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PubMed2003

In vivo establishment and characterization of a paclitaxel-resistant human ovarian cancer cell line showing enhanced growth properties and drug-resistance only in vivo.

PURPOSE: In order to establish a more faithful model of clinically recurrent ovarian cancer after paclitaxel-based chemotherapy, a paclitaxel-resistant human ovarian cancer cell line was established in vivo, and its biological profiles were compared with the conventional in vitro established drug-resistant cell line. METHODS: An in vivo paclitaxel-resistant subline (OM1/Tvivo) was established from the parental human ovarian cancer cell line (OVMG1) by repeated paclitaxel administration into tumor-bearing mice. As a control, the in vivo drug-sensitive subline (OM1/Cvivo) was made in the same manner, without paclitaxel. An in vitro paclitaxel-resistant subline (OM1/Tvitro) was established by exposure to stepwise increased concentrations of the drug in a cell culture medium. Chromosomal analysis, evaluation of growth, invasiveness and metastasis, in vivo and in vitro drug sensitivity, and a pharmacokinetic study were performed. RESULTS: Both in vivo sublines confirmed their human origin by G-band chromosomal analysis and showed a similar cell growth rate in cell culture. As for in vivo tumor growth, OM1/Tvivo showed enhanced tumor growth property compared with OM1/Cvivo, while OM1/Tvitro lost tumorigenicity. Both OM1/Tvivo and OM1/Cvivo sublines as well as their parental OVMG1 could not form either invasive or metastatic lesions. Compared with the OM1/Cvivo subline, the OM1/Tvivo tumor showed stable drug-resistance and lower drug distribution after paclitaxel administration into mice, whereas cultured OM1/Tvivo cells lost both completely. On the other hand, an unreasonably higher level of drug-resistance and lower drug concentration was detected in vitro only in OM1/Tvitro cells after exposure to the drug in a culture medium. CONCLUSIONS: These results suggest that the in vivo established paclitaxel-resistant cell line, rather than the conventional in vitro established cell line, is a suitable and faithful model for clinically recurrent tumors showing transformed aggressiveness. The in vivo specific drug-resistant mechanism should involve an interaction between the tumor and host stromal tissue rather than only changes in cellular drug sensitivity. The present study is probably the first report of an in vivo established paclitaxel-resistant human ovarian cancer cell line, and the elucidation of such an in vivo drug-resistance mechanism may be clinically important in preventing or overcoming acquired drug-resistant ovarian cancers recurring after paclitaxel-based chemotherapy.

Animals↗
PubMed2006

Protein Kinase C alpha is a marker for antiestrogen resistance and is involved in the growth of tamoxifen resistant human breast cancer cells.

Development of resistance to antiestrogen treatment in breast cancer patients is a serious therapeutic problem. The molecular mechanisms contributing to resistance are currently unclear; however it is known that increased activation of growth signaling pathways is involved. Protein Kinase C alpha (PKCalpha) is associated with a diverse range of cancers and is previously shown to be overexpressed in three out of four antiestrogen resistant breast cancer cell lines. In this study we investigated whether PKCalpha contributes to antiestrogen resistant growth. A panel of nine resistant cell lines was investigated, all of which displayed elevated levels of PKCalpha expression relative to parental MCF-7 cells. Stable PKCalpha overexpression in MCF-7 cells significantly reduced sensitivity to the antiestrogens, tamoxifen and ICI 182,780. Two resistant cell lines were chosen for further studies: tamoxifen resistant MCF-7/TAM(R)-1 (TAM(R)-1) and ICI 182,780 resistant MCF-7/182(R)-6 (182(R)-6). Treatment with the PKCalpha inhibitor Ro-32-0432 resulted in a preferential growth inhibition of these two cell lines relative to MCF-7 cells. Moreover, transient down-regulation of PKCalpha resulted in a 30-40% growth inhibition of TAM(R)-1 and 182(R)-6, while MCF-7 remained unaffected. Stable PKCalpha knock-down in TAM(R)-1 using small hairpin RNA, resulted in a tamoxifen sensitive "MCF-7-like" growth phenotype, while the same approach in 182(R)-6 cells did not alter their sensitivity to ICI 182,780. These results demonstrate a functional contribution of PKCalpha to tamoxifen resistant growth. Furthermore, our data suggest the potential for PKCalpha as a marker for antiestrogen resistance and as a promising therapeutic target in the treatment of tamoxifen resistant breast cancer.

Biomarkers, Tumor↗
PubMed1991

Evolution of Staphylococcus aureus resistance to erythromycin in Denmark, 1959 to 1988: correlations between characteristics of erythromycin-resistant bacteraemia strains.

In an attempt to characterize erythromycin-resistant Staphylococcus aureus we present the intricate relationships between the following factors: phage type, period of isolation, antibiogram, minimum inhibitory concentration (MIC) to erythromycin, inducible or constitutive resistance, spectinomycin susceptibility, hospital- or community-acquired infection, and mortality rate. We studied 718 cases of bacteraemia with erythromycin-resistant S. aureus, occurring between 1959 and 1988. Central factors were phage type pattern, period of isolation, and antibiogram. Between 1959 and 1973 the majority of the erythromycin-resistant strains were multiresistant and belonged to the 83A complex and the related group III. They were mainly inducibly resistant, spectinomycin resistant, and had intermediate MICs (1-4 mg l-1) to erythromycin. The majority of these strains came from hospital-acquired infections and still exist today, although in decreased numbers. By contrast, erythromycin-resistant S. aureus isolated in recent years are usually co-resistant only to penicillin and more rarely also to tetracycline. These strains have inducible resistance, are spectinomycin susceptible, and have a high erythromycin MIC. They are isolated both from hospital- and community-acquired infections. Strains with constitutive resistance to macrolides occurred at a stable low level (13%) during the whole observation period and always had high MICs to erythromycin. The mortality rate among patients with S. aureus bacteraemia due to an erythromycin-resistant strain was only associated with the year of infection and decreased from 61% in the first 15-year period to 40% in the subsequent 15 years.

Bacteriophage Typing↗
PubMed1992

Thiol manipulation as a means of overcoming drug resistance in a novel cyclophosphamide-induced resistant cell line.

Acquired drug resistance is a major obstacle in the successful treatment of cancer by chemotherapy. To study mechanisms of resistance to alkylating agents, we have derived an in vitro subline of the murine KHT-iv sarcoma, KHT-rcp/iv, that has acquired resistance to cyclophosphamide. Compared to the parental line, KHT-rcp/iv exhibited an approximately 2.8-fold resistance, determined from the ratio of the slopes of the resistant to the parental survival curve. The subline also was found to be cross-resistant to other alkylating agents, as well as to the epipodophyllotoxin, etoposide, a structurally unrelated compound (resistance factor of approximately 2.2). In view of this broad spectrum of cross-resistance observed, we investigated the possibility that glutathione (GSH), an abundant tripeptide implicated in the detoxification of electrophilic species, may be involved. GSH levels were increased two-fold in the resistant line (16.0 +/- 1.0 fmol/cell) as compared to the parent line (8.1 +/- 0.7 fmol/cell). Also, when the GSH content was reduced to that of the parent with the addition of the thiol depletor buthionine sulfoxinine (BSO), the sensitivity of the subline to cyclophosphamide, as well as to the other agents, was enhanced so that it equaled that of the parent cell line. These results imply that enhanced GSH levels may be a major mechanism of resistance in the KHT-rcp/iv cells. Our findings further suggest that thiol manipulation may prove useful in overcoming this type of pleiotropic drug resistance.

Animals↗
PubMed1995

Relationships between resistance to cisplatin and antifolates in sensitive and resistant tumour cell lines.

Possible relationships between tumour resistance to cisplatin and the folate-based thymidylate synthase (TS) inhibitors, CB3717 and ZD1694 (tomudex), have been investigated in vitro using a panel of tumour cell lines (predominantly human ovarian), either parental or possessing acquired resistance to cisplatin or ZD1694. Across eight parent human tumour cell lines, ZD1694 was the most potent drug (mean IC50 of 1.9 x 10(-8) M), being over 250 times as potent as its prototype CB3717 (mean IC50 of 4.8 x 10(-6) M). In five pairs of acquired cisplatin-resistant human tumour cell lines (three ovarian, one cervical and one testicular) which encompass all of the main known mechanisms of platinum drug resistance, ZD1694, CB3717 and the DHFR inhibitor, methotrexate, all exhibited non-cross-resistance. The cervical line, HX/155cisR, showed collateral sensitivity to ZD1694, CB3717, 5-fluorouracil (FUra) and fluorodeoxyuridine (FdUrd). One cell line, A2780cisR, showed a low level of cross-resistance to FUra (resistance factor, RF, of 1.5) and FdUrd (RF of 3.8). A2780cisR, in common with two other cisplatin-resistant lines, did not possess elevated TS activity compared with its parent. Cisplatin retained activity in four acquired ZD1694-resistant cell lines (encompassing reduced folate transport, elevated TS and defective polyglutamation mechanisms of resistance). Furthermore, combinations of ZD1694 with each of the platinum-based drugs, cisplatin, carboplatin and the recently introduced orally administrable, JM216, all showed additive growth inhibitory effects by median effect analysis. These data suggest that the tumour inhibitory properties of the recently introduced highly potent TS inhibitor, ZD1694, and cisplatin, and, moreover, their respective mechanisms of resistance, do not overlap. Therefore, these drugs may be considered for combination in the clinic.

Antineoplastic Agents↗
PubMed2005

Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension.

BACKGROUND: The aim of this study was to evaluate the cardiovascular outcome in apparently responder hypertensive patients with responder and masked hypertension, and in apparently resistant hypertensive patients with false and true resistant hypertension. METHODS: The occurrence of fatal and nonfatal cardiovascular events was evaluated in 340 patients with responder hypertension (clinic blood pressure [BP] <140/90 mm Hg and daytime BP <135/85 mm Hg), 126 with masked hypertension (clinic BP <140/90 mm Hg and daytime BP >135 or 85 mm Hg), 146 with false resistant hypertension (clinic BP >or=140 or 90 mm Hg and daytime BP <135/85 mm Hg), and 130 with true resistant hypertension (clinic BP >or=140 or 90 mm Hg and daytime BP >135 or 85 mm Hg). RESULTS: During follow-up period (4.98 +/- 2.9 years), the event-rate per 100 patient-years was 0.87, 2.42, 1.2, and 4.1 in patients with responder, masked, false resistant, and true resistant hypertension, respectively. After adjustment for several covariates, including clinic BP (forced into the model), Cox regression analysis showed that cardiovascular risk was significantly higher in masked hypertension (masked versus responder hypertension, relative risk [RR] 2.28, 95% confidence interval [CI] 1.1-4.7, P < .05) and in true resistant hypertension (true resistant versus responder hypertension, RR 2.94, 95% CI 1.02-8.41, P < .05), whereas there was no significant difference between false resistant and responder hypertension. CONCLUSIONS: This study shows that patients with masked hypertension are at higher risk than those with responder hypertension, and that those with false resistant hypertension are at lower risk than those with true resistant hypertension. Ambulatory BP monitoring should be performed in treated hypertensive patients to obtain a better prognostic stratification.

Aged↗
PubMed2002

Resistance to mitochondrial- and Fas-mediated apoptosis in human leukemic cells with acquired resistance to 9-beta-D-arabinofuranosylguanosine.

We have previously reported that in a MOLT-4 leukemia cell line the acquired resistance to 9-beta-D-arabinofuranosylguanine (Ara-G) is due to deficiency of the activating enzymes deoxyguanosine kinase and deoxycytidine kinase [Biochem. Biophys. Res. Commun. 293 (5) (2002) 1489]. In this study we investigated whether apoptotic pathways are affected in two human T-cell lymphoblastic MOLT-4 cell lines with acquired resistance to Ara-G. In contrast to the MOLT-4 wild type cells, Ara-G resistant cells displayed no increase in caspase-3 or caspase-9 activity, DNA fragmentation, cytochrome c release or a drop in the mitochondrial membrane potential (DeltaPsi(mito)) upon Ara-G treatment. A drop in the DeltaPsi(mito) was induced in wild type cells after treatment with tributyltin, an inducer of mitochondrial permeability transition, and with carbonyl cyanide m-chlorophenylhydrazone, an uncoupling agent that reduces the DeltaPsi(mito), although not in Ara-G resistant cells. Ara-G resistant cells displayed higher levels of the anti-apoptotic protein Bcl-xL in immunoblots. A recent study indicates that Ara-G-induced apoptosis is mediated in part via the Fas pathway [Cancer Res. 43 (2047) (2002) 411]. When cells were treated with anti-Fas antibody, the wild type cell line exhibited increased caspase-3-like activity but the Ara-G resistant cells did not. Using FACS analysis and semi-quantitative PCR, 3-6-fold decreased protein levels and almost no detectable mRNA levels of Fas in the resistant cells were recorded. These data indicate that the inability to induce apoptosis via both the apoptosome pathway and the Fas pathway, due to increased levels of Bcl-xL and a lack of Fas, contributes to Ara-G resistance. This resistance to apoptosis in Ara-G resistant cells may serve to explain the overall resistance to a variety of anti-neoplastic drugs.

Apoptosis↗
PubMedDate not supplied

Management of anthelmintic resistance: inheritance of resistance and selection with persistent drugs.

Resistance to the benzimidazole (BZ) anthelmintics is inherited as an incomplete dominant/ incomplete recessive trait and is now widespread in populations of gastrointestinal nematode parasites of sheep. Unlike benzimidazole resistance, which is common in Haemonchus contortus, Trichostrongylus colubriformis and Ostertagia circumcincta, resistance to levamisole is relatively rare in H. contortus, although common in the other 2 species. One explanation for the slow spread of resistance to levamisole in H. contortus is that it is inherited as an autosomal recessive trait, while in T. colubriformis levamisole resistance is inherited as a recessive sex-linked trait. With the introduction of the avermectin/milbemycin class resistance has developed to the relatively short-acting ivermectin, but this time it is inherited as a completely dominant trait. The potentially more serious situation of a persistent anthelmintic selecting a dominant resistance gene was investigated using a simulation model. Efficacy against incoming infective larvae (L3) was assumed to decline or remain high over the period of drug persistence (3 days to 4 weeks), thus allowing the estimation of the relative importance of selecting resistant L3s on the development of resistance in the worm population. These factors were also examined against a background of initial efficacy levels, against adults, and mode of inheritance. Persistence and initial efficacy were found to be far more important in determining the rate of selection for resistance than was selection of resistant L3 as drug efficacy declined.

Animals↗
PubMed2002

A new challenge for successful immunotherapy by tumors that are resistant to apoptosis: two complementary signals to overcome cross-resistance.

Tumor resistance to conventional therapies is a major problem in cancer treatment. While tumors initially respond to radiation or chemotherapies, subsequent treatments with these conventional modalities are ineffective against relapsed tumors. The problem of tumor resistance to chemotherapy and radiation has led to the development of immunotherapy and gene-based therapies. These alternative therapeutic approaches are intensely explored because they are supposed to be more tumor specific and better tolerated than the conventional therapies. Recent advances in apoptosis have revealed that resistance to apoptosis is one of the major mechanisms of tumor resistance to conventional therapies. Resistance to apoptosis is a naturally acquired characteristic during oncogenesis and is selected for after successive rounds of conventional therapies. Resistance to apoptosis involves dysregulation and/or mutation of apoptotic signaling molecules that render tumor cells unresponsive to apoptotic stimuli. Since both immunotherapy and chemotherapy kill tumors by apoptosis and the killings are signaled through a central core apoptotic program, dysregulation of this central program and development of resistance to apoptosis in chemoresistant cells could render them cross-resistant to immunotherapy. Therefore, in order to establish an effective antitumor response and to complement immunotherapy and gene-based therapies, cross-resistance due to resistance to apoptosis must be overcome. In this review, based on prior findings and recent evidence, we put forth a model, verified experimentally, in which chemoresistant tumor cells can be sensitized to immune-mediated killing by subtoxic concentrations of chemotherapeutic drugs/factors. The model involves two complementary signals. The first signal is a sensitizing signal that regulates pro/antiapoptotic targets, thus facilitating the apoptotic signal. The second apoptotic signal initiates a partial activation of the apoptotic signaling pathway, and activation is completed by complementation with signal one. Thus, effective killing of immunoresistant cells is achieved by both signals. The two-signal approach provides a new strategy to overcome cancer cross-resistance to immunotherapy and opens new avenues for the development of more effective and selective immunosensitizing agents.

Adjuvants, Immunologic↗
PubMed1999

Resistance mutations selected in vivo under therapy with anti-HIV drug HBY 097 differ from resistance pattern selected in vitro.

The quinoxaline derivative HBY 097, an orally active nonnucleoside inhibitor of HIV-1 reverse transcriptase (NNRTI), showed an efficient suppression of viral load in a dose-escalating phase I study with mean trough concentrations increasing from 137-1299 ug/l [Rübsamen-Waigmann et al., Lancet 349:1517]. Half-maximal inhibitory concentrations (IC50) for viruses grown from the patients at entry of the study were 0.1-3 nM, except for one patient who had a virus with reduced susceptibility to HBY 097 at entry (IC50: 160 nM). During therapy, only two patients developed a virus with a moderately increased IC50 (2.2 and 15 nM). This reduced susceptibility was associated with the known NNRTI-resistance mutation K ==> N at position 103, in contrast to resistance selection in vitro, which had yielded predominant mutations at positions 179 and 190. The Tyr mutation at position 181, inducing high resistance for other NNRTIs, was never observed. The resistant virus at study entry (IC50 = 160 nM) had a mutation at position 103 as well, combined with an AZT resistance mutation (K ==> R) at position 70, suggesting that nucleoside-resistance mutations may help increasing resistance to HBY 097. This is in line with our in vitro selection studies, where resistance mutations at the 'nucleoside sites' 74 and 75 increased the resistance phenotype of NNRTI mutations. Our findings highlight the crucial importance of IC50 determinations from cultured virus for determination of phenotypic resistance development during therapy and demonstrate that in vivo resistance development cannot be predicted from in vitro selection.

Antiviral Agents↗
PubMed2002

Non-cross resistance of ZD0473 in acquired cisplatin-resistant lung cancer cell lines.

ZD0473 is a new generation platinum agent that, in preclinical studies, shows evidence of an extended spectrum of anti-tumor activity and overcomes platinum resistance mechanisms. The drug contains a bulky methylpyridine ligand at its platinum center, which is responsible for its ability to overcome platinum resistance. We examined the growth inhibitory effects of ZD0473 in human lung cancer cell lines resistant to cisplatin in vitro. Four cisplatin resistant human lung cancer cell lines (PC-14/CDDP, SBC-3/CDDP, PC-9/CDDP, H69/CDDP) showed the expected resistance to cisplatin but were non-cross, or much less, resistant to ZD0473, as determined by an MTT assay. A reduction in the intracellular accumulation of cisplatin, but not of ZD0473, was observed in the PC-14/CDDP cells compared with the levels in PC-14 parental cells. The reduction in cisplatin accumulation is considered a major mechanism of the acquired cisplatin resistance in PC-14/CDDP cells. Therefore, the increase in platinum accumulation is considered a possible mechanism underlying the activity of ZD0473 in cisplatin-resistant cells. Glutathione-mediated resistance to cisplatin was also overcome by ZD0473 in PC-14/CDDP cells. In addition, we showed that the intraperitoneal administration of ZD0473 at its maximum tolerable dose in mice produced a marked in vivo antitumor activity against cisplatin-resistant PC-14/CDDP tumors. These results suggest that ZD0473 may be a potent agent in human lung cancer cells with multifactorial cisplatin resistance.

Antineoplastic Agents↗
PubMed2003

Antimicrobial resistance and resistance gene determinants in clinical Escherichia coli from different animal species in Switzerland.

Antimicrobial susceptibility testing was performed on a total of 581 clinical Escherichia coli isolates from diarrhea and edema disease in pigs, from acute mastitis in dairy cattle, from urinary tract infections in dogs and cats, and from septicemia in laying hens collected in Switzerland between 1999 and 2001. Among the 16 antimicrobial agents tested, resistance was most frequent for sulfonamides, tetracycline, and streptomycin. Isolates from swine presented significantly more resistance than those from the other animal species. The distribution of the resistance determinants for sulfonamides, tetracycline, and streptomycin was assessed by hybridization and PCR in resistant isolates. Significant differences in the distribution of resistance determinants for tetracycline (tetA, tetB) and sulfonamides (sulII) were observed between the isolates from swine and those from the other species. Resistance to sulfonamides could not be explained by known resistance mechanisms in more than a quarter of the sulfonamide-resistant and sulfonamide-intermediate isolates from swine, dogs and cats. This finding suggests that one or several new resistance mechanisms for sulfonamides may be widespread among E. coli isolates from these animal species. The integrase gene (intI) from class I integrons was detected in a large proportion of resistant isolates in association with the sulI and aadA genes, thus demonstrating the importance of integrons in the epidemiology of resistance in clinical E. coli isolates from animals.

Animal Diseases↗
PubMed2000

High prevalence of antibiotic resistance of common pathogenic bacteria in Taiwan. The Antibiotic Resistance Study Group of the Infectious Disease Society of the Republic of China.

We analyzed the antimicrobial susceptibilities of all clinical isolates of 14 common pathogenic bacteria recovered from patients in eight medical centers in Taiwan during 1995 and 1996. Susceptibility to commonly used antimicrobial agents was tested by the disk diffusion method as recommended by the National Committee for Clinical Laboratory Standards. Of the Staphylococcus aureus isolates, 59.3% and 62% were oxacillin-resistant in 1995 and 1996, respectively, whereas 63.2% of the coagulase-negative staphylococci isolates during the study period were oxacillin-resistant. The rate of penicillin-resistance among Streptococcus pneumoniae isolates was 39.7% in 1995 and 53.7% in 1996. Macrolide-resistance was found in 71.4%, 42.1%, and 46.7% of S. pneumoniae, beta-hemolytic streptococci, and viridans streptococci, respectively, in 1996. Less than 2% of the enterococcal isolates were vancomycin resistant, but 77% of them were gentamicin resistant. Resistance to gentamicin was also common in Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Various degrees of resistance to ampicillin, piperacillin, cephalosporins, aztreonam, and ciprofloxacin were detected in Enterobacteriaceae, P. aeruginosa, and A. baumannii. More than 55% of Haemophilus influenzae isolates were ampicillin resistant. In summary, resistance to many antimicrobial agents in various common pathogenic bacteria is very common in Taiwan. Our results implicate that antibiotic resistance in the developing countries need to be monitored closely.

Cross Infection↗
PubMed2001

Low-level antibacterial resistance: a gateway to clinical resistance.

The huge amount of antibiotic substances released in the human environment has probably resulted in an acceleration in the rate of bacterial evolution. It is to note that most interactions between chemotherapeutic agents and microbial populations occur at very low antibiotic concentrations. Thus, natural selection is expected to act on very small increases in the bacterial ability to resist to antibiotic inhibitory effects. On the other hand, there is a wealth of mechanisms to resist to these low antibiotic concentrations. The progressive enrichment in low-level resistant populations favours secondary selections for more specific and effective mechanisms of resistance, particularly in treated patients. These adaptations may have a biological cost in the absence of antibiotics, but frequently compensatory mutations occur, minimizing such genetic burden. In this way, a phenomenon of directional selection takes place, with low possibilities of return to susceptibility. Moreover, low antibiotic concentrations are not only able to select low-level antibiotic resistant variants, but may produce a substantial stress in bacterial populations, that eventually influences the rate of genetic variation and the diversity of adaptive responses. More attention should be devoted to the mechanisms of low-level resistance in microorganisms, as they can serve as stepping stones to develop high level, clinically relevant resistance. These mechanisms should be identified early in the development of drugs in order to adapt the therapeutic strategies (for instance dosage) to minimize the selection of low-level resistant variants, as frequently they emerge by means of concentration-specific selection. At the same time, conventional susceptibility testing should probably be able to detect low-level resistance, and not only clinically-relevant resistance. We should be vigilant of the evolutionary trends of microorganisms; for that a purpose, knowledge of the biology and epidemiology of low-level resistance is becoming a real need.

Animals↗
PubMed1990

Molecular basis of preferential resistance to colchicine in multidrug-resistant human cells conferred by Gly-185----Val-185 substitution in P-glycoprotein.

Expression of P-glycoprotein, encoded by the human MDR1 gene, results in cross-resistance to many lipophilic cytotoxic drugs (multidrug resistance). P-glycoprotein is believed to function as an energy-dependent efflux pump that is responsible for decreased drug accumulation in multidrug-resistant cells. Previous work showed that preferential resistance to colchicine in a colchicine-selected multidrug-resistant cell line was caused by spontaneous mutations in the MDR1 gene that resulted in a Gly-185----Val-185 substitution in P-glycoprotein. We have now compared transfectant cell lines expressing either the wild-type Gly-185 or the mutant Val-185 P-glycoprotein with regard to their levels of resistance to and accumulation and binding of different drugs. In cells expressing the mutant protein, increased resistance to colchicine and decreased resistance to vinblastine correlated with a decreased accumulation of colchicine and increased accumulation of vinblastine. Expression of the mutant P-glycoprotein also resulted in significantly increased resistance to epipodophyllotoxin and decreased resistance to vincristine and actinomycin D; smaller changes in resistance were observed for several other drugs. Unexpectedly, the mutant P-glycoprotein showed increased binding of photoactive analogs of vinblastine and verapamil and the photoactive compound azidopine and decreased binding of a photoactive colchicine analog. These results suggest that the Gly-185----Val-185 substitution affects not the initial drug-binding site of P-glycoprotein but another site, associated with the release of P-glycoprotein-bound drugs to the outside of the cell.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Long-term antibiotic resistance surveillance of gram-negative pathogens suggests that temporal trends can be used as a resistance warning system.

Antibiotic resistance among Gram-negative bacteria and antibiotic consumption were investigated at the Karolinska Hospital, Stockholm, Sweden over a 12-y period. The investigation showed an increase in ciprofloxacin resistance of Escherichia coli from 0% in 1991 to 7% in 1997 and to 11% in 1999. Resistance among Pseudomonas aeruginosa isolates to ciprofloxacin increased from 2.5% in 1991 to 9.0% in 1997 and to 13% in 1999. Resistance levels for norfloxacin showed the same high statistical significance in terms of the temporal trend. A more detailed analysis showed higher resistance against norfloxacin in specific wards. Relationships between antibiotic use and antibiotic susceptibility showed different patterns. The increased ciprofloxacin resistance of E. coli and P. aeruginosa during the study period was paralleled by an increased consumption of quinolones. During the 12-y study period the total use of cephalosporins increased 2.5-fold, while the levels of E. coli resistance to cefuroxime and cefotaxime remained stable. A third pattern was seen with trimethoprim-sulfamethoxazole, namely increasing resistance of E. coli as the use of trimethoprim-sulfamethoxazole declined. The analysis of resistance levels and antibiotic consumption in the present study suggests different mechanisms for the increased resistance. The significant trend of increased resistance to antibiotics over time constitutes an important warning system.

Anti-Bacterial Agents↗
PubMed1999

Surveillance of antimicrobial use and antimicrobial resistance in United States hospitals: project ICARE phase 2. Project Intensive Care Antimicrobial Resistance Epidemiology (ICARE) hospitals.

The search for the means to understand and control the emergence and spread of antimicrobial resistance has become a public health priority. Project ICARE (Intensive Care Antimicrobial Resistance Epidemiology) has established laboratory-based surveillance for antimicrobial resistance and antimicrobial use at a subset of hospitals participating in the National Nosocomial Infection Surveillance system. These data illustrate that for most antimicrobial-resistant organisms studied, rates of resistance were highest in the intensive care unit (ICU) areas and lowest in the outpatient areas. A notable exception was ciprofloxacin- or ofloxacin-resistant Pseudomonas aeruginosa, for which resistance rates were highest in the outpatient areas. For most of the antimicrobial agents associated with this resistance, the rate of use was highest in the ICU areas, in parallel to the pattern seen for resistance. These comparative data on use and resistance among similar areas (i.e., ICU or other inpatient areas) can be used as a benchmark by participating hospitals to focus their efforts at addressing antimicrobial resistance.

Anti-Bacterial Agents↗
PubMed2005

Confronting the emergence of drug-resistant HIV type 1: impact of antiretroviral therapy on individual and population resistance.

Resistance to antiretroviral agents, and in particular the increasing levels of transmitted resistant virus could offset the substantial gains won with potent antiretroviral therapy. Primary and acquired antiretroviral resistance rates reflect the relative usage of different antiretroviral drugs in the population, as well as the inherent genetic barrier to the development of resistance associated with individual drugs. Data on antiretroviral resistance rates, gleaned from the growing HIV-1-infected population treated with a continuously increasing number of antiretroviral drugs and drug combinations, provide insights into patient management approaches for delaying the emergence of resistance and minimizing the degree of resistance. Evolving data suggest that the relative ease by which HIV-1 escapes the selective pressure of chronic drug exposure varies for the different antiretroviral drug classes and individual antiretroviral drugs. The development of resistance in vivo can be anticipated based on these data, in conjunction with the individuals treatment history and resistance testing results. These in turn can guide the judicious use of antiretroviral drugs to attain optimal treatment responses and to preserve therapeutic options for the time when antiretroviral-resistant strains emerge. The recent developments of new antiretroviral drugs, including the use of boosted protease inhibitors, suggest that treatment strategies can limit the development of resistance.

Anti-HIV Agents↗