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PubMed2005

Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants.

BACKGROUND AND AIMS: Resistance is a major challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). We investigated the mechanisms of resistance in patients with progressive GISTs with primary KIT mutations and the efficacy of the kinase inhibitor PKC412 for the inhibition of imatinib-resistant mutants. METHODS: We performed a cytogenetic analysis and screened for mutations of the KIT and PDGFRA kinase domains in 26 resistant GISTs. KIT autophosphorylation status was assessed by Western immunoblotting. Imatinib-resistant GIST cells and Ba/F3 cells expressing these mutant proteins were tested for sensitivity to imatinib and PKC412. RESULTS: Six distinct secondary mutations in KIT were detected in 12 progressive tumors, with V654A and T670I found to be recurrent. One progressive tumor showed acquired PDGFRA -D842V mutation. Amplification of KIT or KIT / PDGFRA was found in 2 patients. Eight of 10 progressive tumors available for analysis showed phosphorylated KIT. Two remaining progressive tumors lost KIT protein expression. GIST cells carrying KIT -del557-558/T670I or KIT -InsAY502-503/V654A mutations were resistant to imatinib, while PKC412 significantly inhibited autophosporylation of these mutants. Resistance to imatinib and sensitivity to PKC412 of KIT -T670I and PDGFRA -D842V mutants was confirmed using Ba/F3 cells. CONCLUSIONS: This study shows the high frequency of KIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of KIT / PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant KIT -T670I and KIT -V654A and of PDGFRA -D842V mutants to PKC412.

Adult↗
PubMed1990

Penicillin-resistant viridans streptococci have obtained altered penicillin-binding protein genes from penicillin-resistant strains of Streptococcus pneumoniae.

Penicillin-resistant strains of Streptococcus pneumoniae possess altered forms of penicillin-binding proteins (PBPs) with decreased affinity for penicillin. The PBP2B genes of these strains have a mosaic structure, consisting of regions that are very similar to those in penicillin-sensitive strains, alternating with regions that are highly diverged. Penicillin-resistant strains of viridans groups streptococci (e.g., S. sanguis and S. oralis) that produce altered PBPs have also been reported. The PBP2B genes of two penicillin-resistant clinical isolates of S. sanguis were identical in sequence to the mosaic class B PBP2B genes found in penicillin-resistant serotype 23 strains of S. pneumoniae. Emergence of penicillin resistance appears to have occurred by the horizontal transfer of an altered PBP2B gene from penicillin-resistant S. pneumoniae into S. sanguis. The PBP2B genes of three penicillin-resistant S. oralis strains were similar to the mosaic class B PBP2B gene of penicillin-resistant strains of S. pneumoniae but possessed an additional block of diverged sequence. Penicillin resistance in S. oralis has also probably arisen by horizontal transfer of this variant form of the class B mosaic PBP2B gene from a penicillin-resistant strain of S. pneumoniae.

Amino Acid Sequence↗
PubMed2005

Troglitazone overcomes doxorubicin-resistance in resistant K562 leukemia cells.

Human myeloid leukemia cells become resistant to doxorubicin (DOX) treatment and this resistance is correlated with an increased glyoxalase 1 (GLO1) expression. Troglitazone (TRG) is an anti-diabetic thiazolidinedione drug previously used to treat insulin-resistance in Type 2 diabetes. We previously showed that TRG down regulates GLO1 gene expression in a number of cell types and reasoned that TRG might be a useful adjunct therapy to overcome DOX resistance. Here we show that TRG treatment overcomes the resistance to DOX in the DOX-resistant K562 human leukemia cells. Higher doses of TRG were found to alter histone H3:H2B ratios with a decreased ratio in DOX-sensitive and increased ratio in DOX-resistant lines. Furthermore, phosphorylated H3 was seen in DOX-resistant but not in DOX-sensitive cells. We conclude that the downstream effect of TRG in DOX-resistant cells may be interference with normal cell cycle events leading to genomic instability. Our data suggest that TRG may be a useful adjunct therapy in circumventing drug resistance in K562 leukemia cells.

Antineoplastic Agents↗
PubMed2006

Imipenem resistance among pseudomonas aeruginosa isolates: risk factors for infection and impact of resistance on clinical and economic outcomes.

OBJECTIVES: To identify risk factors for infection with imipenem-resistant Pseudomonas aeruginosa and determine the impact of imipenem resistance on clinical and economic outcomes among patients infected with P. aeruginosa. DESIGNS: An ecologic study, a case-control study, and a retrospective cohort study. SETTING: A 625-bed tertiary care medical center. PATIENTS: All patients who had an inpatient clinical culture positive for P. aeruginosa between January 1, 1999, and December 31, 2000. RESULTS: From 1991 through 2000, the annual prevalence of imipenem resistance among P. aeruginosa isolates increased significantly (P<.001 by the chi (2) test for trend). Among 879 patients infected with P. aeruginosa during 1999-2000, a total of 142 had imipenem-resistant P. aeruginosa infection (the case group), whereas 737 had imipenem-susceptible P. aeruginosa infection (the control group). The only independent risk factor for imipenem-resistant P. aeruginosa infection was prior fluoroquinolone use (adjusted odds ratio, 2.52 [95% confidence interval {CI}, 1.61-3.92]; P<.001). Compared with patients infected with imipenem-susceptible P. aeruginosa, patients infected with imipenem-resistant P. aeruginosa had longer subsequent hospitalization durations (15.5 days vs 9 days; P=.02) and greater hospital costs (81,330 dollars vs 48,381dollars ; P<.001). The mortality rate among patients infected with imipenem-resistant P. aeruginosa was 31.1%, compared with 16.7% for patients infected with imipenem-susceptible P. aeruginosa (relative risk, 1.86 [95% CI, 1.38-2.51]; P<.001). In multivariable analyses, there remained an independent association between infection with imipenem-resistant P. aeruginosa and mortality. CONCLUSIONS: The prevalence of imipenem resistance among P. aeruginosa strains has increased markedly in recent years and has had a significant impact on both clinical and economic outcomes. Our results suggest that curtailing use of other antibiotics (particularly fluoroquinolones) may be important in attempts to curb further emergence of imipenem resistance.

Adult↗
PubMed1999

Gentamicin-resistance determinants confer background-dependent hygromycin B resistance.

Micromonospora strains that produce aminoglycoside antibiotics have a high level of resistance to their own products and to structurally similar antibiotics with a 4,6-disubstituted deoxystreptamine aminocyclitol component such as neomycin, kanamycin, or gentamicin, but these strains remain susceptible to other aminoglycosides such as neomycin and apramycin, in which the aminocyclitol component has different types of substitutions. Therefore, it was surprising that the aminoglycoside-producing Micromonospora strains examined here also showed high-level resistance to hygromycin B, in spite of the fact that this compound has a structurally different aminocyclitol component and a mode of antibacterial action that was also shown to differ somewhat from the mode of action of gentamicin-type antibiotics. When the resistance genes sgm and grm were cloned in Streptomyces lividans and E. coli, they conferred resistance to the expected aminoglycoside compounds but not to hygromycin B. In contrast, introduction of the same resistance genes to M. melanosporea produced resistance to hygromycin B as well. Such an apparent strain dependence in the expression of hygromycin B resistance was also observed with other genes from related genera that are also responsible for aminoglycoside resistance due to methylation of 16S rRNA: of these genes, only kgm assisted expression of hygromycin B resistance and only in the background of M. melanosporea. A possible mechanism for the background dependent of hygromycin B resistance is discussed.

Anti-Bacterial Agents↗
PubMed2004

Tetracycline and macrolide co-resistance in Streptococcus pyogenes: co-selection as a reason for increase in macrolide-resistant S. pyogenes?

In Denmark, tetracycline resistance in Streptococcus pyogenes is frequent (>30%) whereas macrolide resistance is low (<5%). The aim of this study was to investigate the genetic background of tetracycline- and macrolide resistance in macrolide-resistant S. pyogenes (MRSP) and to investigate the correlation between the use of macrolide and tetracycline and macrolide resistance using international data. A total of 133 MRSP isolates were received at Statens Serum Institut from nine Danish clinical microbiology laboratories between. November 2000, and November 2002. The macrolide-resistance genes, erm(B), erm(A), and mef(A) were detected in 46%, 18%, and 32% of the tested MRSP isolates, respectively. In 4% of MRSP isolates, none of the MR genes were detected. Tetracycline resistance was found in 52% of MRSP. Tetracycline resistance was encoded by either tet(M) or tet(O). erm(B) and mef(A) were associated with tet(M). Sixteen different T types were detected among the 133 MRSP. Analysis of the importance of antibiotic use for development of macrolide resistance in S. pyogenes showed no correlation with macrolide use alone (p = 0.15) but a significant correlation (p = 0.03) for the combination of macrolide and tetracycline use. The frequency of macrolide resistance in Danish S. pyogenes was low and mainly due to erm genes. A high frequency of macrolide-tetracycline coresistance in S. pyogenes is found in many countries including Denmark, hence tetracycline use must be considered as a co-factor in selection of MRSP.

Anti-Bacterial Agents↗
PubMed2005

Characterization of erythromycin-resistant Streptococcus pneumoniae in Korea, and In Vitro activity of telithromycin against erythromycin-resistant Streptococcus pneumoniae.

To characterize the phenotypes and genotypes of erythromycin-resistant clinical isolates of Streptococcus pneumoniae in Korea and to evaluate the in vitro activity of telithromycin against these erythromycin-resistant isolates, we tested a total of 676 isolates of S. pneumoniae collected from 1997 to 2002 in a tertiary hospital in Seoul, Republic of Korea. MICs for erythromycin and telithromycin were determined by the agar dilution method. The macrolide resistance phenotypes of erythromycin-resistant isolates were determined by the erythromycin- clindamycin-rokitamycin triple disk (ECRTD) and MIC induction tests, whereas their macrolide resistance genotypes were determined by PCR for the erm(B), erm(A), subclass erm(TR), and mef genes. To discriminate between mef(A) and mef(E), PCR-restriction fragment length polymorphism (RFLP) analyses were performed. Of the 676 S. pneumoniae isolates, 459 (67.9%) were resistant to erythromycin. Of the 459 erythromycin-resistant isolates, 343 (74.7%) were assigned to the cMLS phenotype, 48 (10.4%) to the iMcLS phenotype, 4 (0.9%) to the iMLS phenotype, and 64 (14.0%) to the M phenotype. The erm(B) gene was detected in 251 (54.6%) isolates, the mef gene was detected in 64 (14.0%), and both the erm(B) and mef genes were detected in 144 (31.4%) isolates. All of the mef genes detected were identified as mef(E). Of the 459 erythromycin- resistant isolates, all but one were susceptible to telithromycin. The MIC(50)/MIC(90) to telithromycin of isolates carrying erm(B), mef(E), and both genes was 0.06/0.5 microg/ml, 0.03/0.125 microg/ml, and 0.5/1.0 microg/ml, respectively. Although the MICs of telithromycin for the erythromycin-resistant isolates varied according to genotype, telithromycin was very active against these erythromycin-resistant S. pneumoniae.

Anti-Bacterial Agents↗
PubMed2003

Prevalence and association of macrolide-lincosamide-streptogramin B (MLS(B)) resistance with resistance to moxifloxacin in Clostridium difficile.

Clostridium difficile remains the leading cause of nosocomially acquired diarrhoea. C. difficile usually exhibits resistance against beta-lactam antibiotics, whereas susceptibility to other drugs may vary. This study investigated the antimicrobial susceptibility of C. difficile to different antibiotics over a period of time and characterizes molecular mechanisms for resistance. One hundred and seventy-three toxigenic and 19 non-toxigenic C. difficile strains, recovered from patients in two university hospitals in Germany between 1986 and 2001, were investigated for their susceptibility to erythromycin, clindamycin, moxifloxacin, vancomycin and metronidazole employing the Etest. The genetic background for resistance was analysed using PCR and DNA sequencing. All strains were susceptible to vancomycin and metronidazole. Resistance to erythromycin, clindamycin and moxifloxacin was found in 27%, 36% and 12% of the tested strains, respectively. High-level resistance (MIC > 128 mg/L) against erythromycin and clindamycin was detected in 25% of the strains tested. Thirty-four of the macrolide-lincosamide-streptogramin B (MLS(B))-resistant strains carried the erythromycin resistance methylase gene. The results indicate an increase in the prevalence of resistance to MLS(B) and fluoroquinolone antibiotics in C. difficile. Fluoroquinolone resistance is associated with resistance to MLS(B) antimicrobials.

Anti-Bacterial Agents↗
PubMed2004

In vivo pharmacodynamic efficacy of gatifloxacin against Streptococcus pneumoniae in an experimental model of pneumonia: impact of the low levels of fluoroquinolone resistance on the enrichment of resistant mutants.

OBJECTIVES: To investigate the impact of low levels of fluoroquinolone resistance on the emergence of resistant mutants, we examined the mutant selection window (MSW) hypothesis in experimental pneumonia in rabbits infected with pneumococci with various susceptibility levels to fluoroquinolones and treated with gatifloxacin using a human-like regimen (equivalent to 400 mg once daily). The MSW corresponds to the range of concentrations between the minimal inhibitory concentration (MIC) and the mutant prevention concentration (MPC), which is the antibiotic concentration that prevents selection of resistant mutants. MATERIALS AND METHODS: Five pneumococcal strains were tested and were defined as follows [MIC of ciprofloxacin (mg/L)/MIC of gatifloxacin (mg/L)/MPC of gatifloxacin (mg/L)/involved quinolone resistance mechanisms]: strain 16089=0.5/0.25/0.25/wild-type; strain MS1A=2/0.5/1/efflux; strain MS2A=8/1/8/parC S79F; strain MR3B4=10/1/8/parC S79T; strain Gyr-1207=6/4/4/gyrA S81F. RESULTS: A 48 h human-like treatment with gatifloxacin was significantly bactericidal on pneumonia induced by strain 16089 ( > 6 log(10) killing) as well as the efflux derivative strain MS1A ( > 5 log(10) killing). However, a small number of parC-gyrA mutants were recovered in 26% of the animals infected with this efflux strain. As expected, no decrease in viable bacteria counts was observed when pneumonia was induced by the gyrA resistant strain. In contrast, because of the enrichment of highly resistant mutants in 100% of the animals, no significant bacterial reduction was observed after treatment of pneumonia induced by the two susceptible parC mutated strains. A classification and regression tree (CART) analysis identified T(MSW) (percentage of the time during which gatifloxacin serum concentrations are inside the MSW) and AUC(MSW) (area under curve between MIC and MPC values) as the best parameters associated with the enrichment of resistant pneumococci. CONCLUSIONS: This study shows that the acquisition of a low level of fluoroquinolone resistance (especially a parC mutation and to a lesser extent an efflux mechanism) is associated with a clearly lower potential for preventing resistance development. These data support the concept that resistant mutants are selectively enriched when antibiotic concentrations fall inside the mutant selection window and suggest that in vivo dynamic models have to be used to predict the relative abilities of quinolones to prevent mutant selection.

Animals↗
PubMed2005

Occurrence of integrons and resistance genes among sulphonamide-resistant Shigella spp. from Brazil.

OBJECTIVES: To determine the occurrence of class 1 and 2 integrons and antimicrobial resistance genes among sulphonamide-resistant Shigella strains isolated in Brazil during 1999-2003. METHODS: Sixty-two Shigella (Shigella flexneri, n = 47 and Shigella sonnei, n = 15) were tested against 21 antimicrobial agents. The presence of integrons classes 1 and 2 and antimicrobial resistance genes was investigated by PCR using specific primers. RESULTS: A total of eight antimicrobial resistance profiles were identified, with the profile of resistance to sulfamethoxazole, trimethoprim, spectinomycin, streptomycin and tetracycline being the most common among S. sonnei, and additionally to ampicillin and chloramphenicol among S. flexneri. Class 1 integrons were found in only two strains, whereas class 2 integrons were found in 56 (90.3%) of the strains. All class 2-positive strains had a similar fragment of 2214 bp harbouring a gene cassette array conferring resistance to trimethoprim, streptothricin and spectinomycin/streptomycin. The genes coding for resistance to chloramphenicol (catA1), tetracycline [tet(A) and tet(B)] and ampicillin (bla(OXA) and bla(TEM)), were detected in resistant strains. CONCLUSIONS: The detection of class 1 and 2 integrons and additional antimicrobial resistance genes allowed us to identify the most frequent antimicrobial resistance patterns of Shigella spp. isolated in Brazil.

DNA Transposable Elements↗
PubMed2005

Increasing incidence of quinolone resistance in human non-typhoid Salmonella enterica isolates in Korea and mechanisms involved in quinolone resistance.

OBJECTIVES: We investigated the trends of nalidixic acid resistance in human non-typhoid Salmonella enterica in a Korean population, and examined some possible mechanisms involved in this resistance. METHODS: A total of 261 clinical strains were tested. For all strains, the MICs of nalidixic acid were determined. Nalidixic acid-resistant strains underwent further analysis, including determination of MICs of other antibiotics, mutation analysis within the topoisomerase genes, organic solvent tolerance test, western blotting for AcrA, marOR mutation analysis, ciprofloxacin accumulation test, and PCR for the qnr gene. The clonal relationships of Salmonella strains were examined by random amplified polymorphic DNA analysis. RESULTS: The incidence of nalidixic acid resistance increased from 1.8% in 1995-96 to 21.8% in 2000-02. The resistance rate was higher in S. enterica serotype Enteritidis (21.6%) than in serotype Typhimurium (12.1%). The nalidixic acid resistance rates in Salmonella Enteritidis varied according to the phage type (PT) and Salmonella Enteritidis PT 1 was most commonly associated with resistance to nalidixic acid. Several cases of clonal spread, especially by Salmonella Enteritidis PT 1, were identified. Of the 46 nalidixic acid-resistant strains, 43 had single mutations in the gyrA gene. Four strains were organic solvent-tolerant and were associated with decreased ciprofloxacin accumulation; three of these showed increased expression of AcrA and had novel mutations in marOR (84L). The qnr gene was not identified. CONCLUSIONS: Recently, the rate of nalidixic acid resistance in Korean clinical Salmonella strains markedly increased and it was partly due to the clonal spread of Salmonella Enteritidis, especially PT 1. The main mechanism of nalidixic acid resistance was a mutation in the gyrA region.

Anti-Bacterial Agents↗
PubMed1989

Quantitative determination of factors contributing to doxorubicin resistance in multidrug-resistant cells.

There is a large discrepancy between the changes in drug accumulation and the changes in drug cytotoxicity that accompany development of anthracycline resistance in multidrug-resistant cells. In our study, a quantitative relationship has been established between reversal of multidrug resistance by resistance modifiers and a concomitant decrease in intracellular levels of doxorubicin measured at equitoxic concentrations (IC50) in CHRC5 and 2780AD multidrug-resistant cells. (IC50 = concentration required for 50% growth inhibition.) We have demonstrated that resistance modifiers like verapamil and Ro 11-2933/001 act by increasing the effectiveness of intracellular doxorubicin, apparently by inducing redistribution of the drug from the cytoplasm to the nucleus of a multidrug-resistant cell, as shown by quantitative fluorescence microscopy. At complete reversal of resistance, as measured directly or inferred by extrapolation, the amount of intracellular doxorubicin at the IC50 as well as the ratio of nuclear doxorubicin to cytoplasmic doxorubicin were the same as those in sensitive cells. These results offer an explanation for the frequently observed discrepancies between drug accumulation and cytotoxicity and also show quantitatively that a decrease in drug accumulation and a change in intracellular drug distribution together are the only determinants of doxorubicin resistance in the multidrug-resistant cells studied.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Resistance against ricin-induced apoptosis in a brefeldin A-resistant mutant cell line (BER-40) of Vero cells.

We have found that a brefeldin A (BFA)-resistant mutant cell line derived from Vero cells (BER-40) is highly resistant to ricin-induced apoptosis as compared with parental Vero cells. In BER-40 cells, all apoptotic events caused by ricin including cytolysis, nuclear morphological changes, and DNA fragmentation occur to a lesser extent than in Vero cells, even though both cell lines show similar sensitivities to ricin-mediated inhibition of protein synthesis. Furthermore, no significant apoptotic signaling events, such as increases in caspase-3 and -9-like activities, release of cytochrome c from mitochondria, or the cleavage of PARP, were observed in BER-40 cells under the conditions at which these changes were evident in Vero cells. Intracellular biochemical changes associated with ricin-induced apoptosis, such as the depletion of glutathione and an increase in free Zn2+, were also less apparent in BER-40 cells than in Vero cells. BER-40 cells were also found to be highly resistant to apoptosis induced by other toxins with different intoxication mechanisms such as diphtheria toxin, modeccin, and anisomycin. These results suggest that the entire apoptotic signal transduction mechanism in BER-40 cells, which may be triggered after the inhibition of protein synthesis by toxins, becomes resistant. Since MDCK cells, a naturally BFA resistant cell line, are highly sensitive to ricin-induced apoptosis, it seems likely that the BFA resistance phenotype may not necessarily lead to resistance to apoptotic cell death. Probably the underlaying BFA-resistance mechanism in BER-40 cells is distinct from that in MDCK cells, and the resistance to ricin-induced apoptosis of BER-40 cells may be a unique phenotype acquired concomitantly with BFA-resistance.

Animals↗
PubMed1988

Resistance of multidrug-resistant lines to natural killer-like cell-mediated cytotoxicity.

Multidrug resistance (MDR) refers to a complex phenotype that describes a number of features characterized primarily by resistance to a wide range of structurally unrelated drugs. In this paper we investigated the relationship between drug resistance and resistance to NK-mediated cytotoxicity. Studies with two independently selected multidrug-resistant cell lines indicated that increased drug resistance was associated with both an increased resistance to NK-mediated cytotoxicity and increased levels of membrane P-glycoprotein expression. This resistance to cytotoxicity appears to result partly from an alteration in the membrane structure of the target cells inasmuch as there was a reduction in effector:target cell recognition. Resistance to NK-mediated cytotoxicity should be included with the numerous pleiotropic changes associated with the multidrug resistance phenotype.

Cell Line↗
PubMed1997

Messenger RNA expression of resistance proteins and related factors in human ovarian carcinoma cell lines resistant to doxorubicin, taxol and cisplatin.

Doxorubicin- (OAW-dox, SK-OV-dox), taxol- (OAW-tax, SK-OV-tax) and cisplatin- (SK-OV-cis) resistant cells derived from the parental OAW-42 and SK-OV-3 cell lines were established. OAW-42 sublines showed high resistance, the SK-OV-3 sublines only low resistance. OAW-42 sublines showed a cross-resistance profile typical of multidrug resistance (MDR). The sublines of SK-OV-3 showed a cross-resistance profile different from the OAW-42 sublines. The mRNA expression of several resistance proteins and related factors was analyzed. An overexpression of P-glycoprotein 170 (P-170), glutathione-S-transferase-pi (GST-pi), thymidylate synthase (TS), glutathione peroxidase (GP) and c-jun was found in OAW-dox and OAW-tax cells. Additionally, OAW-tax cells expressed a higher mRNA level of protein kinase Cbeta2. DNA analysis revealed a 2-fold gene amplification of P-170, whereas the genes for GST-pi, TS and GP were not amplified. SK-OV-dox and SK-OV-tax cells showed a decreased level of histone 3 (H3) and TS mRNA. This shows that the sublines of OAW-42 developed resistance by co-expression of several resistance-related proteins and proto-oncogenes whereas the sublines of SK-OV-3 expressed resistance by decreased expression of the proliferation-dependent proteins H3 and TS.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Establishment and characterization of adriamycin-resistant human colorectal adenocarcinoma HCT-15 cell lines with multidrug resistance.

The multidrug resistance (MDR) phenotype, either intrinsic and/or acquired, is discussed in relation to several MDR-associated markers such as P-glycoprotein (P-gp) encoded by mdr1, multidrug-resistance-associated protein (MRP) encoded by MRP and lung-resistance-associated protein (LRP) encoded by LRP. Well-characterized in vitro models are required to elucidate the mechanisms of MDR. The aim of the present study is the establishment of a drug-resistant subline from human colorectal adenocarcinoma HCT-15 that intrinsically expresses moderate levels of P-gp, MRP and LRP. Three adriamycin-resistant sublines (HCT-15/ADM1, HCT-15/ADM2 and HCT-15/ADM2-2) were established by stepwise exposure in growth medium that was supplemented with 25-200 ng/ml adriamycin-resulting in a 2.2- to 7.8-fold increase in IC(50) values by using the XTT assay. They were cross-resistant to MDR-related drugs, epirubicin, mitoxantrone, vincristine, etoposide and taxol, but not the MDR-unrelated drug, mytomycin C. The resistance to adriamycin was confirmed in vivo by a lack of sensitivity in athymic nude mice. Gene expression data for mdr1/P-gp, MRP/MRP and LRP/LRP on both mRNA and protein levels demonstrated that the molecules contributing to MDR in resistant sublines are mainly P-gp and partially MRP. The newly established adriamycin-resistant sublines of HCT-15 will provide clinically relevant tools to investigate how to overcome drug resistance and elucidate possible mechanisms of acquired MDR in human colon cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Limited evolution of HIV antiretroviral drug resistance-associated mutations during the performance of drug resistance testing.

We investigated the evolution of HIV reverse transcriptase (RT)- and protease-associated antiretroviral (ARV) drug resistance mutations during the time taken to perform genotypic drug resistance testing. Thirty treatment-experienced patients who were adherent to therapy and who underwent genotypic drug resistance testing provided blood samples at randomization and when reviewing the test results (baseline). Patients remained on their existing therapy between randomization and baseline. The predominant HIV strains in 10 patients (33%) either lost and/or gained primary RT inhibitor (RTI)- or protease inhibitor (PI)-associated resistance mutations during the testing period. Of the 9 patients with RT mutations, 2 lost, 5 gained, and 2 both lost and gained RTI resistance mutations. One patient gained a significant PI-associated resistance mutation on an existing PI-resistant background. The evolution that occurred in the RT may have altered the effectiveness of subsequent ARV therapy in some patients. Neither viral load at randomization, ARV drug class used at randomization, time between collection of blood samples, duration of current therapy, nor number of ARV drugs used influenced gain or loss of resistance mutations. There was a significant association between duration of previous ARV therapy and gain of RTI-associated resistance mutations ( p =.02), however. In general, our results suggest that patients should continue current therapy until test results are available. A few patients would be expected to gain ARV drug-associated resistance mutations during this time, however.

Adult↗
PubMed2004

Relationship between drug resistance and HIV-1 disease progression or death in patients undergoing resistance testing.

OBJECTIVE: To evaluate factors associated with drug resistance detected by genotypic antiretroviral resistance testing (GART), and to determine the association between the level of resistance and subsequent human immunodeficiency type 1 (HIV-1) disease progression or death. DESIGN: Observational cohort study. METHODS: We identified highly active antiretroviral therapy (HAART)-treated patients who had GART as part of clinical management. Factors associated with greater numbers of resistance mutations were assessed by ordinal logistic regression. Survival analysis was used to assess time to a new opportunistic condition or death following GART. RESULTS: A total of 572 patients were identified who had GART: of these, 50% had 0-2 resistance mutations, 33% had 3-6 mutations, and 17% had >/= 7 mutations. In multivariate analysis, prolonged use of HAART in the setting of incomplete viral suppression was significantly associated with more drug resistance. Patients with fewer resistance mutations were significantly more likely to achieve viral suppression after GART than patients with more mutations. Compared to patients with two or less resistance mutations, those with three to six mutations, or seven or more mutations were not at higher risk of HIV-1 disease progression or death over a median follow-up of 15 months. In contrast, continued HAART use following GART was strongly associated with slower disease progression, particularly at lower CD4 cell counts. CONCLUSION: These results support the hypothesis the drug-resistant HIV-1 may be less pathogenic than wild-type virus, and that continued use of HAART might provide clinical benefit, despite persistent viremia and HIV-1 drug resistance.

Adult↗