannot be extrapolated to monotherapy or patients with other epilepsy types.

Acetates↗
PubMed2001

Role of glutathione S-transferase P1, P-glycoprotein and multidrug resistance-associated protein 1 in acquired doxorubicin resistance.

While P-glycoprotein (Pgp) and multidrug resistance-associated protein 1 (MRP1) are known to be important in acquired doxorubicin resistance, the role of glutathione S-transferases (GST) remains unclear. Our study assessed roles of these 3 factors in a human drug-sensitive carcinoma cell line (HEp2), a subclone made resistant by prolonged incubation in doxorubicin (HEp2A), and HEp2 cells stably transfected with human GSTP1. Drug-resistant HEp2A cells showed greater total GST activity, GSTP class enzyme expression, Pgp expression, MRP1 transcript expression, drug efflux and at least 13-fold greater resistance to doxorubicin than the parent HEp2 cell line. GSTM class enzyme expression was similar in both cell types, while GSTA class enzymes were not detected. In the resistant HEp2A cells, cytotoxicity was markedly enhanced by the Pgp/MRP inhibitor verapamil at low doxorubicin concentrations. The GST inhibitor curcumin also enhanced cytotoxicity in HEp2A cells when the Pgp/MRP efflux barrier had been reversed by verapamil or overcome by high doxorubicin concentrations. In addition, curcumin had a chemosensitising effect at low doxorubicin concentrations in HEp2 cells. Stable transfection of HEp2 cells with human GSTP1 increases doxorubicin resistance 3-fold over control cells. Our study indicates involvement of GSTP enzymes as well as efflux mechanisms in the acquired doxorubicin-resistance phenotype.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Circumvention of confluence-dependent resistance in a human multi-drug-resistant colon-cancer cell line.

Colorectal adenocarcinomas are inherently resistant to anthracyclines and other topoisomerase-II inhibitors. Resistance to doxorubicin of colon cancer cells (Caco2) depends on 2 main mechanisms. The first is typical multi-drug resistance, characterized by the mdr1 gene and its product the P170 membrane glycoprotein. P170 effluxes anthracyclines out of cancer cells and is antagonized in vitro by verapamil. The second mechanism, which develops when cell-culture density increases, we have designated confluence-dependent resistance. Confluence-dependent resistance depends on the reduced topoisomerase II content of the G0/G1-phase cells which accumulate in the confluent population. We show here that short treatments of confluent Caco2 cells with slightly toxic concentrations of DNA-damaging agents (cisplatin, melphalan or mitomycin C) produced a transient accumulation of cells in S- and G2/M-phases of the cell cycle. Concomitantly with the increase in the S-phase population, the topoisomerase II cellular level and the sensitivity of cells to doxorubicin were greatly enhanced. Overcoming confluence-dependent resistance through S-phase accumulation and inhibition of multi-drug resistance by verapamil were fully additive, and a nearly complete reversal of confluent Caco2 cells' resistance to doxorubicin was obtained when both strategies were combined.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Update on HIV resistance and resistance testing.

The introduction of highly active antiretroviral therapy, including a combination of antivirals directed at various steps in the viral life cycle, has led to significant decreases in morbidity and mortality associated with human immunodeficiency virus (HIV-1) infections. Despite the availability of numerous antivirals, many extensively treated patients gradually loose the ability to control viral replication because of development of antiviral resistance. Laboratory tests have been developed and validated to assist in recognizing such resistance and to help predict which antivirals may be more likely to control viral replication in a given patient. Both genotypic and phenotypic assays have been developed to assess HIV-1 antiviral resistance. The assay methodologies, including the advantages and disadvantages of each method, as well as the limitations of each method are reviewed. The ability to predict likely drug response from a genotype or a phenotype is continually evolving, and the more recently discovered mutation/drug resistance associations are discussed in terms of their implications for HIV resistance assays. To provide additional options for those who have developed resistance to all currently available drugs, new antivirals, such as the fusion inhibitors, are being developed. These new classes of antivirals block the HIV viral life cycle at sites other than reverse transcriptase and protease. Unique and novel resistance assays are being developed to measure HIV resistance to these new drugs.

Anti-HIV Agents↗
PubMed2001

Cross-resistance and inheritance of resistance to Bacillus thuringiensis toxin Cry1Ac in diamondback moth (Plutella xylostella L) from lowland Malaysia.

A field population of Plutella xylostella from Malaysia (SERD4) was divided into five sub-populations and four were selected (G2-G5) with the Bacillus thuringiensis insecticidal crystal (Cry) toxins Cry1Ac, Cry1Ab, Cry1Ca and Cry1Da. Bioassay at G6 gave resistance ratios of 88, 5, 2 and 3 for Cry1Ac, Cry1Ab, Cry1Ca and Cry1Da respectively compared with the unselected sub-population (UNSEL-SERD4). The Cry1Ac-selected population showed little cross-resistance to Cry1Ab, Cry1Ca and Cry1Da, (3-, 2- and 3-fold compared with UNSEL-SERD4), whereas the Cry1Ab-SEL sub-population showed marked cross-resistance to Cry1Ac (40-fold), much greater than Cry1Ab itself. In contrast, the Cry1Ca- and Cry1Da-SEL sub-population showed little if any cross-resistance to Cry1Ac and Cry1Ab. The mode of inheritance of resistance to Cry1Ac was examined in Cry1Ac-selected SERD4 by standard reciprocal crosses and back-crosses using a laboratory insecticide-susceptible population (ROTH). Logit regression analysis of F1 reciprocal crosses indicated that resistance to Cry1Ac was inherited as an incompletely dominant trait. At the highest dose of Cry1Ac tested, resistance was recessive, while at the lowest dose it was almost completely dominant. The F2 progeny from a back-cross of F1 progeny with ROTH were tested with a concentration of Cry1Ac that would kill 100% of ROTH. The mortality ranged between 50 and 95% in seven families of back-cross progeny, which indicated that more than one allele on separate loci were responsible for resistance to Cry1Ac.

Animals↗
PubMed2003

Genetic basis of resistance and studies on cross-resistance in a population of diamondback moth, Plutella xylostella (Lepidoptera: Plutellidae).

The genetic basis of abamectin resistance was studied in a strain of the diamondback moth, Plutella xylostella (L), following laboratory selection of a field population collected at Xuanhua, Hebei Province, China. Data from the testing of F1 progeny from reciprocal crosses between abamectin-resistant and abamectin-susceptible strains indicated that resistance might be autosomal and incompletely recessive with a degree of dominance of -0.13. Chi-squared analyses from the response of a backcross of crossed F1 progeny and the resistant strain and F2 progeny were highly significant, suggesting that the resistance was probably controlled by more than one gene. The results of cross-resistance studies showed that there was little cross-resistance between abamectin and four pyrethroid insecticides (deltamethrin, beta-cypermethrin, fenvalerate and bifenthrin) and no cross-resistance between abamectin and the acylureas chlorfluazuron or flufenoxuron.

Animals↗
PubMed1997

Trypanosoma brucei: lack of cross-resistance to melarsoprol in vitro by cymelarsan-resistant parasites.

We have examined cross-resistance between trypanocidal drugs using a well-characterised drug-sensitive line, 247, and its cymelarsan-resistant derivative, 247melCyR. The cymelarsan-resistant line was cross-resistant to trimelarsen and melarsen oxide, and partially cross-resistant to two diamidines, pentamidine and berenil (diminazene aceturate). It was cross-resistant to lipid-soluble melarsoprol in vivo but to only a trivial degree in two in vitro assays. The potential role of adenosine transport in arsenical-induced killing of parasites was investigated. Adenosine, adenine, and the diamidines, but not inosine, were able to inhibit killing of drug-sensitive STIB 247 trypanosomes by cymelarsan and melarsen oxide in a concentration-dependent manner. These results are consistent with the view that these arsenical compounds enter trypanosomes via an adenosine-specific transporter. Melarsoprol-induced killing of trypanosomes was unaffected, however, by either purine and to only a slight degree by the diamidines. These data suggest that melarsoprol can enter trypanosomes by a route other than through an adenosine transporter and that there may be two mechanisms contributing to arsenical resistance in this drug-resistant line of trypanosomes.

Adenine↗
PubMed2000

Deterministic modeling of negative cross-resistance strategies for use in transgenic host-plant resistance.

Negative cross-resistance refers to a situation in which an insect population that is tolerant (resistant, virulent) to one insecticide is hyper-sensitive (avirulent) to a second insecticide and insects hyper-sensitive to the first compound are tolerant to the second. Most research dealing with negative cross-resistance has focused on the molecular biology and chemical aspects of this phenomenon. We explored, from a population genetics perspective, whether negative cross-resistance is feasible in the control of an insect population. As a first step towards this goal, we used a deterministic approach to evaluate different control scenarios and to identify some of the potential limitations of negative cross-resistance strategies. Specifically, we investigated how such approaches could be used in a host-plant resistance program. Homo- and heterozygous insect fitness influenced the effectiveness of the toxins in controlling the insect population. The negative cross-resistance strategy was most useful when the insects' virulence to both host-plant toxins was recessive. When virulence was dominant, there were many periods when intervention with an outside (or third) class of compounds, which had a different mode of action than that of the negative cross-resistance compounds, was needed to control the insect population. The greater the number of insect generations per plant generation, in the absence of immigration or emigration in the insect population, the greater the requirement for intervention with a third class of compound to maintain effective control of the insect population. When the toxins were rotated every insect generation, and virulence in the insect was recessive to both toxins, effective control of the insect population was maintained without intervention of a third class of compounds.

Animals↗
PubMed1980

Extrachromosomal oligomycin-resistant mutants of the petite-negative yeast Kluyveromyces lactis. Properties of mitochondrial ATPase and cross-resistance to inhibitors of phosphoryl transfer reactions.

The mitochondrial ATPase from oligomycin-resistant mutants which map on different regions of an extrachromosomal DNA (01 and 011 class mutants) showed an increased resistance to oligomycin and venturicidin when assayed in vitro as compared to the sensitive strains. The resistance to oligomycin of the isolated mitochondrial ATPase from 01 class mutants was higher than that of the 011 class mutants. Cross resistance of the oligomycin-resistant mutants to the antibiotics peliomycin and ossamycin, which also inhibit phosphoryl transfer reactions in mitochondria (Walter et al., 1967), was observed, 01 mutants being more resistant to ossamycin than 011 class mutants. At the concentrations of peliomycin studied, no difference in sensitivity among both groups of oligomycin-resistant mutants could be detected. Mitochondrial respiration and isolated mitochondrial ATPase activity are sensitive to venturicidin, suggesting that the previously observed (Brunner et al., 1977) in vivo venturicidin resistance of K. lactis is probably due to an impairment of the influx of the drug at the level of the plasma membrane.

Adenosine Triphosphatases↗
PubMed1994

Lack of cross-resistance to a new cytotoxic arylchloroethyl urea in various drug-resistant tumor cells.

1-Aryl 3-(2-chloroethyl) ureas (CEUs), a new class of potent antineoplastic agents, were recently developed in our laboratory. These compounds were designed from the aromatic moiety of chlorambucil and the unnitrosated pharmacophore of carmustine. In the present study we investigated the effect of the potent CEU derivative 4-tert-butyl-[3-(2-chloroethyl)ureido] benzene (tBCEU) on tumor cell lines selected for resistance to a wide range of anticancer drugs. The resistance mechanisms found in these cells included increased expression of P-glycoprotein, increased intracellular concentration of glutathione and/or glutathione-S-transferase activity, alteration of topoisomerase II, and increased DNA repair. Whereas the resistant cell lines were found to be highly resistant to a panel of clinically known anticancer drugs, tBCEU was found to be equally cytotoxic to both resistant and parental cells. The nitrobenzylpyridine assay indicated that tBCEU is a weaker alkylating agent than chlorambucil. This lack of cross-resistance in various resistant tumor cells suggests that tBCEU could be potentially useful in the treatment of cancers resistant to conventional anticancer drugs.

Animals↗
PubMed1979

Studies on 1-beta-D-arabinofuranosyl cytosine-resistant mutants of Chinese hamster fibroblasts: III. Joint resistance to arabinofuranosyl cytosine and to excess thymidine--a semidominant manifestation of deoxycytidine triphosphate pool expansion.

Variants isolated from mutagenized Chinese hamster fibroblasts by a single cycle of exposure to ara-C distributed into two classes: (1) deoxycytidine (dC) kinase deficient clones with a high level of resistance, this phenotype was recessive in hybrids; and (2) clones exhibiting joint resistance to thymidine (dT) and to "low" ara-C concentration, this phenotype was accounted for by an increased dCTP pool. The incorporation of exogenous dC into macromolecules was markedly altered in these variants. In hybrids, the phenotype of joint resistance to dT and ara-C was semidominant. Through a second selection step, variants cumulating recessive high resistance to ara-C and semidominant dT resistance were recovered. The identification of these two classes of ara-C-resistant variants suggests an interpretation of the known phenotypes of ara-C resistance as manifestations of chromosomal gene mutations. Dominant resistance mutations might contribute to the survival of cancer cells during prolonged ara-C chemotherapy.

Animals↗
PubMed1979

Resistance to bromodeoxyuridine mutagenesis and toxicity in mammalian cells selected for resistance to hydroxyurea.

Mutant cell lines resistant to hydroxyurea (HU), an inhibitor of the enzyme ribonucleotide reductase, were selected from a line of Syrian hamster melanoma cells. Mutant lines were selected for resistance to 0.3 mM HU, and from these lines, second-step mutants were selected for resistance to 1.9 mM HU. The HUr lines were tested ffor their responses to 5-bromodeoxyuridine (brdU), in terms of toxicity, mutagenesis, and incorporation of BrdU into DNA. All of the HUr lines showed increased resistance to the toxic effects of BrdU. in addition, the HUr lines all were resistant to BrdU mutagenesis. Overall, there was good correlation among the levels of resistance to HU toxicity, BrdU toxicity, and BrdU mutagenesis in the HUr lines. These tests were carried out under conditions such that the parental and HUr cells incorporated equal amounts of BrdU into nuclear DNA. Therefore, the resistance of the HUr cells to the effects of BrdU cannot be attributed to decreased incorporation of BrdU into DNA. These results suggest that the HUr cells have an lateration in ribonucleotide reductase activity that simultaneously confers resistance to HU and BrdU. The properties of the HUr cells suggest that the perturbation of deoxcytidine metabolism by BrdU. The properties of the HUr cells suggest that the perturbation of deoxcytidine metabolism by BrdU triphosphate inhibition of ribonucleotide reductase activity plays a key role in the toxic and mutagenic effects of BrdU in mammalian cells.

Animals↗
PubMed1989

Selection of constitutively resistant mutants of inducible clindamycin-resistant Bacteroides vulgatus.

The rate of spontaneous mutation to constitutive clindamycin resistance and the kinetics of selection of such mutants in preinduced and non-preinduced cells was evaluated in the Bacteroides vulgatus strain RYC18F6 (original MIC less than or equal to 0.25 micrograms/ml), which shows inducible resistance to clindamycin and erythromycin. Mutants demonstrating a high level of constitutive resistance to clindamycin (64 micrograms/ml) occurred at a frequency of 10(-7). Culture in broth containing either subinhibitory or inhibitory levels of clindamycin resulted in induction of clindamycin resistance. This permitted survival of a part of the population that seemed to facilitate the further growth of constitutively resistant mutants (up to a frequency of 10(-1)). At both low and high clindamycin concentrations mutants appeared to be selected over merely induced cells. Preincubation of cultures with erythromycin gave rise to an apparently higher level of induction. Under these circumstances, the selection of constitutively resistant mutants was less effective (10(-4). The use of erythromycin or clindamycin against populations of Bacteroides spp. exhibiting inducible resistance may contribute to selection of mutants showing constitutive clindamycin resistance.

Bacteroides↗
PubMed1994

Beta-lactam resistance among Escherichia coli and Klebsiella species blood culture isolates in Finnish hospitals. Finnish Study Group for Antimicrobial Resistance.

The aim of this study was to investigate beta-lactam resistance in Escherichia coli and Klebsiella spp. blood culture isolates in Finland. Special attention was given to extended-spectrum beta-lactamases. A total of 566 Escherichia coli and 108 Klebsiella spp. blood culture isolates were collected from hospitals throughout Finland and their susceptibility to beta-lactam antibiotics studied. Twenty percent of Escherichia coli and 69% of Klebsiella spp. strains were resistant to ampicillin. The mechanisms of resistance were studied by hybridization, isoelectric focusing and the clavulanate double-disk potentiation test. Of the ampicillin-resistant Escherichia coli strains, 83% produced TEM-1. Of the ampicillin-resistant Klebsiella spp. strains, 43% produced SHV-1. Only nine Escherichia coli and three Klebsiella spp. isolates were resistant to cefuroxime (MIC > or = 32 micrograms/ml), and none were resistant to third-generation cephalosporins. These data were compared with cefuroxime and third-generation cephalosporin consumption levels in Finnish hospitals. Although the use of cephalosporins is far more extensive in Finland than in other Scandinavian countries, none of the isolates produced extended-spectrum beta-lactamases. In conclusion, resistance to cefuroxime has remained rare in Finland, and cefuroxime is still an alternative to third-generation cephalosporins in the treatment of septicemia.

Bacteremia↗
PubMed2006

High-level resistance to cobalt and nickel but probably no transenvelope efflux: Metal resistance in the Cuban Serratia marcescens strain C-1.

Molecular mechanisms underlying inducible cobalt and nickel resistance of a bacterial strain isolated from a Cuban serpentine deposit were investigated. This strain C-1 was assigned to Serratia marcescens by 16S rDNA analysis and DNA/DNA hybridization. Genes involved in metal resistance were identified by transposon mutagenesis followed by selection for cobalt- and nickel-sensitive derivatives. The transposon insertion causing the highest decrease in metal resistance was located in the ncrABC determinant. The predicted NcrA product was a NreB ortholog of the major facilitator protein superfamily and central for cobalt/nickel resistance in S. marcescens strain C-1. NcrA also mediated metal resistance in Escherichia coli and caused decreased accumulation of Co(II) and Ni(II) in this heterologous host. NcrB may be a regulatory protein. NcrC was a protein of the nickel-cobalt transport (NiCoT) protein family and necessary for full metal resistance in E. coli, but only when NcrA was also present. Without NcrA, NcrC caused a slight decrease in metal resistance and mediated increased accumulation of Ni(II) and Co(II). Because the cytoplasmic metal concentration can be assumed to be the result of a flow equilibrium of uptake and efflux processes, this interplay between metal uptake system NcrC and metal efflux system NcrA may contribute to nickel and cobalt resistance in this bacterium.

Bacterial Proteins↗
PubMed1999

Structure-activity profiles of eleutherobin analogs and their cross-resistance in Taxol-resistant cell lines.

PURPOSE: Eleutherobin, a natural product, is an antimitotic agent that promotes the polymerization of stable microtubules. Although its mechanism of action is similar to that of Taxol, its structure is distinct. A structure-activity profile of synthetic eleutherobin derivatives that have modifications at C3, C8 and C15 was undertaken to define the structural requirements for microtubule stabilization and cross-resistance in Taxol-resistant cell lines. METHODS: The biological activity of five eleutherobin analogs was assessed using three techniques: (1) cytotoxicity and drug-resistance in three paired Taxol-sensitive and -resistant cell lines; (2) polymerization of microtubule protein in vitro in the absence of GTP and (3) induction of microtubule bundle formation in NIH3T3 cells. RESULTS: Eleutherobin had an IC50 value comparable to that of Taxol, whereas neoeleutherobin, which has a carbohydrate domain that is enantiomeric with that of the parent compound, was less cytotoxic and had 69% of the maximum microtubule polymerization ability of eleutherobin. Both of these compounds exhibited cross-resistance in MDRI-expressing cell lines. Removal or replacement of the C15 sugar moiety resulted in reduced microtubule polymerization and cytotoxicity compared to eleutherobin and loss of cross-resistance in the cell lines SKVLB and J7-T3-1.6, both of which express high levels of P-glycoprotein. By contrast, removal of the urocanic acid group at C8 resulted in virtually complete abrogation of biological activity. The compound lost its ability to polymerize microtubules, and its cytotoxicity was reduced by a minimum of 2000-fold in lung carcinoma A549 cells. CONCLUSIONS: Removal or modification of the sugar moiety alters the cytotoxic potency of eleutherobin and its pattern of cross-resistance in Taxol-resistant cells, although such compounds retain a small percentage of the microtubule-stabilizing activity of eleutherobin. The N(1)-methylurocanic acid moiety of eleutherobin, or perhaps some other substituent at the C8 position, is essential for Taxol-like activity. These findings will be important for the future design and the synthesis of new and more potent eleutherobin derivatives.

ATP Binding Cassette Transporter, Subfamily B, Mem↗