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At least 19 recordsLinked to original sources
PubMed1991

Genetic characterisation of resistance to metal ions in methicillin-resistant Staphylococcus aureus: elimination of resistance to cadmium, mercury and tetracycline with loss of methicillin resistance.

Susceptibility to six metal ions--cadmium (Cd), mercury (Hg), arsenate (Asa), arsenite (Asi), antimony (Sb) and zinc (Zn)--was tested in 23 independent isolates of methicillin-resistant Staphylococcus aureus (MRSA) obtained from Guy's Hospital (GH) during 1984-1986, which included 10 isolates of the UK epidemic EMRSA-1 strain. Strains were also tested for resistance to antibiotics and the nucleic-acid-binding compounds propamidine isethionate and ethidium bromide. A further 19 methicillin-resistant isolates, including 10 EMRSA-1 were obtained from other sources. Ten methicillin-sensitive, antibiotic sensitive isolates were from Guy's Hospital. Resistance to Hg was associated with methicillin resistance in 19 of the 20 EMRSA-1 isolates, all of which were resistant to Cd. Resistance to Cd and Hg was found in 13 out of 22 other MRSA isolates. Hg resistance was not present in the methicillin-sensitive isolates which were often (13 out of 19) moderately resistant to Cd. Multiple resistance to metal ions, including resistance to Hg, Asa, Asi and Sb, was uncommon. Resistance to Cd (MIC greater than 32 mg/L or 8-16 mg/L) was associated with increased resistance to Zn. In 11 of the consecutive MRSA isolates from Guy's Hospital seven distinct strains were recognised by phage type. Methicillin resistance in these strains varied from 16 to 1024 mg/L at 30 degrees C with a 2-8-fold lower minimum inhibitory concentration at 37 degrees C indicating some degree of heterogeneity. Representatives of the EMRSA-1 strain had the higher levels of resistance. Loss of methicillin resistance occurred in 0.2-5.0% of colonies tested after storage at room temperature in 10 of these isolates.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacteriophages↗
PubMed1990

Emergence of ciprofloxacin resistance in nosocomial methicillin-resistant Staphylococcus aureus isolates. Resistance during ciprofloxacin plus rifampin therapy for methicillin-resistant S aureus colonization.

We initiated a randomized, single-blinded trial of ciprofloxacin plus rifampin vs sulfamethoxazole and trimethoprim plus rifampin in the therapy for patients who underwent colonization with methicillin-resistant Staphylococcus aureus (MRSA). Patients who were colonized with MRSA received 2 weeks of either regimen. The study was terminated after the enrollment of 21 subjects due to the recognition of ciprofloxacin resistance in 10 of 21 new MRSA isolates during the last 2 months of the study. Five of the 10 patients with ciprofloxacin-resistant MRSA isolates had never received ciprofloxacin. Long-term (6-month) eradication had been achieved in only three of 11 ciprofloxacin plus rifampin and four of 10 sulfamethoxazole and trimethoprim plus rifampin recipients. The use of this new fluoroquinolone for the eradication of MRSA colonization is usually not effective and may risk the development of ciprofloxacin resistance in MRSA within the hospital environment.

Anti-Bacterial Agents↗
PubMed1989

Effect of erythromycin and tumour necrosis factor on the drug resistance of multidrug-resistant cells: reversal of drug resistance by erythromycin.

WEHI 164 murine fibrosarcoma cells were rendered multidrug-resistant (MDR) by culture in the presence of actinomycin D. In addition to resistance to actinomycin D, the cells acquired resistance to doxorubicin, mitomycin, vincristine and cycloheximide. The fact that development of resistance to one type of lipophilic chemotherapeutic drug also results in resistance to other structurally unrelated lipophilic drugs suggests that non-toxic lipophilic agents may interfere with drug resistance by saturating the pathway by which MDR-cells inhibit drug cytotoxicity. We show that the antibiotic erythromycin significantly reverses the resistance of MDR WEHI 164 cells to doxorubicin and actinomycin D. In addition to cross-resistance to chemotherapeutic drugs, 3 out of 4 actinomycin D-resistant WEHI 164 cell lines also showed higher resistance to tumour necrosis factor (TNF) than the parental WEHI 164 cells. However, whereas verapamil, a calcium antagonist known to reverse multidrug-resistance, rendered resistant cells more sensitive to chemotherapeutic drugs, it protected the cells from killing by TNF, suggesting that drug resistance and TNF resistance may not be directly connected. A synergistic cytotoxic effect of TNF and actinomycin D was obtained on both the parental and the MDR cells. However, higher concentrations of TNF and actinomycin D were required to obtain a cytotoxic effect in the MDR cells, reflecting actinomycin D and TNF resistance in these cells.

Animals↗
PubMed1983

Isolation of drug resistant mutants of varicella-zoster virus: cross resistance of acyclovir resistant mutants with phosphonoacetic acid and bromodeoxyuridine.

Mutants of Varicella-Zoster Virus (VZV) which are resistant to phosphonoacetic acid (PAA), bromodeoxyuridine (BuDR), and acyclovir (ACV) were obtained by serial passages of VZV with increasing concentrations of these drugs. A PAA-resistant mutant and a BuDR-resistant mutant were found also to be resistant to ACV. Five of 8 ACV-resistant mutants acquired resistance to PAA, but none acquired resistance to BuDR. The BuDR-resistant mutant did not induce viral thymidine kinase (TK) activity, but all the ACV-resistant mutants selected in ACV showed viral TK activity which was suppressed with anti-VZV serum and had almost the same electrophoretic mobility as that of the parent strain on polyacrylamide gel electrophoresis in non-denaturing conditions. However, in competitive TK assay with ACV, 2 of 8 ACV-resistant mutants showed no change of phosphorylation of radioactive thymidine, while the other 6 showed decreased phosphorylation of radioactive thymidine. It was suggested that TK induced by the former 2 ACV-resistant mutants had lost affinity to ACV, and so the mutants could grow in the presence of ACV. Thus of the 8 ACV-resistant mutants selected in ACV, 2 were sensitive to PAA with altered TK activity, 5 were resistant to PAA with unaltered TK activity, and 1 was sensitive to PAA with unaltered TK activity, and may have altered DNA polymerase activity to ACV, retaining sensitivity to PAA. These results suggest that resistance of VZV to ACV results from alterations in the virus-specified TK or DNA polymerase, as demonstrated in HSV resistant to ACV.

Acyclovir↗
PubMed1990

[Cross-resistance relationship between streptomycin and kanamycin resistances in Mycobacterium smegmatis (strain Jucho)--comparison of the development patterns of resistances to streptomycin and kanamycin among Mycobacterium tuberculosis, Mycobacterium avium complex, and Mycobacterium smegmatis].

The resistance development pattern of Mycobacterium smegmatis strain 17023 (Jucho) to streptomycin and kanamycin was studied. The medium used was Ogawa egg medium, and the level of resistance was determined for each clone derived from single colony by the 'actual count' method. Hence, the resistance level was estimated as the highest concentration of drugs, in which small inocula consisting of 20 to 100 colony-forming units could grow after seven days incubation. Only one type of resistance mutants resistant to more than 1,000 micrograms/ml streptomycin was isolated and these mutants were also resistant to 8 micrograms/ml kanamycin. On the other hand, only one type of kanamycin-resistant mutants resistant to 8 micrograms/ml kanamycin was isolated and these mutants were also resistant to more than 1,000 micrograms/ml streptomycin. Accordingly, there was a complete cross-resistance relationship between streptomycin and kanamycin resistances. Therefore, there existed only one phenotype, which is simultaneously resistant to streptomycin and kanamycin. The mutants occurred at a rate of about 2 x 10(-8) per viable bacterial population of the parent strain. Streptomycin-dependent mutants occurred at a rate of about 2 x 10(-9). The number of resistant phenotypes to streptomycin and kanamycin was only one in M. smegmatis, while it was five in M. tuberculosis and 2 or 3 in M. avium complex (Tsukamura, M. and Mizuno, S.: J. Gen. Microbiol. 88: 269-274, 1975; Tsukamura, M.: Kekkaku 62: 445-458, 1987). The simplicity of the resistance system of M. smegmatis suggests that this organism is evolutionally primitive in the world of mycobacteria.

Drug Resistance, Microbial↗
PubMed1990

[Mechanisms for resistance and cross-resistance patterns of cisplatin-resistant tumor lines].

Mechanisms for cisplatin resistance were studied using mouse leukemias acquired resistance to the drug. Uptakes of cisplatin by L-1210/DDP and P 388/DDP were significantly decreased, compared with the respective sensitive lines. Glutathione contents in both the resistant lines were 1.7 times more than in the respective sensitive ones. While glutathione contents were reduced to about 10% by incubation of cells with D, L-buthionine-S, R-sulfoximine, sensitivity of the resistant cells remained unchanged. Therefore, glutathione might not relate to the mechanism for resistance in these lines. Cross-resistance patterns of L-1210/DDP and P 388/DDP as well as Colon 26/DDP to cisplatin analogs were investigated. Carrier ligands of the analogs, by which antitumor spectra would be controlled, were different from each other and leaving groups were Cl2, as a rule. As a result, L-1210/DDP showed cross-resistance only to two analogs. In contrast, P 388/DDP did so to all complexes tested. The resistance indices to four analogs were more than 50. Colon 26/DDP also showed cross-resistance to all of them, but the degrees of resistance in this line were lower than those in P 388/DDP. These facts revealed that the pattern of cross-resistance was dependent on each cell line and the completely different patterns were shown between the mouse leukemia resistant lines. It was suggested that in developing a new platinum analog, we should select a carrier ligand to which as many resistant lines would show lack of cross-resistance.

Animals↗
PubMed1986

Biochemical and cross-resistance studies with HeLa cell mutants resistant to cardiac glycoside SC4453. Regulation of the resistant form of Na+/K+-ATPase in the mutant cells.

In HeLa cells, stable mutants which are between 25-to about 200-fold resistant to the cardiac glycoside derivative SC4453 (a digoxin analog which contains a pyridazine ring in place of a lactone ring in the C-17 position) have been isolated after a single step selection in the presence of the drug. Based on their cross-resistance pattern towards various cardiac glycosides, the mutants resistant to SC4453 (SCR mutants) appear to be of two different kinds and they differ from the two classes of ouabain-resistant mutants described previously (Gupta, R. S., and Chopra, A. (1985) J. Biol. Chem. 260, 6843-6850). One type of SCR mutants (designated as group C) exhibit a high degree of cross-resistance to all cardiac glycosides and their genins (viz. ouabain, digitoxin, digoxin, digoxigenin, convallatoxin, gitoxin, strophanthidin, and bufalin). In contrast, the second type of SCR mutant (group D) exhibit considerable resistance to only SC4453, digoxin, and digoxigenin, but showed very little or no cross-resistance to the other cardiac glycosides examined. The cross-resistance of the mutants towards cardiac glycosides was highly specific as they exhibited no cross-resistance towards a large number of other structurally and functionally related compounds (viz. ethacrynic acid, sanguinarine nitrate, penicillic acid, methyl quinolizinum bromide, 5,5'-diphenylhydantoin, deoxycorticosterone, vanadium pentoxide, and adriamycin). The cellular uptake of 86Rb in the mutant cells was found to be resistant to specific cardiac glycosides. Studies on the sensitivity of plasma membrane Na+/K+-ATPase to cardiac glycosides show that about 10-15% of the enzymic activity in the mutant cells was highly resistant to inhibition by the specific drugs to which the mutants exhibit increased resistance. Very interestingly, when the mutant cells are grown in cardiac glycoside-containing medium, the resistant form of the enzyme accounts for about 50-60% of the total enzyme. These results show that both classes of SCR mutants are affected in Na+/K+-ATPase and that the amount of the resistant enzyme in the mutant cells is regulated in response to cardiac glycosides.

Cardiac Glycosides↗
PubMed2026

Emergence of cefiderocol resistance in carbapenem-resistant Escherichia coli ST167 prior to clinical use: A multifactored resistance landscape.

OBJECTIVES: Cefiderocol is a novel siderophore cephalosporin with potent activity against multidrug-resistant Gram-negative bacteria. Here, we reported the prevalence and mechanisms of cefiderocol resistance in carbapenem-resistant Escherichia coli (CREC) in China before its clinical use. METHODS: A total of 443 non-duplicate CREC isolates collected from 67 hospitals in China (2013-2021) underwent antimicrobial susceptibility testing according to CLSI guidelines. Whole-genome sequencing, transcriptomic analysis, siderophore quantification, and targeted genetic manipulation were performed to investigate the underlying resistance mechanisms. RESULTS: Among the 443 CREC isolates, 102 (23.0%) were resistant to cefiderocol, and 34 (7.6%) showed intermediate susceptibility. Multivariable logistic regression identified ST167 lineage (OR, 3.05; 95% CI, 1.12-8.29; P = 0.028), blaNDM-5 carriage (OR, 9.04; 95% CI, 2.96-27.57; P < 0.001), and cirA truncation (OR, 49.56; 95% CI, 20.33-120.79; P < 0.001) as independent factors associated with cefiderocol resistance. Among ST167 isolates, cefiderocol-resistant isolates showed increased yersiniabactin carriage and siderophore production but comparable TonB-dependent transporter expression profiles. Phylogenetic analysis revealed that cefiderocol-resistant ST167 isolates clustered into a distinct subclade enriched with resistance-associated determinants, including a recurrent FhuA P50S substitution detected in 59/64 (92.2%) resistant isolates. Functional assays showed that the P50S substitution increased cefiderocol minimum inhibitory concentration (0.032-0.125 &#xb5;g/mL), particularly in an NDM-5-producing background (0.032-0.5 &#xb5;g/mL). CONCLUSIONS: Cefiderocol resistance is highly prevalent among high-risk ST167 CREC isolates before the clinical introduction of cefiderocol in China, highlighting the need for continued surveillance of this epidemic lineage. Cefiderocol resistance is mediated by multiple resistance determinants, and we identify the recurrent FhuA P50S substitution as a novel contributor to reduced cefiderocol susceptibility.

Antimicrobial resistance↗
PubMed1992

Radiation sensitivities in various anticancer-drug-resistant human lung cancer cell lines and mechanism of radiation cross-resistance in a cisplatin-resistant cell line.

To determine whether there exists cross-resistance between anticancer drugs and radiation, six drug-resistant human lung cancer cell lines and their parental cell lines were examined for radiosensitivity using a growth-inhibition assay. Only one cisplatin-resistant cell line, PC-9/CDDP, showed cross-resistance to radiation. The other three cisplatin-resistant cell lines (PC-7/CDDP, PC-4/CDDP, and H69/CDDP), an etoposide-resistant cell line (H69/VP) and a camptothecin-resistant cell line (PC-7/CPT) did not show cross-resistance to radiation. To analyze the mechanism of radiation resistance in PC-9/CDDP cells, the formation and repair of radiation-induced DNA single-strand breaks (ssb) and double-strand breaks (dsb) were examined by alkaline elution and neutral elution respectively. Although the formation of DNA ssb and repair of both DNA ssb and DNA dsb were the same for both cell lines, the formation of DNA dsb in PC-9/CDDP cells was significantly less than those in PC-9 cells. Measurement of intracellular glutathione content in all of the cell lines revealed that only PC-9/CDDP cells had a significant increase of glutathione content compared to the parental cells. Buthionine sulfoximine treatment of PC-9/CDDP cells caused an increase of DNA dsb to the same levels as in PC-9 cells after irradiation and caused a complete radiosensitization. These results indicate that cross-resistance to radiation in drug-resistant cells in a rare phenomenon, and increased glutathione content may play a crucial role in the emergence of cross-resistance to radiation in the drug-resistant cells.

Antineoplastic Agents↗
PubMed1975

Genetic analysis of drug resistance in Neisseria gonorrhoeae: production of increased resistance by the combination of two antibiotic resistance loci.

The studies reported here demonstrate that increased resistance of Neisseria gonorrhoeae to penicillin, tetracycline, and chloramphenicol results from the combined effect of two resistance loci. As shown by experiments with deoxyribonucleic acid from transformants carrying only a single resistance locus, transformants with an incresed level of resistance to penicillin result from the combination of a penicillin-specific locus, pen, and a multiple resistance locus, mtr. Similarly, transformants with an increased level of resistance to tetracycline result from the combination of mtr and a tetracycline-specific locus, tet. Transformants with an increased level of resistance to chloramphenicol result from the combination of mtr and a chloramphenicol-specific locus, cml. Deoxyribonucleic acid dilution experiments established that only a single dose of each of the two required resistance loci is necessary to give higher-level resistance. Higher-level-resistant transformants were not obtained when a double dose of one resistance locus or a combination of loci pairs other than mtr and pen, mtr and tet, or mtr and cml was introduced into a recipient. Combinations of the mtr and tet genes resulted in increased resistance to semisynthetic tetracyclines. The presence of the mtr and pen genes resulted in increased resistance to penicillinase-stable penicillins.

Anti-Bacterial Agents↗
PubMed1987

Verapamil reversal of vincristine resistance and cross-resistance patterns of vincristine-resistant Chinese hamster ovary cells.

The phenotypic properties of a large number of low-level vincristine (VCR)-resistant Chinese hamster ovary cell lines have been studied. In particular, we examined the correlation between the reversal of VCR resistance by verapamil (VRP) and cross-resistance patterns to other drugs. Cross resistance to other vinca alkaloids developed in parallel with VCR resistance. Doxorubicin resistance was observed in many of the cell lines, occurring even at the lowest levels of VCR resistance. Increased sensitivity to taxol (TAX) was a feature of half of the lines tested and there was no increased resistance to 5-fluorouracil or chlorambucil. Two main groups of mutants have been identified: (a) those that are thought to be membrane mutants which are cross-resistant to TAX and whose VCR resistance is reversible by VRP; and (b) those that appear to be tubulin mutants, which have increased sensitivity to TAX and resistance to VCR in the presence of VRP. It was not possible to distinguish between the different mechanisms of low-level resistance by drug accumulation studies in unsupplemented medium. However, VCR accumulation in the presence of VRP did correlate with the cross-resistance results.

Alkaloids↗
PubMed1984

Resistance types in Citrobacter freundii. Occurrence and resistance to ampicillin, carbenicillin, cephalothin and mecillinam. Transfer of ampicillin resistance.

The resistance types of Citrobacter freundii were investigated. The strains were divided into three groups according to susceptibility to penicillin derivatives. Group 1, comprising the ampicillin-carbenicillin sensitive strains (A-s/Ca-s), constituted 22%. Group 2 (ampicillin-resistant (A-r)/Ca-s) constituted 45% and group 3 (A-r/Ca-r) 32%. Two strains (1%) were recorded as A-s/Ca-r. Group 3 contained a higher proportion of multi-resistant strains than groups 1 and 2. The log2IC50 with ampicillin, carbenicillin, cephalothin and mecillinam in the tube-dilution method were determined for 32 strains. Groups 1 and 2 differed only as regards cephalothin resistance. The strains of group 3 were more A-r than the group 2 ones. The mecillinam susceptibility did not differ between the three groups. No strains in group 2 could transfer A-resistance. In group 3 ten out of 16 strains were able to transfer A-resistance. Resistance to sulphonamide, tetracycline, and streptomycin was also transferred, but with low frequency. The A-r/Ca-r strains could be divided into two subgroups, probably reflecting different modes of developing beta-lactam resistance. One group was very A- and Ca-r, less cephalothin-r, more mecillinam-r and could transfer A-resistance. The other group had very high cephalothin-resistance and could not transfer A-resistance. Citrobacter freundii and Enterobacter cloacae are very similar as regards resistance conditions.

Ampicillin↗
PubMed1984

Cross-resistance of vincristine-resistant sublines of P388 leukemia to mitoxantrone with special emphasis on the relationship between in vitro and in vivo cross-resistance.

In vitro and in vivo cross-resistance to mitoxantrone of two vincristine-resistant sublines of P388 leukemia with different degrees of resistance in vitro was compared with that to adriamycin. A subline with a lower degree of resistance to vincristine exhibited approximately the same responses in vivo to mitoxantrone and adriamycin as the original P388 leukemic cell line, although it was evidently cross-resistant in vitro to these agents. Another subline having a higher degree of resistance to vincristine showed a 25-fold cross-resistance in vitro and gave no response in vivo to adriamycin. With mitoxantrone, on the other hand, this subline was solidly resistant as compared with the sensitive line but still retained significant responsiveness in vivo irrespective of a 150-fold cross-resistance in vitro. These results suggest that cross-resistance on a cellular basis does not necessarily correspond to in vivo cross-resistance. The relationship between in vitro and in vivo cross-resistance is discussed.

Animals↗
PubMed1991

Understanding "insulin resistance": both glucose resistance and insulin resistance are required to model human diabetes.

A mathematical model of normal glucose/insulin homoeostasis has been based on the known, experimentally determined responses of the liver and periphery to different glucose/insulin concentrations. Different defects of glucose resistance and insulin resistance have been applied to the model to investigate the degree to which these abnormalities could successfully predict the range of fasting glucose and insulin values found in normal, obese, and diabetic subjects. Modeling glucose resistance or insulin resistance at the liver or the periphery alone did not increase the plasma glucose to levels observed in diabetes, even when associated with marked deficiency of beta-cell function. A defect of either glucose resistance or insulin resistance affecting both periphery and liver allowed a wider range of basal glucose and insulin concentration values, but resulted in unphysiologically low hepatic glucose output: with modeling insulin resistance, hyperglycemia suppressed glucose output, whereas with glucose resistance, raised insulin levels suppressed hepatic glucose output. A wide range of glucose and insulin values, with appropriate basal hepatic glucose output, could only be modeled by insulin resistance at both the liver and periphery with additional glucose resistance at the liver. The modeling results are in accord with investigative studies that suggest secondary hepatic and peripheral glucose resistance in response to hyperglycemia. Modeling provides a systematic means of examining the likely effect of different putative defects in a complex physiological system.

Diabetes Mellitus↗
PubMed1990

Changes in muntjac fibroblasts associated with the acquisition of cadmium resistance. A pre-resistance, transitional and post-resistance study.

A series of cell lines with different levels of resistance to continuous cadmium exposure has been developed from an immortal but non-transformed muntjac fibroblast cell line. Concentrations accepted in their culture medium range from 0.1 microM for the cadmium sensitive parent line to 5 microM for the intermediate "cadmium-tolerant" line, to 5, 10, 20 and 50 microM for the four "cadmium-resistant" lines. The present paper follows the morphological changes which accompanied the development of resistance through a 20-month pre-resistance period, a relatively abrupt 6-week transitional period and a 3-year post-resistance period, during which time levels of cadmium resistance were increased. Initial changes which led to the cadmium-tolerant CR5 cell line included (i) increased efficiency in autophagocytosing damaged cell components and in ridding the cell of residual waste materials, (ii) a reduction in fluid filled vacuoles and (iii) improved recycling and/or replacement of cadmium-damaged cell membrane. With the advent of cadmium resistance the intracellular damage necessitating these activities disappeared, yet the series of changes which occurred included a massive build-up of Golgi and the appearance of a trans-Golgi tubular network in addition to cytoskeletal and membrane changes. Though metallothionein levels are greater in the cadmium-resistant variants, their increase appears inadequate on their own to account for the high levels of resistance. The post-resistance changes which accompanied each step-up in cadmium resistance included further membrane and glycocalyx changes, in addition to continued increases in Golgi bodies and tubular network. This paper details the morphological changes which occurred throughout the 5-year period, tests the direct dependence of each on the presence of cadmium and examines their possible contribution to a cadmium protective mechanism.

Animals↗
PubMed1989

Atypical multidrug resistance in a therapy-induced drug-resistant human leukemia cell line (LALW-2): resistance to Vinca alkaloids independent of P-glycoprotein.

Near diploid leukemic T-cells (LALW-2), exposed to cytotoxic drugs only as a consequence of therapy administered to the donor patient, have been maintained by serial xenograft in nude mice. In comparison with the leukemic line CCRF-CEM, using a growth inhibition assay, LALW-2 cells were resistant to Vinca alkaloids and actinomycin D (relative resistance, 200-fold or more), were slightly resistant to Adriamycin (relative resistance, 4-fold), and showed no resistance to daunorubicin or teniposide. By comparison, a vincristine-resistant CEM subline developed in our laboratory (CEM/VCR R) was resistant to all these agents by at least 30-fold. The VCR R subline served as a positive control, confirming the previously reported correlation between multidrug resistance and amplification of the P-glycoprotein gene. Comparison of CEM, CEM/VCR R, and LALW-2 cells establish that the P-glycoprotein gene was not amplified or overexpressed in the LALW-2 cells; neither could the gene product be detected by immunoblotting in extracts from these cells. The LALW-2 cells were further distinguished from CEM/VCR R cells due to the lack of increased vincristine efflux by the xenografted cells, an effect readily demonstrable in the CEM/VCR R cells. However, although LALW-2 cells efflux vincristine at the same rate as CCRF-CEM cells, the xenografted cells exhibited a reduced rate of vincristine accumulation. Uptake of daunorubicin by LALW-2 cells was not distinguished from that by CEM cells, consistent with similar 50% inhibitory dose levels for this drug in both cell populations, and differentiating both from CEM/VCR R cells. Thus, clinical resistance in this case appears to be an "atypical" form of multidrug resistance specifically distinguished by resistance to Vinca alkaloids and actinomycin D occurring in the absence of increased amounts of P-glycoprotein and manifesting decreased drug uptake.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Multi-drug resistant falciparum malaria in Cameroon in 1987-1988. II. Mefloquine resistance confirmed in vivo and in vitro and its correlation with quinine resistance.

To further document the phenomenon of Plasmodium falciparum resistance to mefloquine formerly described in Cameroon, complementary in vivo and in vitro studies were conducted. Two hundred six P. falciparum isolates were studied in vitro using an isotopic microassay with mefloquine solutions prepared daily. Using the cutoff limit of 30 nmol, 26 (20%) of 133 isolates from the northern part of the country were defined as being resistant to mefloquine. In contrast, only one of 73 isolates collected in the southern part of the country was resistant. In vivo 7-day assays were performed in the northern area in 57 asymptomatic P. falciparum carriers (age range 1-10 years) who were given a single 25 mg/kg dose of mefloquine (Lariam). Among 46 cases in which followup was possible, P. falciparum asexual parasites were cleared within five days in 38 cases, by days 6 and 7 in two cases, and remained detectable up to day 7 in six cases. Thus, these latter patients have a RII-RIII level of resistance by in vivo criteria. No resistance was found in 40 additional patients studied similarly in the southern region. These observations were made before any mefloquine drug pressure was exerted in the country, but results of cross-resistance and drug consumption studies support the hypothesis that in the northern region, where a close correlation (r = 0.67) was found between the response to quinine and mefloquine, the more frequent use of quinine may have induced a primary quinine resistance and a secondary mefloquine resistance (without chloroquine resistance).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

[Establishment of adriamycin-resistant human small-cell lung cancer cells in culture: analysis of the mechanism of resistance and cross-resistance].

An adriamycin-resistant cell line was established in culture by continuous exposure of SBC-3 cells, a cell line of human small-cell lung cancer, to increasing concentrations of adriamycin, followed by a cloning procedure. The resistant cells (SBC-3/ADM) were 30 times more resistant to the drug than the parent cells in terms of 70% lethal dose, determined by soft agar clonogenic assay. Uptake studies using [3H] daunomycin, which was completely cross-resistant to adriamycin, showed decreased influx and enhanced efflux of the agent. This resistance to adriamycin may be attributed to an alteration in membrane transport, resulting in reduced intracellular accumulation of the drug. Using the SBC-3/ADM cells, the activity of a variety of drugs was analyzed by soft agar clonogenic assay in order to search for a means of circumventing drug resistance. The SBC-3/ADM cells were markedly resistant to anthracycline antibiotics such as THP-adriamycin and 4'-epi-adriamycin. The cells were also resistant to structurally or pharmacodynamically unrelated compounds such as vincristine, mitomycin C, 40497S, an active compound of ifosfamide, and etoposide. However, the cells were as sensitive to mitoxantrone as the parent cells, and were considerably susceptible to cisplatin. These results suggest that mitoxantrone and cisplatin may exert a sufficient degree of activity for use against small-cell lung cancer resistant to adriamycin.

Carcinoma, Small Cell↗