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PubMed2001

Bactericidal activities of two daptomycin regimens against clinical strains of glycopeptide intermediate-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and methicillin-resistant Staphylococcus aureus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations.

Daptomycin is an investigational lipopeptide antibiotic active against gram-positive organisms. The mechanism of action is unique, resulting in interference with cell membrane transport. The bactericidal activity of daptomycin was evaluated against glycopeptide-intermediate susceptible Staphylococcus aureus (GISA), vancomycin-resistant Enterococcus faecium (VREF), and methicillin-resistant S. aureus (MRSA) in an in vitro infection model with simulated endocardial vegetations. Simulated regimens of daptomycin at 6 mg/kg/day (D6) and 10 mg/kg/day (D10) were utilized. MICs and MBCs for daptomycin were determined in the absence and in the presence of albumin with the following results (MIC/MBC): for GISA-992, 0.5/1.0 and 16/16; for VREF-590, 2.0/2.0 and 32/32; and for MRSA-494, 0.25/0.25 and 1.0/4.0 microg/ml, respectively. During the first 8 h daptomycin significantly reduced the inoculum for all organisms. Daptomycin at 6 mg/kg/day and 10 mg/kg/day had log(10) CFU/g reductions of 5 and 6, 3.4 and 5, and 6.4 and 6.5 by 8 h for GISA-992, VREF-590, and MRSA-494, respectively. Against both GISA-992 and VREF-590, the D10 regimen achieved the limit of detection at 72 h, with D6 regimens showing slight regrowth. A concentration-dependent killing effect was noted to occur, with daptomycin demonstrating a more rapid and greater kill from the D10 versus the D6 regimen. The results of this study suggest that daptomycin demonstrates significant (P < 0.05) activity against gram-positive organisms in a simulated sequestered infection site.

Anti-Bacterial Agents↗
PubMed2006

Expression dynamics of drug resistance genes, multidrug resistance 1 (MDR1) and lung resistance protein (LRP) during the evolution of overt leukemia in myelodysplastic syndromes.

It is well-known that leukemic cells of overt leukemia (OL) that have transformed from myelodysplastic syndromes (MDS) are more resistant to chemotherapy as compared with de novo AML cells. Thus, to examine the expression levels of drug-resistant genes and their alterations with the development of OL in MDS, the expression of mRNA for MDR1 and LRP was determined in bone marrow samples from control, de novo AML, MDS, MDS at the time of OL transformation (MDS --> OL), and after transformation (OL) by quantitative real-time RT-PCR. The expression of MDR1 in MDS bone marrow at the time of initial diagnosis was as low as that for control subjects. However, the expression level was significantly elevated at the time of the development of OL (MDS --> OL) compared with the initial MDS subjects (P < 0.05), while expression was relatively reduced after OL development (OL). The expression of LRP was significantly higher in MDS and MDS --> OL samples than control subjects. However, the high expression of LRP in MDS --> OL was significantly reduced after OL development (OL). The expression levels of drug-resistant genes in MDS --> OL or OL were not significantly higher than those of de novo AML samples, although LRP expression in MDS or MDS --> OL was relatively higher than that of de novo AML. Detecting increases in the expression of MDR1 would be useful for predicting OL development in MDS patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1960

Studies of the origin of bacterial viruses. VI. Effect of manganese on the proportion of phage-producing. terramycin-resistant, streptomycin-resistant, and phage-resistant cells in lysogenic megatherium cultures.

Exposure of B. megatherium 899 to about 5 x 10(-3)M MnCl(2) for 10 minutes at 25 degrees C. results in an increase of about ten times in the proportion of phage-producing cells, terramycin-resistant cells, streptomycin-resistant cells, and phage-resistant cells. The proportion of phage-producing cells reaches a maximum in about 4 hours and that of the other cells is reached in about 8 hours.

Bacteriophages↗
PubMed1987

[Resistance and disintegration behavior of gastric juice-resistant drug products. 3. Pharmaceutical-technological and analytical studies of gastric juice-resistant commercial preparations].

Enteric coated commercial dosage forms often do not correspond with acid resistance and disintegration requirements of the Ph. Eur. About 15-20% of 181 tested samples disintegrate during acid resistance test or do not disintegrate in buffer solution pH = 6.8. The percentage was extremely high amongst enteric coated pancreatin or cardiac glycosides (about 30%) preparations. Storage conditions and time influence acid resistance and disintegration time. 80% of 34 products coated with celluloseacetate phthalate, hydroxypropylmethylcellulose phthalate or polymethacrylic acid ester did not change disintegration time after 2 years storage at 20 degrees C. After storage at 40 degrees C the number decreased to 40%. After 5 years at 20 degrees C number of products which were not stable increased.

Chemistry, Pharmaceutical↗
PubMed1976

[Variability of the ova of mulberry silkworm (Bombyx mori L.) with regard to capacity for thermal parthenogenesis and heat resistance. 4. Relationship between the capacity of oocytes from different females for thermal parthenogenesis and heat resistance of ova at the early stage of development and heat resistance of the muscles of these females].

The reliable positive correlation was established between the variability of unfertilized eggs by their ability of thermal parthenogenesis and the heat resistance of fertilized eggs at the early stages of development. At the same time the ability of oocytes of parthenogenesis correlates negatively with the heat resistance of muscles. The data obtained suggest that the variability of oocytes by their ability of thermal parthenogenesis is partially due to the variability of heat resistance of their proteins.

Animals↗
PubMed2006

Detection of methicillin/oxacillin resistance and typing in aminoglycoside-susceptible methicillin-resistant and kanamycin-tobramycin-resistant methicillin-susceptible Staphylococcus aureus.

Eighty-five atypical isolates of Staphylococcus aureus divided into 73 aminoglycoside-susceptible methicillinresistant (AS-MRSA) and 12 kanamycin-tobramycin-resistant methicillin-susceptible (KTR-MSSA) were phenotypically and genotypically examined for methicillin resistance. Among these tests, the diffusion method using the oxacillin and cefoxitin disks on Mueller-Hinton agar with and without NaCl, the incubation at 35 degrees C or 30 degrees C for 24 or 48 hr, respectively, and the determination of oxacillin MICs by E-test were performed. We also examined the presence of the mecA gene by PCR and its product PBP 2a by the Slidex MRSA Detection test after induction by cefoxitin disk. All of the AS-MRSA strains (100%) were detected by the cefoxitin disk in all conditions and by the oxacillin disk on Mueller-Hinton agar with 2% of NaCl at 35 degrees C. Without NaCl, the sensitivity fell to 97.2% by oxacillin disk. The oxacillin MICs for these isolates ranged from 2 to 128 mg/L. The mecA gene determinant and its product PBP 2a were detected in all AS-MRSA strains. All KTR-MSSA strains were phenotypically methicillin-susceptible and oxacillin MICs were below or borderline of breakpoint (< or =2 mg/L). The mecA gene determinant and its product were detected in one strain. Pulsed-field gel electrophoresis (PFGE) was applied and revealed the presence of two major patterns A (36.9%) and B (46.2%) in AS-MRSA isolates and seven patterns in the KTR-MSSA strains.

Aminoglycosides↗
PubMed1993

Resistance to cefoperazone-sulbactam in Klebsiella pneumoniae: evidence for enhanced resistance resulting from the coexistence of two different resistance mechanisms.

We investigated the in vitro activity and the in vivo efficacy of the beta-lactam-beta-lactamase inhibitor combination cefoperazone-sulbactam against an isogenic series of Klebsiella pneumoniae strains. Both cefoperazone and cefoperazone-sulbactam were active in vitro against a susceptible clinical strain, and the combination was highly effective in the treatment of rat intra-abdominal abscesses. Loss of expression of a 39-kDa outer membrane protein resulted in at least a fourfold increase in the MICs of cefoperazone and cefoperazone-sulbactam but did not appreciably affect the in vivo efficacy of either regimen. Introduction of plasmid RP4, which encodes the TEM-2 beta-lactamase, into the susceptible strain resulted in the loss of in vitro activity and in vivo efficacy for cefoperazone. The in vitro activity of cefoperazone-sulbactam against this strain was diminished, but the antibiotic combination remained highly active in vivo. Introduction of RP4 into the strain lacking the 39-kDa outer membrane protein resulted in a fourfold increase in the in vitro MIC of cefoperazone-sulbactam in comparison with the beta-lactamase-producing susceptible strain and resulted in a loss of in vivo efficacy against infections caused by this strain. These results suggest that the combination of different resistance mechanisms, neither of which alone results in substantially diminished cefoperazone-sulbactam efficacy in vivo, can cause in vivo resistance to the beta-lactam-beta-lactamase inhibitor combination in K. pneumoniae.

Abscess↗
PubMed2004

Prevalence of mutations within the quinolone resistance-determining region of gyrA, gyrB, parC, and parE and association with antibiotic resistance in quinolone-resistant Salmonella enterica.

Salmonella enterica isolates (n = 182) were examined for mutations in the quinolone resistance-determining region of gyrA, gyrB, parC, and parE. The frequency, location, and type of GyrA substitution varied with the serovar. Mutations were found in parC that encoded Thr57-Ser, Thr66-Ile, and Ser80-Arg substitutions. Mutations in the gyrB quinolone resistance-determining region were located at codon Tyr420-Cys or Arg437-Leu. Novel mutations were also found in parE encoding Glu453-Gly, His461-Tyr, Ala498-Thr, Val512-Gly, and Ser518-Cys. Although it is counterintuitive, isolates with a mutation in both gyrA and parC were more susceptible to ciprofloxacin than were isolates with a mutation in gyrA alone.

Anti-Bacterial Agents↗
PubMed2005

Are transporter genes other than the chloroquine resistance locus (pfcrt) and multidrug resistance gene (pfmdr) associated with antimalarial drug resistance?

Mu et al. (Mu, J., M. T. Ferdig, X. Feng, D. A. Joy, J. Duan, T. Furuya, G. Subramanian, L. Aravind, R. A. Cooper, J. C. Wootton, M. Xiong, and X. Z. Su, Mol. Microbiol. 49:977-989, 2003) recently reported exciting associations between nine new candidate transporter genes and in vitro resistance to chloroquine (CQ) and quinine (QN), with six of these loci showing association with CQ or QN in a southeast Asian population sample. We replicated and extended this work by examining polymorphisms in these genes and in vitro resistance to eight drugs in parasites collected from the Thailand-Burma border. To minimize problems of multiple testing, we used a two-phase study design, while to minimize problems caused by population structure, we analyzed parasite isolates collected from a single clinic. We first examined associations between genotype and drug response in 108 unique single-clone parasite isolates. We found strong associations between single nucleotide polymorphisms in pfmdr and mefloquine (MFQ), artesunate (AS), and lumefantrine (LUM) response. We also observed associations between an ABC transporter (G7) and response to QN and AS and between another ABC transporter (G49) and response to dihydro-artemisinin (DHA). We reexamined significant associations in an independent sample of 199 unique single-clone infections from the same location. The significant associations with pfmdr-1042 detected in the first survey remained. However, with the exception of the G7-artesunate association, all other associations observed with the nine new candidate transporters disappeared. We also examined linkage disequilibrium (LD) between markers and phenotypic correlations between drug responses. We found minimal LD between genes. Furthermore, we found no correlation between chloroquine and quinine responses, although we did find expected strong correlations between MFQ, QN, AS, DHA, and LUM. To conclude, we found no evidence for an association between 8/9 candidate genes and response to eight different antimalarial drugs. However, the consistent association observed between a 3-bp indel in G7 and AS response merits further investigation.

ATP-Binding Cassette Transporters↗
PubMed2003

Taxane-based reversal agents modulate drug resistance mediated by P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein.

Overexpression of ATP-binding cassette transport proteins, including P-glycoprotein (Pgp), multidrug resistance (MDR) protein (MRP-1), and breast cancer resistance protein (BCRP), is a well-characterized mechanism of MDR in tumor cells. Although the cytotoxic taxanes paclitaxel and docetaxel are substrates for Pgp-mediated efflux, the semisynthetic taxane analogue ortataxel inhibits drug efflux mediated by Pgp as well as, as we recently demonstrated, MRP-1 and BCRP. Nevertheless, ortataxel is not optimal for development as a clinical MDR modulator because of its cytotoxicity [corrected]. We sought to identify noncytotoxic taxane-based broad-spectrum modulators from a library of noncytotoxic taxane-based reversal agents (tRAs) designed by eliminating the C-13 side chain of the taxane molecule, which inhibits microtubule depolymerization. Twenty tRAs, selected based on modulation of paclitaxel cytotoxicity in Pgp-overexpressing MDA435/LCC6(mdr1) cells, were studied for modulation of retention and cytotoxicity of substrates of MRP-1 and BCRP as well as Pgp in established cell lines overexpressing each of these transporters. Four tRAs modulated MRP-1 and 17 modulated BCRP in addition to Pgp. The four broad-spectrum tRAs strongly modulated daunorubicin and mitoxantrone efflux and enhanced their cytotoxicity in cell lines overexpressing the three MDRs, decreasing IC(50) values by as much as 97% [corrected]. These tRAs, especially tRA 98006, have promise for development as clinical broad-spectrum MDR modulators and warrant more preclinical analysis to determine pharmacokinetic interactions and efficacy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Multidrug resistance in small cell lung cancer: expression of P-glycoprotein, multidrug resistance protein 1 and lung resistance protein in chemo-naive patients and in relapsed disease.

The aim of this study was to investigate the expression of multidrug resistance-associated proteins in metastatic small cell lung cancer (SCLC) cells correlated to cisplatin/etoposide chemotherapy response and the level of those proteins in relapsed disease. Samples were obtained by transbronchial fine needle aspiration biopsy (TBNA) of enlarged mediastinal lymph nodes in 17 patients. After cytological confirmation of SCLC, cells were stained by a panel of mAbs against internal epitopes of P-gp (JSB-1), MRP1 (MRPr1), LRP (LRP-56) and cytokeratin (MNF116) and analyzed by flow cytometry. We observed a significant negative correlation for better response rate to chemotherapy with individual expression of P-gp (r=-0.93, P<0.0001; Pearson correlation) and MRP1 (r=-0.78, P=0.0002; Pearson correlation) in chemo-naive SCLC cells and a non-significant correlation for LRP expression. P-gp and MRP1 expression was markedly increased in metastatic cells in four out of five patients with relapsed disease (4-12 months after starting chemotherapy), in comparison to their chemo-naive values. In conclusion, the results suggest that P-gp and MRP1 might be associated with SCLC cell survival during metastasis and chemotherapy, and that overexpression of those transporters in relapsed disease could assist short-term chemotherapy efficiency.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2004

Aggressive control measures for resistant Acinetobacter baumannii and the impact on acquisition of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus in a medical intensive care unit.

The medical ICU implemented aggressive control measures following an outbreak of multidrug-resistant, clonal Acinetobacter baumannii. Multivariable regression analyses comparing acquisition (6 months preceding to 6 months during or following the outbreak) revealed decreased VRE and MRSA acquisition. Aggressive control measures can reduce VRE, and perhaps MRSA, transmission.

Acinetobacter↗
PubMed1962

Episome-mediated transfer of drug resistance in Enterobacteriaceae. V. Spontaneous segregation and recombination of resistance factors in Salmonella typhimurium.

Watanabe, Tsutomu (Keio University, Tokyo, Japan) and Keong W. Lyang. Episomemediated transfer of drug resistance in Enterobacteriaceae. V. Spontaneous segregation and recombination of resistance factors in Salmonella typhimurium. J. Bacteriol. 84:422-430. 1962.-It was found that spontaneous segregation of the transmissible multiple drug resistance [resistance to streptomycin (Sm), chloramphenicol (Cm), tetracycline (TC), and sulfonamide (Su)] takes place so frequently in Salmonella typhimurium strain LT-2 (Su, Sm, Cm, Tc) as to allow a clone analysis of the segregation of resistance factors with replica plating. Su-, Sm-, and Cm- resistance factors together were spotaneously lost most frequently, whereas the spontaneous loss of Tc-resistance factor alone was rather infrequent. The complete loss of the resistance factors was also noted with low frequencies. The mechanism of the spontaneous segregation of the resistance factors was assumed to be due to either genetic exchange between the resistance factors and host genome or incomplete replication of the transmissible resistance factors (composed of resistance factors and resistance-transfer factor). In relation to the mechanism of spontaneous segregation of the transmissible resistance factors, circular models of the transmissible resistance factors are presented. Four-drug-resistant strains were produced by transferring segregant types of transmissible resistance factors (Su, Sm, Cm) and (Tc) to the strains with (Tc) and (Su, Sm, Cm), respectively. In these four-drug-resistant strains, the two types of transmissible resistance factors were found to be in two different states; in one state the two types of transmissible resistance factors exist in the same cells independently of each other, and in the other state a transmissible resistance factor, which was produced as a result of recombination of the two types of transmissible resistance factors, is present. Two unusual strains of LT-2 with Su-, Sm-, and Cm-resistance factors and with four resistance factors were found. These strains could not transfer their resistance factors to Escherichia coli K-12 by conjugation. Their resistance factors were spontaneously segregated as frequently as those of LT-2 (Su, Sm, Cm) and LT-2 (Su, Sm, Cm, Tc), and the transfer of (Tc) to strain LT-2 with nontransmissible Su-, Sm-, and Cm-resistance factors gave rise to two types of clones; one could transfer the four resistance factors as a unit to K-12 by conjugation, and another could transfer only (Tc) and frequently segregated two types of clones; one had (Tc) and another had nontransmissible Su, Sm-, and Cm-resistance factors. From these findings, the unusual strains with nontransmissible resistance factors are assumed to have a "defective" resistance-transfer factor.

Anti-Bacterial Agents↗
PubMed1992

Resistance of Escherichia coli to nourseothricin (streptothricin): sensitization of resistant strains by abolition of its outer membrane resistance.

The polycationic antibiotic, nourseothricin, represents a mixture of several streptothricins, mainly D and F. The molecular weight of the latter compound amounts to 486. Obviously, although very slowly, it can pass the outer membrane via the porin pores. It has been shown earlier that nourseothricin is able to generate some kind of channels into the outer membrane through which it can pass the cell wall. On the other hand, there were indications that resistant strains containing a streptothricin-inactivating acetyl transferase possess an additional protecting system, namely a reduced penetrability of the outer membrane. In this study, it could be shown that such strains indeed could be rendered sensitive by damaging the barrier function of the outer membrane.

Cell Membrane↗
PubMed2000

Comparison of antimicrobial resistance phenotypes and resistance genes in Enterococcus faecalis and Enterococcus faecium from humans in the community, broilers, and pigs in Denmark.

Enterococcus faecalis and E. faecium isolated from humans in the community (98 and 65 isolates), broilers (126 and 122), and pigs (102 and 88) during 1998 were tested for susceptibility to 12 different antimicrobial agents and for the presence of selected genes encoding resistance using PCR. Furthermore, the presence of vancomycin resistant enterococci was examined in 38 human stool samples using selective enrichment. Widespread resistance to chloramphenicol, macrolides, kanamycin, streptomycin, and tetracycline was found among isolates from all three sources. All E. faecium isolates from humans and pigs were susceptible to avilamycin, whereas 35% of isolates from broilers were resistant. All E. faecium isolates from humans were susceptible to vancomycin, whereas 10% and 17% of isolates from broilers and pigs, respectively, were resistant. A vancomycin resistant E. faecium isolate was found in one of the 38 human fecal samples examined using selective enrichment. All vancomycin resistant isolates contained the vanA gene, all chloramphenicol resistant isolates the cat(pIP501) gene, and all five gentamicin resistant isolates the aac6-aph2 gene. Sixty-one (85%) of 72 erythromycin resistant E. faecalis examined and 57 (90%) of 63 erythromycin resistant E. faecium isolates examined contained ermB. Forty (91%) of the kanamycin resistant E. faecalis and 18 (72%) of the kanamycin resistant E. faecium isolates contained aphA3. The tet(M) gene was found in 95% of the tetracycline resistant E. faecalis and E. faecium isolates of human and animal origin, examined. tet(K) was not observed, whereas tet(L) was detected in 17% of tetracycline resistant E. faecalis isolates and in 16% of the E. faecium isolates. tet(O) was not detected in any of the isolates from pigs, but was observed in 38% of E. faecalis isolates from broilers, in two E. faecalis isolates from humans and in three E. faecium isolates from broilers. tet(S) was not detected among isolates from animals, but was observed in 31% of E. faecalis and one E. faecium isolate from humans. This study showed a frequent occurrence of antimicrobial resistance and the presence of selected resistance genes in E. faecalis and E. faecium isolated from humans, broilers and pigs. Differences in the occurrence of resistance and tetracycline resistance genes were observed among isolates from the different sources. However, similar resistance patterns and resistance genes were detected frequently indicating that transmission of resistant enterococci or resistance genes takes place between humans, broilers, and pigs.

Animals↗
PubMed1996

Zidovudine resistance is suppressed by mutations conferring resistance of human immunodeficiency virus type 1 to foscarnet.

Both foscarnet (PFA) and zidovudine (AZT) select for drug-resistant variants of human immunodeficiency virus type 1 (HIV-1), but the interactions between the mutations causing such resistance are unknown. The introduction of the previously identified PFA resistance mutation W to G at codon 88 (W88G), E89K, L92I, or Q161L into an HIV-1 strain having the four known AZT resistance mutations completely reversed high-level AZT resistance. Two additional PFA resistance mutations, W88S and S156A, partially suppressed AZT resistance. Phenotypic reversion of AZT resistance by W88S, W88G, E89K, L921, and S156A was associated with a concomitant suppression of PFA resistance. The degree to which PFA resistance mutations reversed AZT resistance was directly correlated with each mutation's ability to confer high-level PFA resistance (> or = 5.0-fold) and AZT hypersusceptibility in a wild-type genetic background. Highly PFA-resistant HIV- 1 strains were hypersusceptible to AZT; conversely, AZT-resistant strains with M41L and T215Y; M41L, L210W, and T215Y; or M41L, D67N, K70R, and T215Y mutations were 2.2- to 2.5-fold hypersusceptible to PFA. Prolonged in vitro selection of wild-type or AZT-resistant HIV-1 strains with the combination AZT and PFA failed to generate coresistant virus, indicating that dual resistance was relatively difficult to achieve. Strains selected by passage in PFA plus AZT were phenotypically PFA resistant and AZT susceptible despite multiple reverse transcriptase mutations known to confer AZT resistance. These data show that PFA resistance mutations can phenotypically reverse AZT resistance and that AZT and PFA resistance might be mutually exclusive. The reciprocal interactions between AZT and PFA resistance-conferring mutations have implications for structure-function studies of the HIV-1 reverse transcriptase.

Antiviral Agents↗
PubMed1989

Cross-resistance and glutathione-S-transferase-pi levels among four human melanoma cell lines selected for alkylating agent resistance.

A panel of four cell sublines, each selected for resistance to a different antineoplastic agent, has been developed from a human malignant melanoma cell line G3361. Following repeated exposure to escalating doses of the drug of interest, cloned sublines were developed that are 9-fold resistant to cisplatin (G3361/CP), 11-fold resistant to 4-hydroxyperoxy-cyclophosphamide (4-HC) (G3361/HC), 4-fold resistant to carmustine (BCNU) (G3361/BCNU), and 4-fold resistant to melphalan (G3361/PAM). The cross-resistance of each resistant cell line was determined for cisplatin, BCNU, 4-HC, melphalan, carboplatin, nitrogen mustard, and Adriamycin. In general, the alkylating agent-resistant cell lines were specifically resistant to the drug used for selection with the exception of the G3361/CP line, which was greater than 10-fold resistant to the cisplatin analogue carboplatin, 4-fold resistant to 4-HC, and slightly (1.5-fold) resistant to melphalan, and the G3361/BCNU line, which was slightly (1.8-fold) resistant to melphalan. Collateral sensitivity of the G3361/CP, G3361/PAM, and G3361/4HC lines to killing by BCNU was also observed. Glutathione-S-transferase activity was elevated in each of the alkylating agent-resistant cell lines by 3- to 5-fold with chlorodinitrobenzene substrate. On Western blotting, the glutathione-S-transferase-pi (GST-pi) isoenzyme protein was elevated in the resistant cells by 3- to 5-fold. A complementary DNA (pTS4-10) coding for GST-pi has been cloned from a lambda gt11 library, sequenced, and used as a probe to determine the relative levels of GST-pi mRNA in the alkylating agent-resistant cell lines. GST-pi mRNA levels were elevated (8- to 15-fold) in the resistant cell lines, indicating that the GST-pi increases were mediated through an increase in mRNA levels. GST-pi elevations are a frequent event in cells selected for alkylating agent resistance, and in some cases, of multiple drug resistance. However, the lack of cross-resistance among cell lines selected for resistance to different alkylating agents, all of which have elevated GST-pi levels, indicates that increased levels of GST-pi cannot be the predominate mechanism for resistance to the tested drugs in these cell lines.

Alkylating Agents↗