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PubMed2005

Clindamycin-resistance in methicillin-resistant Staphylococcus aureus isolated from animals.

Clindamycin is widely used in veterinary medicine to treat a variety of bacterial infections. Resistance to clindamycin amongst staphylococci may be due to modification of the ribosomal target site. Resistance due to this mechanism is encoded by the erm genes, which may be either constitutively or inducibly expressed. Inducible expression of resistance is not usually demonstrable by routine laboratory susceptibility testing, however, a relatively simple double disc agar diffusion test (D-test) may be used to detect the presence of inducible resistance. Two hundred and eighty-five isolates of methicillin-resistant Staphylococcus aureus (MRSA) isolated from infections in animals were tested using the D-test for the presence of inducible clindamycin resistance. One hundred and seven (71%) of the strains tested demonstrated inducible resistance to clindamycin, which were not detected on initial susceptibility testing. It has been shown that there is potential for staphylococci to develop resistance to clindamycin whilst on treatment when inducible resistance mechanisms are present. Therefore, routine screening for inducible resistance may be prudent.

Animals↗
PubMed2001

Longitudinal observations on mutations conferring ganciclovir resistance in patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis: The Cytomegalovirus and Viral Resistance Study Group Report Number 8.

PURPOSE: Cytomegalovirus retinitis is the most common intraocular infection in patients with acquired immunodeficiency syndrome (AIDS). With prolonged suppressive anticytomegalovirus maintenance therapy, resistance occurs in over 25% of patients. We evaluated longitudinal changes in the cytomegalovirus genotype in patients with cytomegalovirus retinitis who developed ganciclovir resistance that was demonstrated in either the blood or urine. METHODS: Patients with AIDS and previously untreated cytomegalovirus retinitis were followed prospectively for the occurrence of resistance while on treatment. Blood and urine specimens were obtained periodically for cytomegalovirus culture according to a predetermined schedule. Positive isolates were tested for phenotypic susceptibility and for mutations in the UL97 and UL54 genes. RESULTS: A mutation conferring resistance to ganciclovir in either the UL97 or UL54 gene was detected in 18 patients. In general, patients with a genotypically resistant virus developed increasing phenotypic resistance over time. There was a suggestion that unless therapy was changed, UL97 mutations tended to persist. In seven of eight patients, the mutations identified in isolates from the blood and urine were identical. In selected patients, there was a suggestion that a mixed population of cytomegalovirus might be present. Progression of the retinitis in an involved eye (15 of 18), contralateral eye retinitis (10 of 11), and extraocular cytomegalovirus disease (5 of 18) occurred commonly among patients with resistant virus. CONCLUSION: Resistance-conferring mutations in the cytomegalovirus genome emerge and may persist when the selective pressure for resistance is maintained. Some patients appear to harbor complex subpopulations of virus with different mutations and different levels of phenotypic resistance. Changes in therapy may result in a shift in virus population and changes in the cytomegalovirus genotype identified.

AIDS-Related Opportunistic Infections↗
PubMed2002

Antimicrobial resistance in Salmonella enterica serovars Enteritidis and Typhimurium isolated from animals in Korea: comparison of phenotypic and genotypic resistance characterization.

Fourteen and 22 each of Salmonella Enteritidis and Salmonella Typhimurium (S. Typhimurium) were isolated from animals from 1983 to 1999 in Korea and tested for their antibiotic resistance patterns, phage types and resistance gene patterns. S. Typhimurium isolates were highly resistant to streptomycin, sulfisoxazole and tetracycline, 95, 95 and 86%, respectively. The incidence of multiple antibiotic resistance (resistant to more than two drugs tested) of S. Typhimurium isolates was extremely high (100%) comparing to S. Enteritidis isolates (21%). Two of the five ACSSuT (ampicillin, chloramphenicol, streptomycin, sulfisoxazole and tetracycline) resistant type S. Typhimurium isolates were phage type definitive type 104 (DT104). For the detection of resistance related genes in S. Enteritidis and S. Typhimurium isolates, particularly ACSSuT type S. Typhimurium, antibiotic resistance genes, cmlA/tetR, bla(PSE-1) and bla(TEM), and genus Salmonella specific gene, sipB/C, were amplified using four pairs of primers in a hot-start multiplex polymerase chain reaction (PCR). Two Korean isolates of S. Typhimurium DT104 showed bla(TEM) amplicons instead of bla(PSE-1) for the ampicillin resistance and they were susceptible to florfenicol. The multiplex PCR used in this study was useful in characterization of multiple drug resistant Salmonella isolates, especially ACSSuT type S. Typhimurium, and identification of beta-lactamase gene distribution among Salmonella isolates.

Animals↗
PubMed1998

Molecular mechanisms of loss of beta 2-microglobulin expression in drug-resistant breast cancer sublines and its involvement in drug resistance.

In this study, we investigated the mechanism of the loss or decreased expression of beta 2-microglobulin (beta 2m) in several drug-resistant sublines of MCF-7 and in a doxorubicin (DOX)-resistant variant of the T-47D breast cancer cell line. beta 2m protein and RNA are not expressed in highly metastatic, multidrug-resistant MCF-7/Adr cells with high resistance to DOX. Nuclear run-on transcription and RNA stability assays demonstrate that while beta 2m in MCF-7/Adr cells is transcribed, its mRNA is rapidly degraded after synthesis in these cells, indicating that it is controlled by post-transcriptional mechanisms. We also show that an MCF-7 subline (MCF-7/Adr-5) expressing a very low level of resistance to DOX has a decreased level of beta 2m expression. Treatment with actinomycin D revealed that the half-life of beta 2m mRNA in MCF-7 and MCF-7/Adr-5 cell lines was comparable. Nuclear run-on transcription analysis revealed a decreased rate of beta2m transcription in MCF-7/Adr-5 cells compared to that in MCF-7 cells. Moreover, beta 2m mRNA remained undetectable in MCF-7/Adr cells following cycloheximide treatment. However, in MCF-7 cells, increased beta 2m mRNA was observed after 12 h, and a similar level of increased mRNA expression was observed after 36 h of cycloheximide treatment in MCF-7/Adr-5 cells; these results suggest that one of the mechanisms controlling beta 2m mRNA expression might be a negative regulatory protein in MCF-7/Adr-5 cells. Analysis of the beta 2m status of other drug-resistant MCF-7 sublines revealed that deregulation of beta 2m is not limited to DOX resistance, but can also be detected in cells selected for resistance to mAMSA and DOX-verapamil. In addition, our data show that reduced beta 2m expression correlates with the decreased levels of estrogen receptor (ER) expression in the DOX-resistant MCF-7/Adr and T-47D/Adr-4 human breast cell lines. Furthermore, we provide evidence that the partial inhibition of beta 2m by antisense RNA results in 2-3-fold decreased sensitivity of MCF-7 cells to DOX and mAMSA. Moreover, the addition of exogenous beta 2m protein near its physiological human serum concentration can modulate the DOX sensitivity of the MCF-7 antisense beta 2m and control transfectants. Therefore, these results indicate that lost or decreased beta 2m expression is involved in the development of the drug-resistant phenotype and correlates with the loss of ER in human breast cancer cell lines.

Breast Neoplasms↗
PubMed1998

A bacterial antibiotic-resistance gene that complements the human multidrug-resistance P-glycoprotein gene.

Bacteria have developed many fascinating antibiotic-resistance mechanisms. A protein in Lactococcus lactis, LmrA, mediates antibiotic resistance by extruding amphiphilic compounds from the inner leaflet of the cytoplasmic membrane. Unlike other known bacterial multidrug-resistance proteins, LmrA is an ATP-binding cassette (ABC) transporter. The human multidrug-resistance P-glycoprotein, encoded by the MDR1 gene, is also an ABC transporter, overexpression of which is one of the principal causes of resistance of human cancers to chemotherapy. We expressed lmrA in human lung fibroblast cells. Surprisingly, LmrA was targeted to the plasma membrane and conferred typical multidrug resistance on these human cells. The pharmacological characteristics of LmrA and P-glycoprotein-expressing lung fibroblasts were very similar, and the affinities of both proteins for vinblastine and magnesium-ATP were indistinguishable. Blockers of P-glycoprotein-mediated multidrug resistance also inhibited LmrA-dependent drug resistance. Kinetic analysis of drug dissociation from LmrA expressed in plasma membranes of insect cells revealed the presence of two allosterically linked drug-binding sites indistinguishable from those of P-glycoprotein. These findings have implications for the reversal of antibiotic resistance in pathogenic microorganisms. Taken together, they demonstrate that bacterial LmrA and human P-glycoprotein are functionally interchangeable and that this type of multidrug-resistance efflux pump is conserved from bacteria to man.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Relationship between the intracellular daunorubicin concentration, expression of major vault protein/lung resistance protein and resistance to anthracyclines in childhood acute lymphoblastic leukemia.

In vitro resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL), but the underlying mechanisms are poorly understood. Using flow cytometry, we studied the contribution of daunorubicin (DNR) accumulation and retention, cell size, expression of the major vault protein/lung resistance protein (LRP), P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) to the cytotoxicity of DNR (by MTT assay) in childhood ALL. The accumulated and retained DNR content was not related to the degree of DNR resistance, nor did the content differ between 53 initial and 20 relapse ALL samples (P >0. 05), although the latter were median two-fold more resistant to DNR (P = 0.004). Leukemic cell volume correlated with resistance to the anthracyclines DNR (Rs 0.32, P = 0.012) and idarubicin (Rs 0.46, P = 0.011) but not to other classes of drugs such as prednisolone, vincristine, L-asparaginase and etoposide. Relapsed patients had 1. 5-fold larger cells than patients at initial diagnosis of ALL (P = 0. 001). After cell volume correction, the intracellular DNR concentration was lower in relapsed compared with initial ALL cells (eg 60 min accumulation, P = 0.003). Moreover, the intracellular DNR concentration inversely correlated with DNR resistance, both in the accumulation (Rs -0.44, P < 0.001) and retention (Rs -0.33, P = 0. 016) test condition. The accumulated DNR concentration inversely correlated with expression of LRP (Rs -0.36, P = 0.012) but not with P-gp and MRP. Expression of LRP, but not of P-gp and MRP, significantly correlated with DNR resistance in childhood ALL (Rs 0. 33, P = 0.03). In conclusion, the intracellular DNR concentration and the expression level of LRP may contribute to DNR resistance in childhood ALL. The strength of the correlations also indicates that resistance to anthracyclines can not be explained by one single mechanism.

Antibiotics, Antineoplastic↗
PubMed1992

Frequency and transferability of trimethoprim and sulfonamide resistance in methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis.

A total of 374 Staphylococcus aureus and 126 Staphylococcus epidermidis strains from 14 countries were studied for their resistance to methicillin, trimethoprim (Tp) and sulfonamides (Su), alone and combined (TpSu). The frequency of resistance to Tp, Su and TpSu was much higher in methicillin-resistant S. epidermidis (MRSE) than in methicillin-resistant S. aureus (MRSA). Considerable differences, however, existed in isolates from different countries. Resistance to Tp, Su or TpSu in MRSA was low or absent in isolates from Switzerland, Spain, Japan, Mexico, Argentina and Chile, but high in isolates from Germany and Brazil. High level Tp resistance mostly resided on large plasmids. It could be transferred in 17 out of 97 strains. Su resistance was never cotransferred. Strains cured of their large Tp resistance plasmids remained Su-resistant, which suggests a chromosomal location of Su resistance.

Anti-Bacterial Agents↗
PubMed2000

Mutations at amino acid position 315 of the katG gene are associated with high-level resistance to isoniazid, other drug resistance, and successful transmission of Mycobacterium tuberculosis in the Netherlands.

The prevalence of mutations at amino acid (aa) position 315 in the katG gene of isoniazid (INH)-resistant Mycobacterium tuberculosis isolates in The Netherlands and the mutation's association with the level of INH resistance, multidrug resistance, and transmission were determined. Of 4288 M. tuberculosis isolates with available laboratory results, 295 (7%) exhibited INH resistance. Of 148 aa 315 mutants, 89% had MICs of 5-10 microg/mL, whereas 75% of the other 130 INH-resistant strains had MICs of 0.5-1 microg/mL. Of the aa 315 mutants, 33% exhibited monodrug resistance, compared with 69% of other INH-resistant strains (P<.0001). Multidrug resistance was found among 14% of the aa 315 mutants and 7% of the other INH-resistant strains (P>.05). The probability of being in an IS6110 DNA restriction fragment length polymorphism cluster was similar for aa 315 mutants and INH-susceptible strains, but the probability was reduced in other INH-resistant strains. Thus, aa 315 mutants lead to secondary cases of tuberculosis as often as INH-susceptible strains do.

Antitubercular Agents↗
PubMed2004

Characterization and localization of drug resistance determinants in multidrug-resistant, integron-carrying Salmonella enterica serotype Typhimurium strains.

The genetic background of the antimicrobial resistance of 10 selected multiresistant Salmonella serotype Typhimurium (S. Typhimurium) strains (including the emerging monophasic variant [4,5,12:i:- ]) was investigated. All strains shared class 1 integrons (with seven types of variable regions) and belonged to different lineages (L1-L6) according to their phage types, DNA polymorphisms by XbaI-pulsed-field gel electrophoresis (PFGE), integrons, and/or resistance patterns. The strains were screened for the presence and localization (chromosomal or plasmid) of 32 DNA sequences representing integron-, Tn21-like transposon-, resistance-, and virulence-plasmid genes. Strains belonging to lineage L1 (definitive phage type DT104) carried the 90-kb Salmonella virulence plasmid together with the complete or partial chromosomally located Salmonella Genomic Island 1 (SGI1). All strains belonging to the other five lineages carried their resistance determinants on various resistance plasmids. Two of these strains showed complex plasmid profiles, which included a 95 kb virulence plasmid together with two or four resistance plasmids. Two strains carried a resistance plasmid that lacked the virulence-plasmid-encoding sequences. The remaining two strains carried two different hybrid virulence-resistance plasmids. Twenty-three of the DNA sequences could be assigned to distinct XbaI genomic restriction patterns (PFGE profiles). In this way, the influence of the resistance and virulence plasmids on the PFGE profiles was determined, and several groups of resistance genes could be identified. The data obtained represent a useful epidemiological tool for tracing the emergence and distribution of multiresistant S. Typhimurium worldwide.

Base Sequence↗
PubMed2002

Antibiotic resistance in 1962 invasive isolates of Escherichia coli in 27 Spanish hospitals participating in the European Antimicrobial Resistance Surveillance System (2001).

In Europe, antimicrobial resistance of invasive pathogens has been monitored since 1998 by the European Antimicrobial Resistance Surveillance System (EARSS). The goal of this study is to analyse the susceptibility data of invasive Escherichia coli collected by 27 Spanish laboratories in 2001. Each laboratory identified strains and tested their susceptibility using its own methods. To assess the comparability of susceptibility test results, a quality assurance exercise was performed. We report data from 1962 invasive isolates of E. coli: 1959 from blood and three from cerebrospinal fluid, corresponding to the same number of patients. Resistance to ampicillin, co-trimoxazole, ciprofloxacin and gentamicin was found in 58.46%, 32.91%, 17.19% and 6.39% of isolates, respectively. Extended-spectrum beta-lactamase (ESBL) production was detected in 30 strains (1.55%). Ciprofloxacin resistance was higher in isolates from men and in-patients than in those from women and out-patients (P < 0.001). Resistance to ampicillin and co-trimoxazole was more widespread in children than in adults: 70.37% versus 57.87% (P = 0.01) and 41.84% versus 32.53% (P = 0.05). Non-significant differences in resistance to fluoroquinolones were observed between isolates from children (11.1%) and adults (17.54%), despite the fact that fluoroquinolones are not administered to children. Significantly, resistance to non-beta-lactam antibiotics (co-trimoxazole, ciprofloxacin and gentamicin) was more prevalent in ampicillin-resistant strains and ESBL-producing strains than in ampicillin-susceptible strains and non-ESBL-producing strains. Multidrug resistance was present in 13.92% of isolates; the most prevalent phenotype was resistance to ampicillin, co-trimoxazole and ciprofloxacin, which was detected in 59.36% of multiresistant strains and in 8.22% of strains overall.

Adult↗
PubMed2003

Modulation of the multidrug resistance (MDR) system in the nematode Haemonchus contortus by changing cholesterol content: effects on resistance to anthelmintics.

OBJECTIVES: The efficiency of the anthelmintics used to treat small domestic ruminants infected with nematodes is compromised by the emergence of resistant parasites. Both specific and non-specific mechanisms of resistance exist. The non-specific mechanisms involve multiple resistance phenomena and are dependent on the multidrug resistance (MDR) system, which is also responsible for the development of chemotherapy-resistant tumour cells. We showed previously that the system also exists in nematodes. Membrane 'pumps', known as P-glycoproteins (Pgp), are activated in the MDR system. The nature of the membrane, in particular the lipids, appears to condition the activity of the pumps. Thus, we studied the effects of cholesterol on drug transport activity in the nematode Haemonchus contortus. MATERIALS AND METHODS: We used methyl-beta-cyclodextrin to carry out cholesterol depletion and cholesterol loading experiments. The resulting changes in resistance were estimated by measuring changes in drug transport (a) by means of in vitro egg hatch assays in the presence of a benzimidazole anthelmintic, thiabendazole and (b) by measuring the transport of rhodamine 123 (R123), a specific substrate of Pgp. We used biochemical assays to estimate the cholesterol concentration in the parasites. RESULTS: Changes in the cholesterol content induced changes in anthelmintic resistance; cholesterol depletion gave increased resistance and cholesterol loading gave decreased resistance. These changes also altered the transport of R123. CONCLUSION: Cholesterol depletion or cholesterol loading allow modulation of xenobiotic resistance in nematode eggs as they do in tumour cells. The effect appears to be correlated with changes in the function of membrane P-glycoproteins. The lipid environment thus influences the nematode Pgp activity.

Animals↗
PubMed2003

[Pulsed-field gel electrophoresis type and antimicrobial susceptibility of arbekacin mupirocin and teicoplanin resistant methicillin-resistant Staphylococcus aureus].

Among the isolates of methicillin resistant Staphylococcus aureus (MRSA) which were isolated at Juntendo University Hospital between 1992 and 1998, there were 2 arbekacin resistant strains, 9 mupirocin resistant strain and 7 teicoplanin resistant strains. For each resistant strain, we studied pulsed-field gel electrophoresis (PFGE) pattern, coagulase type, antimicrobial susceptibility pattern and investigated a distribution of the resistant strains at the hospital wards. Two arbekacin resistant strains showed PFGE type A (A3 and A7, respectively). Nine mupirocin resistant strains were type C1; 3 strains, type A (A1, A4, A8); 3 strains and type D, E, G for 1 one each strain. The antimicrobial susceptibility pattern was not similar to each other and the strains were isolated from different year. It is suggested that these strains were not same origin. Seven teicoplanin resistant strains had PFGE type B (B1; 5 strains, B2/B5; 1 each strain). The antimicrobial susceptibility pattern of the strains was similar to each other and the strains were isolated from the same hospital ward between 1995 and 1997. From the above fact, the resistant strains appear to be hospital strains which have same origin.

Anti-Bacterial Agents↗
PubMed1990

Ciprofloxacin-resistant methicillin-resistant Staphylococcus aureus in an acute-care hospital.

Use of ciprofloxacin as an alternative to vancomycin for treatment of methicillin-resistant Staphylococcus aureus infection has been paralleled by the emergence of resistant strains. This phenomenon has also been noticed in our hospital. To confirm our observation, methicillin and ciprofloxacin susceptibilities were tested by disk diffusion and broth microdilution techniques. We studied 83 methicillin-resistant Staphylococcus aureus isolates obtained from various sources over a 4-month period. Ciprofloxacin resistance (MIC, greater than 2 micrograms/ml) was detected in 69 isolates (83%). Prior use of ciprofloxacin was reported for 24 of 69 patients with ciprofloxacin-resistant strains and 0 of 14 patients with ciprofloxacin-susceptible strains. The day of detection during the hospital stay and the location of the source patient were not significantly different between resistant and susceptible strains. Bacteriophage typing showed a higher occurrence of nontypeable strains among ciprofloxacin-resistant strains (54%). Review of our microbiology register showed a progressive increase in the rate of resistance to ciprofloxacin during the first year of use, with initial rates being about 10% and recent rates being higher than 80%. On the other hand, methicillin-susceptible S. aureus remained uniformly susceptible to ciprofloxacin (98.4%). We conclude that prior use of ciprofloxacin is an important factor for the selection of ciprofloxacin-resistant strains and that ciprofloxacin has limited usefulness against methicillin-resistant S. aureus.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Differing activities of quinolones against ciprofloxacin-susceptible and ciprofloxacin-resistant, methicillin-resistant Staphylococcus aureus.

The in vitro activities of nine quinolones (seven fluoroquinolones, nalidixic acid, and acrosoxacin) against methicillin-resistant Staphylococcus aureus (MRSA) were compared with those of the glycopeptides teicoplanin and vancomycin. MICs against 160 strains of ciprofloxacin-susceptible (MIC, less than 2.0 micrograms/ml) MRSA and 40 strains of ciprofloxacin-resistant (MIC, greater than or equal to 2.0 micrograms/ml) MRSA were determined. The following MICs for 50% of the strains tested (in micrograms per milliliter) were obtained for ciprofloxacin-susceptible and -resistant strains, respectively: tosufloxacin, 0.06 and 2.0; ofloxacin, 0.25 and 16; ciprofloxacin, 0.5 and 16; pefloxacin, 0.5 and 32; acrosoxacin, 1.0 and greater than 256; enoxacin, 1.0 and 64; fleroxacin, 1.0 and 32; norfloxacin, 2.0 and 64; nalidixic acid, 64 and 512; teicoplanin, 1.0 and 1.0; vancomycin, 2.0 and 2.0. In mutation rate studies using a range of antibiotic concentrations to reflect those achievable in vivo, resistant mutants grew only on plates containing nalidixic acid (rate of mutation to resistance, 10(-7) to 10(-8) and on plates containing low concentrations of ciprofloxacin, enoxacin, and norfloxacin (rate of mutation to resistance, 10(-8) to 10(-9). In time-kill studies, 99.9% killing was found within 8 h for all of the quinolones tested (norfloxacin and nalidixic acid were not tested). Teicoplanin and vancomycin were less rapidly bactericidal. For the clinical isolates of ciprofloxacin-resistant MRSA, different levels and patterns of quinolone resistance were found. Generally, cross-resistance among the fluoroquinolones was complete; however, incomplete cross-resistance did occur with the nonfluorinated quinolone acrosoxacin.

Anti-Bacterial Agents↗
PubMed2000

Animal and human multidrug-resistant, cephalosporin-resistant salmonella isolates expressing a plasmid-mediated CMY-2 AmpC beta-lactamase.

Salmonella spp. are important food-borne pathogens that are demonstrating increasing antimicrobial resistance rates in isolates obtained from food animals and humans. In this study, 10 multidrug-resistant, cephalosporin-resistant Salmonella isolates from bovine, porcine, and human sources from a single geographic region were identified. All isolates demonstrated resistance to cephamycins and extended-spectrum cephalosporins as well as tetracycline, chloramphenicol, streptomycin, and sulfisoxazole. Molecular epidemiological analyses revealed eight distinct chromosomal DNA patterns, suggesting that clonal spread could not entirely explain the distribution of this antimicrobial resistance phenotype. However, all isolates encoded an AmpC-like beta-lactamase, CMY-2. Eight isolates contained a large nonconjugative plasmid that could transform Escherichia coli. Transformants coexpressed cephalosporin, tetracycline, chloramphenicol, streptomycin, and sulfisoxazole resistances. Plasmid DNA revealed highly related restriction fragments though plasmids appeared to have undergone some evolution over time. Multidrug-resistant, cephalosporin-resistant Salmonella spp. present significant therapeutic problems in animal and human health care and raise further questions about the association between antimicrobial resistance, antibiotic use in animals, and transfer of multidrug-resistant Salmonella spp. between animals and man.

Animals↗
PubMed2005

Characterization of a R115777-resistant human multiple myeloma cell line with cross-resistance to PS-341.

The farnesyl transferase inhibitor R115777 has been found to have clinical activity in diverse hematopoietic tumors. Clinical efficacy, however, does not correlate with Ras mutation status or inhibition of farnesyl transferase. To further elucidate the mechanisms by which R115777 induces apoptosis and to investigate drug resistance, we have identified and characterized a R115777-resistant human myeloma cell line. 8226/R5 cells were found to be at least 50 times more resistant to R115777 compared with the parent cell line 8226/S. K-Ras remained prenylated in both resistant and sensitive cells after R115777 treatment; however, HDJ-2 farnesylation was inhibited in both lines, implying that farnesyl transferase (the drug target) has not been mutated. Whereas many 8226 lines that acquire drug resistance have elevated expression of P-glycoprotein, we found that P-glycoprotein expression is not increased in the 8226/R5 line and intracellular accumulation of R115777 was not reduced. In fact, 8226/R5 cells were insensitive to a diverse group of antitumor agents including PS-341, and multidrug resistance did not correlate with the expression of heat shock proteins. Comparison of gene expression profiles between resistant and sensitive cells revealed expression changes in several genes involved in myeloma survival and drug resistance. Future experiments will attempt to identify genes that are directly linked to the resistant phenotype. Identification of molecules associated with R115777 and PS-341 resistance is clinically relevant because both compounds are being tested in solid tumors and hematopoietic malignancies.

Boronic Acids↗
PubMed2006

[Study on the relationship between the resistance to MTX and the transport protein superfamily of ATP-binding cassette that induces multiple drug resistance].

A major problem, especially the multidrug resistance, in chemotherapy was the resistance to the chemotherapeutic agents. ATP-binding cassette transporter superfamily that mediated the efflux of drugs was involved in multidrug resistance. In order to understand the relationship between the resistance to MTX and the transport protein superfamily of ATP-binding cassette, and to investigate the mechanism of resistance to MTX, the study detected the expressions of mdr1, mrp1, mrp2, mrp3, mrp5, mrp6 and abcg2 that encoded the transport proteins by SuperArray analysis and the expressions of MRP1and MRP5 proteins by Western blot analysis. The results showed that the multidrug resistance proteins were the chief member of ATP-binding cassette transporter superfamily related to resistance to MTX. And the high expression levels of mrp1 and mrp5 were detected. Moreover, it revealed by SuperArray analysis that expression of mrp5 in MTX-resistant cells was significantly higher than that in normal mouse cells. Besides, corresponding excessive expression of MRP5 protein in MTX-resistant cells was also confirmed by Western blot. So, MRP5 could play important roles in the resistance to MTX and would be a new potential drug target.

3T3 Cells↗
PubMed2001

Multidrug resistance in tumour cells: characterization of the multidrug resistant cell line K562-Lucena 1.

Multidrug resistance to chemotherapy is a major obstacle in the treatment of cancer patients. The best characterised mechanism responsible for multidrug resistance involves the expression of the MDR-1 gene product, P-glycoprotein. However, the resistance process is multifactorial. Studies of multidrug resistance mechanisms have relied on the analysis of cancer cell lines that have been selected and present cross-reactivity to a broad range of anticancer agents. This work characterises a multidrug resistant cell line, originally selected for resistance to the Vinca alkaloid vincristine and derived from the human erythroleukaemia cell K562. This cell line, named Lucena 1, overexpresses P-glycoprotein and have its resistance reversed by the chemosensitisers verapamil, trifluoperazine and cyclosporins A, D and G. Furthermore, we demonstrated that methylene blue was capable of partially reversing the resistance in this cell line. On the contrary, the use of 5-fluorouracil increased the resistance of Lucena 1. In addition to chemotherapics, Lucena 1 cells were resistant to ultraviolet A radiation and hydrogen peroxide and failed to mobilise intracellular calcium when thapsigargin was used. Changes in the cytoskeleton of this cell line were also observed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗