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PubMed1990

Role of oxygen free radical formation in the mechanism of menogaril resistance in multidrug resistant tumor cells.

The mechanisms of action and resistance to menogaril, a clinically active anthracycline antitumor drug, were evaluated in sensitive and doxorubicin-selected multidrug resistant human breast tumor (MCF-7) cell lines. While MCF-7/ADRR cells were highly resistant (250-500-fold) to doxorubicin, they displayed only marginal resistance (10-fold) to menogaril. In contrast to doxorubicin, the mechanism of resistance to menogaril in these cells does not involve differential inhibition of DNA synthesis as measured by thymidine incorporation. P-170-glycoprotein-dependent drug transport did not contribute to resistance as there was no difference in the accumulation and retention of menogaril by sensitive and resistant cell lines. However, there was a 2-fold decrease in oxygen free radical formation in the resistant cells, compared to sensitive cells, in the presence of menogaril. Since resistant cells contain 12-fold higher glutathione peroxidase activity than the parental sensitive cells, the detoxification of hydrogen peroxide may be responsible for the decreased free radical formation and thus, may play a role in the resistance to menogaril.

Antineoplastic Agents↗
PubMed1992

Plasmodium chabaudi: association of reversal of chloroquine resistance with increased accumulation of chloroquine in resistant parasites.

The effects of tricyclic antidepressants, desipramine and imipramine, and phenothiazines, chlorpromazine and trifluoperazine, on chloroquine (CQ)-resistant and CQ-sensitive lines of P. chabaudi were examined in vivo. In mice that received daily injections of these drugs the growth of CQ-resistant and CQ-sensitive parasites was unaffected or affected very slightly, if at all. A combination of CQ and each drug suppressed the growth of CQ-resistant parasites in a dose-dependent manner. In addition, in CQ-sensitive parasites each drug also increased the susceptibility to CQ. Measurements of CQ levels by high-performance liquid chromatography showed that CQ accumulated in sensitive parasites to more than twice the level in resistant parasites at 2 to 4 hr after an injection of CQ. Verapamil and desipramine substantially increased CQ levels in both CQ-resistant and CQ-sensitive parasites. These results suggest that not only Ca2+ antagonists but tricyclic antidepressants reverse CQ resistance in CQ-resistant parasites and enhance the inhibitory effect in sensitive parasites by increasing CQ levels in those parasites. The effects of Ca2+ antagonists, tricyclic antidepressants, and phenothiazines on a pyrimethamine-resistant line of P. chabaudi were also studied. None of the Ca2+ antagonists (verapamil, nicardipine, and diltiazem) affected the growth of the parasite in combination with 20 mg/kg pyrimethamine. Tricyclic antidepressants and phenothiazines suppressed pyrimethamine-resistant parasites to some extent. However, the extent of this suppression was less pronounced as compared with that of suppression of CQ resistance by the same drugs.

Animals↗
PubMed1988

An altered pattern of cross-resistance in multidrug-resistant human cells results from spontaneous mutations in the mdr1 (P-glycoprotein) gene.

Multidrug resistance in human cells results from increased expression of the mdr1 (P-glycoprotein) gene. Although the same gene is activated in cells selected with different drugs, multidrug-resistant cell lines can be preferentially resistant to their selecting agent. The mdr1 cDNA sequence from vinblastine-selected KB cells, which are uniformly resistant to different lipophilic drugs, was compared with the corresponding sequence from colchicine-selected KB cells preferentially resistant to colchicine. These sequences differ at three positions, resulting in a single amino acid change in P-glycoprotein. These differences result from mutations that occurred during colchicine selection. The appearance of these mutations coincides with the emergence of preferential resistance to colchicine. We have constructed biologically active mdr1 cDNA clones that express either wild-type or mutant P-glycoprotein. Multi-drug-resistant transfectants obtained with the mutant sequence were characterized by increased relative resistance to colchicine compared with transfectants obtained with wild-type sequence. mdr1 mutations are therefore responsible for preferential resistance to colchicine in multidrug-resistant KB cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Development of tumour cell resistance to tumour necrosis factor does not confer resistance to cytotoxic drugs.

Tumour necrosis factor (TNF) is a protein product of macrophages with potential anti-cancer activity. As with other anti-cancer agents, tumour cells can develop resistance to the cytotoxic effects of TNF. The aim of his study was to see whether development of resistance to TNF resulted in a concomitant resistance to other anti-cancer agents, in particular those associated with multidrug resistance. Three TNF-susceptible tumour cell lines (L929, U937 and RK13) and their TNF-resistant sublines were compared for susceptibility in vitro to several cytotoxic drugs. The TNF-resistant sublines were not significantly more resistant to these drugs. In addition, an L929 subline selected for resistance to actinomycin D retained its susceptibility to TNF. These observations show that tumour cell resistance to TNF develops independently of resistance to cytotoxic drugs.

Animals↗
PubMed1996

Vincristine resistant HL-60 cells show cross-resistance to hypoxanthine-xanthine oxidase.

This is the first observation that active an oxygen-producing system showed cross-resistance to vincristine (VCR) resistant cells or other anticancer agent-resistant cells. The extent of cross-resistance against oxygen radicals and anticancer agents in wild type and VCR resistant human promyelocytic leukemia cell line, HL-60 and HL-60/VCR, is compared. Superoxide was generated by reaction with hypoxanthine(HX)-xanthine oxidase(XO). HL-60/VCR was 81-fold resistant to VCR, 11.8-fold resistant to adriamycin, and 8.5-fold resistant to the XO concentration required for 50% growth inhibition compared with HL-60. Because oxygen radicals injure the cell membrane, the results indicate an increased resistance to membrane damage by oxygen radicals in drug resistant cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1986

Adriamycin resistance, heat resistance and radiation response in Chinese hamster fibroblasts.

We have investigated the effect of heat, radiation or Adriamycin (ADR) on Chinese hamster fibroblasts (HA-1), their heat resistant variants, and their ADR resistant variants. Heat or ADR resistance did not confer cross resistance to radiation. Cells resistant to heat did show cross resistance to ADR. Cells selected for ADR resistance were not cross resistant to heat and they did not exhibit drug potentiation by hyperthermia, characteristic of ADR sensitive cells. Cytofluorometric measurement showed decreased ADR uptake in both heat and ADR resistant cells. The possibility of cross resistance between heat and ADR should be considered when designing treatment protocols involving combined modality trials.

Animals↗
PubMed1993

Cross-resistance to beta-lactam-beta-lactamase inhibitor combinations and clindamycin among cefoxitin-resistant and cefoxitin-susceptible strains of the Bacteroides fragilis group.

In the present study the cross-resistance rates of cefoxitin-resistant and cefoxitin-susceptible strains of the Bacteroides fragilis group were compared with regard to beta-lactam-beta-lactamase inhibitor combinations and clindamycin. Piperacillin-tazobactam was the most active agent tested with an overall resistance rate of 0.2% and no resistance among cefoxitin-resistant strains. Ticarcillin-clavulanate was the least active combination with an overall resistance rate of 1.6% but a resistance rate of 13.1% among cefoxitin-resistant strains. For ampicillin-sulbactam, amoxicillin-clavulanate, and clindamycin resistance, rates of cefoxitin-resistant versus cefoxitin-susceptible strains were 9.1% and 0.4%, 8.3% and 0.9%, and 28% and 12.9%, respectively.

Anti-Bacterial Agents↗
PubMed2006

Phenotypic and genotypic detection of ESBL mediated cephalosporin resistance in Klebsiella pneumoniae: emergence of high resistance against cefepime, the fourth generation cephalosporin.

OBJECTIVES: Cephalosporins belonging to second and third generation are commonly used in India for the treatment of Klebsiella pneumoniae. Report on resistance among K. pneumoniae strains to second and third generation cephalosporins are on rise in this country, which has been attributed to emergence of strains expressing extended-spectrum beta-lactamases (ESBLs). The aim of this study was to evaluate the in vitro susceptibility of K. pneumoniae to broad-spectrum cephalosporins particularly to cefepime, a recently introduced fourth generation cephalosporin in relation to ESBL production. METHODS: This study has been carried out in two phases among K. pneumoniae strains isolated between October 2001 and September 2002 (phase I, before marketing of cefepime in India) and between August 2003 and July 2004 (phase II, after marketing of cefepime in India). Minimum Inhibitory Concentration (MIC) was determined by a commercial strip containing gradient of antimicrobials (Strip E-test). Detection for ESBL production was carried out by DDST, E-test ESBL and PCR. RESULTS: Antimicrobial resistance profile of K. pneumoniae strains to five cephalosporins as analyzed by WHONET 5 identified 15 different resistance profiles among the 108 phase I isolates, ranging from resistance to none (19.44%) to all the five cephalosporin (8.33%) and eight different resistance profiles among the 99 phase II isolates, ranging from resistance to none (9.1%) to all the five cephalosporins (36.4%). Among the 108 phase I isolates a total of 71 (65.72%) and out of 99 phase II isolates, a total of 87 (88.0%) could be identified as ESBL producers. Among the isolates, regardless of the phase of the isolation, those characterized by production of ESBL showed overall higher frequency of resistance to cephalosporins (range 19.7-85.9% and 51.7-100% in phase I and phase II, respectively) compared to those for ESBL non-producers (range 0-13.5% and 0-25% in phase I and phase II, respectively). Ten randomly selected isolates from the most common resistance phenotypes probably belonged to a single strain as evident by MIC patterns, genotypic characterization and resistance profile to non-cephalosporin group of antimicrobials thereby pointing out the possibility of an outbreak. CONCLUSIONS: PCR may be regarded as a reliable method for detection of ESBL since in addition to the strains that could be identified as ESBL producers by DDST and E-test ESBL; PCR could demonstrate ESBL production among additional 32 strains (15 in phase I and 17 in phase II). Continued uses of cephalosporin group appear to be a potential risk factor for emergence of ESBL producing K. pneumoniae strains. In addition, as noted in the present study, the rise of resistance to cefepime that has been introduced recently in this country for therapeutic use could be of concern.

Anti-Bacterial Agents↗
PubMed2004

Postnatal development of resistance to short-term high-dose toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in TCDD-resistant and -semiresistant rats.

Despite great interspecies differences in adult 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) sensitivity, the toxic potency of TCDD is similar across species in fetal mortality. Han/Wistar (Kuopio; H/W) rats are exceptionally resistant to acute toxicity of TCDD, but show sensitivity to embryotoxicity and teratogenicity. The resistance of adult H/W rats to acute TCDD toxicity is based on a point mutation in the transactivation domain of the aryl hydrocarbon receptor (AHR) and to an unknown gene "B". This study investigated the time course of postnatal development of resistance to TCDD and the significance of genotypic variation in resistance development. H/W, line A (a new line with the H/W-type mutated AHR), and line B rats (a line with normal AHR but moderately resistant because of gene "B") were exposed to a single dose of TCDD 2-56 days after birth. H/W and line A rats received 1000 microg/kg; male and female B rats received 200 and 100 microg/kg, respectively. Survival was monitored for 42 days. Interestingly, although TCDD ceased growth and weight gain in all TCDD groups, the younger dosed animals did not seem to reach the body weight of the older dosed animals even in 100 days. The survival results after 42 days showed that line A rats are fairly resistant to TCDD immediately after birth, and their full TCDD resistance develops during the first week of life. The moderate resistance of line B rats develops approximately at the time of weaning. This difference in the time course of resistance development suggests that there are basic differences in pathways mediating resistance in lines A and B rats.

Alleles↗
PubMed1999

Correlation between the kinetics of anthracycline uptake and the resistance factor in cancer cells expressing the multidrug resistance protein or the P-glycoprotein.

Multidrug resistance (MDR) in model systems is known to be conferred by two different integral proteins, the 170-kDa P-glycoprotein (Pgp) and the 190-kDa multidrug resistance-associated protein (MRP1). One possible pharmacological approach to overcome drug resistance is the use of specific inhibitors, which enhance the cytotoxicity of known antineoplastic agents. However, while many compounds have been proven to be very efficient in inhibiting Pgp activity only some of them are able to inhibit MRP1. The other likely approach is based on the design and synthesis of new non-cross-resistant drugs with physicochemical properties favoring the uptake of the drug by the resistant cells. The intracellular drug retention influences its cytotoxic effect. The level of the intracellular drug content is a function of the amount of drug transported inside the cell (influx) and the amount of drug expelled from the cell (efflux). In this work, the kinetics of drug uptake and the kinetics of active efflux of several anthracycline derivatives in both Pgp expressing K562/Adr cells and MRP1 expressing GLC4/Adr cells was determined. Our data have shown that in both cell lines there is no correlation between the resistance factor and the kinetics of drug efflux by these pumping systems. However, a very good correlation between the resistance factor and the kinetics of drug uptake has been established in both cell lines: the resistance factor decreases when the kinetics of drug uptake increases. This work has clearly shown that when the rate of transmembrane transport of anthracycline is high enough, the efflux mediated by the protein transporter is not able to pace with it. The protein transporter essentially operates in a futile cycle and the resistance factor is tending to one. It does not mean, however, that when the resistance factor is close to one the anthracycline is not transported by the pump.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Antimicrobial resistance from enterococci in a pediatric hospital. Plasmids in Enterococcus faecalis isolates with high-level gentamicin and streptomycin resistance.

BACKGROUND: Enterococcus spp. is an important nosocomial and community-acquired pathogen. Recent studies have documented the increasing importance of this pathogen in children, particularly in the hospital setting. Our objective in this study was to report the frequency of antimicrobial resistance in enterococci and to determine the characteristics of high-level gentamicin resistance (HLGR) plasmids in Enterococcus faecalis clinical isolates. METHODS: Two hundred eighty-nine enterococcal isolates were collected during an 18-month period from a tertiary-care pediatric hospital in Mexico City. Isolates were screened for antibiotic resistance, including HLGR. High-level, gentamicin-resistant E. faecalis strains were selected for pulsed-field electrophoresis (PFGE) typing and plasmid analysis. Transferability of resistance markers was carried out using filter matings. RESULTS: Seventy-six percent of isolates were E. faecalis, 10% were E. avium, 5.2% E. faecium, 5.2% E. raffinossus, 1.38% E. malodoratus, 0.6% E. hirae, and 0.6% E. casseliflavus. Antimicrobial resistance was ampicillin and penicillin 29%, imipenem 17%, and vancomycin 3%, HLGR 5%. The following 15 high-level, gentamicin-resistant isolates were identified: six E. faecalis; four E. avium; three E. faecium, and two E. casseliflavus. Five of the six E. faecalis isolates were different by PFGE and transferred gentamicin and streptomycin resistance on filter membranes. Transfer frequencies ranged from 8.2 x 10(-4) to 6.92 x 10(-5) transconjugants/recipient cell. The plasmid content of donors and transconjugants were homogeneous (one plasmid of 47 kb). CONCLUSIONS: In this pediatric hospital, antimicrobial resistance in Enterococcus spp. is common. Frequency of high-level, gentamicin-resistant strains is low. Mechanism of HLGR appears to be due to a single plasmid dissemination.

Drug Resistance, Microbial↗
PubMed1995

A bi-modal transfer of antibiotic resistance by conjugation and transduction from an imipenem-resistant strain of Pseudomonas aeruginosa.

A strain of Pseudomonas aeruginosa No. 76/17224 resistant to carbenicillin (CAR), kanamycin (KAN), cefalotin (CLO), cefotaxime (CTX), ceftazidime (CAZ), aztreonam (AZA), imipenem (IMI) and ofloxacin (OFL) was isolated at the Frankfurt University Hospital. This strain transferred, by conjugation, antibiotic resistance determinants to CAR, CLO, CTX, CAZ and AZA. In addition, we isolated a wild-type phage from this strain. We used this phage to transduce the resistance determinants to four susceptible recipient strains of P. aeruginosa. The phage designated AP-76 transduced the resistance determinants to KAN, CAR, CTX and CAZ to all four recipient strains. Imipenem and aztreonam resistance determinants were directly transduced to two recipient strains only, i.e. to PAO-1670 and ML-1008. The IMI resistance determinant was not co-transduced with any other resistance determinant(s) selected directly. Our results indicated that IMI resistance determinant was not associated with other resistance determinants. IMI was actively hydrolysed by IMI-resistant transductants and this hydrolysis was inhibited by clavulanate but not by EDTA.

Bacteriophages↗
PubMed2005

Mefloquine resistance reversal action of ketoconazole - a cytochrome P450 inhibitor, against mefloquine-resistant malaria.

Plasmodium knowlesi (W1) shows a high level of innate resistance to mefloquine as shown by recrudescence of blood-induced infection in rhesus monkeys, following oral mefloquine treatment with up to 80-160 mg/kg total dose over 3-4 days. Ketoconazole, at a dose of 75 mg/kg/day x 10 days given orally to P. knowlesi-infected rhesus monkeys, exerted a suppressive antimalarial effect in 1 of the 2 monkeys as evidenced by a delayed recrudescence (on day 30) and curative action in case of the other monkey, whereas a lower dose of ketoconazole (25 mg/kg/day x 10 days) failed to suppress infection effectively. When ketoconazole at a low dose (25 mg/kg/day x 10 days) treatment was combined with mefloquine (20 mg/kg/ day x 4), 1 of the 2 infected monkeys was cured, while the combination of a higher dose of ketoconazole (75 mg/kg/day x 10 days) with mefloquine (20 mg/kg/day x 4), had a complete curative effect on P. knowlesi infection in all the treated monkeys (7/7). Besides exerting direct antimalarial action against a mefloquine-resistant P. knowlesi, ketoconazole also acts as an inhibitor of hepatic microsomal CYP4503A, which regulates and slows down mefloquine biotransformation to carboxymefloquine, resulting in a possible elevation of the effective plasma drug level, which seems to be responsible for elimination of the resistant P. knowlesi. The study shows a resistance reversal effect of a ketoconazole - mefloquine combination that could be exploited for the control of mefloquine-resistant malaria infection. The study shows that ketoconazole can reverse mefloquine resistance of P. knowlesi. These findings can also be applied to reverse mefloquine resistance of P.falciparum in areas where mefloquine resistance is already established. The precise role of parasite CYP450 in mefloquine resistance and its possible role, if any, in expelling the intracellular mefloquine from the resistant plasmodia still remains to be elucidated.

Animals↗
PubMed2002

Antibiotic resistance peptides: interaction of peptides conferring macrolide and ketolide resistance with Staphylococcus aureus ribosomes: conformation of bound peptides as determined by transferred NOE experiments.

Two antibiotic resistance peptides, the E-peptide (MRLFV) and the K-peptide (MRFFV) conferring macrolide and ketolide resistance, respectively, were studied in the complex state with bacterial Staphylococcus aureus ribosomes. Interactions of antibiotic resistance peptides with ribosomes were investigated using two-dimensional transferred nuclear Overhauser effect spectroscopy (TRNOESY), suggesting that the peptide-ribosome interaction was associated with the low-affinity binding level. K-Peptide displayed a significantly better response in TRNOEs NMR experiments, in agreement with a better overall antibiotic activity of ketolides. This difference highlights a mimetic effect displayed by the E- and K-peptides. This study shows that conformation plays an essential role for the affinity binding site and, thus, for the resistance mechanism. Specific conformations were preferred in the bound state; their superimposition exhibited a similar cyclic peptidyl chain, while the side chain region varies. The F4 phenyl moiety in E-peptide has moved out of the turn region compared to its folding in the ketolide resistance peptide. In the K-peptide binding surface, the F4 aromatic chain is maintained by stacking with the guanidyl group of the R2 residue providing a particular hydrophobic and globular fragment, which may be important for the ketolide resistance peptide mode of action. Additionally, T(2) (CPMG) measurements were used to characterize equilibrium binding of antibiotic resistance peptides to bacterial ribosomes. The results bring to the fore E- and K-peptide competition with antibiotics for binding to the ribosomes. Their specific interaction and their competitive effects reveal a novel aspect of interaction of resistance peptides with ribosomes and suggest new insights about their mode of action. The resistance mechanism may imply two steps, a competitive effect of the resistance peptide for the macrolide (or ketolide) binding site followed by a "bottle brush" effect in which the drug and the peptide are driven out their binding site on the ribosome.

Binding Sites↗
PubMed1986

Characterization of a doxorubicin-resistant murine melanoma line: studies on cross-resistance and its circumvention.

A B16 mouse melanoma cell line resistant to doxorubicin was obtained by continuous in vitro exposure to the drug. The ID50 for this line was 200 times higher than that for the parental cell line. The resistant cell line had some biological characteristics similar to those of the sensitive parental cell line, like saturation density and protein content. Differences were found in doubling time which was longer, cloning efficiency which was lower and DNA content which was higher in the resistant as compared to the parental line. Intracellular distribution of doxorubicin was also different having a nuclear-cytoplasmic ratio higher in sensitive than in resistant cells. Melanin content was an unstable feature in the sensitive cell line, whereas melanin was always present in resistant cells. Resistance to doxorubicin was maintained during 50 in vitro passages in the absence of the drug. Cross-resistance was found with vincristine and other anthracyclines, like daunorubicin and 4'-epi-doxorubicin but not with cis-platinum, and a new doxorubicin derivative, 4'-deoxy-4'-iodio-doxorubicin. The B16 line showed a lower resistance index to 4'-deoxy-doxorubicin and 4-demethoxy-daunorubicin (30 and 3 respectively), as compared to doxorubicin. Doxorubicin-resistance was partially circumvented by pretreatment of resistant cells with verapamil, a calcium chelating agent, and by trifluoperazine, a calmodulin-antagonist.

Animals↗
PubMed1993

Acquisition of platinum drug resistance and platinum cross resistance patterns in a panel of human ovarian carcinoma xenografts.

In vivo models of acquired resistance to the platinum-based agents cisplatin (CDDP), carboplatin (CBDCA), iproplatin (CHIP) and tetraplatin have been established using a panel of six parent human ovarian carcinoma lines, two (HX/110 and PXN/87) being derived from previously untreated patients. Resistance has been generated to CDDP (three lines), CBDCA (one line), CHIP (three lines) and tetraplatin (one line) either by treatment in vivo or (for one line to CDDP) through exposure in vitro and subsequent transfer to mice. With the four tumours where resistance was generated using CDDP or CBDCA, a complete cross-resistance to the remaining platinum agents studied was observed. In contrast, in one of three lines with derived resistance to the platinum (IV) agent, CHIP, (PXN/951) a retention in sensitivity was observed with CDDP and CBDCA. Only one of the six parent tumour lines (PXN/100) was markedly sensitive to tetraplatin. Where resistance was generated to tetraplatin (PXN/100T) there was some retention of activity by CDDP. For the CDDP-resistant line established in vitro, there was a close agreement between the cross-resistance profile obtained in vitro vs that obtained in vivo. This tumour panel may be useful in the elucidation of cellular and molecular resistance mechanisms to platinum drugs operative in vivo. Moreover, as they appear to mimic the clinical observations of shared cross-resistance between CDDP, CBDCA and CHIP, they may represent valuable preclinical evaluation models for the discovery of drugs capable of conferring responses in CDDP-refractory ovarian cancer.

Animals↗
PubMed1995

Expression of multidrug resistance-associated protein (MRP), MDR1 and DNA topoisomerase II in human multidrug-resistant bladder cancer cell lines.

The acquisition of the multidrug resistance phenotype in human tumours is associated with an overexpression of the 170 kDa P-glycoprotein encoded by the multidrug resistance 1 (MDR1) gene, and also with a 190 kDa membrane ATP-binding protein encoded by a multidrug resistance-associated protein (MRP) gene. Human bladder cancer is a highly malignant neoplasm which is refractory to anti-cancer chemotherapy. In order to understand the mechanism underlying multidrug resistance in bladder cancer, we established three doxorubicin-resistant cell lines, T24/ADM-1, T24/ADM-2 and KK47/ADM, and one vincristine-resistant cell line, T24/VCR, from human bladder cancer T24 and KK47 cells respectively. Both T24/ADM-1 and T24/ADM-2 cells which had elevated MRP mRNA levels showed both a cross-resistance to etoposide and a decreased intracellular accumulation of etoposide. T24/VCR cells which had elevated levels of MDR1 mRNA and P-glycoprotein but not of MRP mRNA, showed cross-resistance to doxorubicin. On the other hand, KK47/ADM cells, which had elevated levels of both MRP and MDR1 mRNA and a decreased level of topoisomerase II mRNA, were found to be cross-resistant to etoposide, vincristine and a camptothecin derivative, CPT-11. Our present study demonstrates a concomitant induction of increased levels of MRP mRNA, decreased levels of topoisomerase II mRNA and decreased drug accumulation during development of multidrug resistance in human bladder cancer cells. The enhanced expression of the MRP gene is herein discussed in a possible correlation with the decreased expression of the topoisomerase II gene.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Genetic markers of resistance to pyrimethamine and sulfonamides in Plasmodium falciparum parasites compared with the resistance patterns in isolates of Escherichia coli from the same children in Guinea-Bissau.

The antifolate drugs sulphadoxine and pyrimethamine are used for treatment of chloroquine-resistant Plasmodium falciparum in Africa. Resistance to pyrimethamine has been associated with point mutations in the dhfr-gene and resistance to sulphadoxine with mutations in the dhps-gene. There is concern that the use of the antifolates trimethoprim and sulphamethoxazole for treatment of other infectious diseases will result in the selection of malaria parasites with mutations in these genes. In Guinea-Bissau, where sulfonamide and trimethoprim-containing drugs have been used extensively, we decided to assess the prevalence of mutations in the dhfr-and dhps-gene in P. falciparum isolated from children suffering from acute malaria and to assess the resistance patterns to trimethoprim/sulphamethoxazole in Escherichia coli isolated from the same patients. A thick film and a blood sample for polymerase chain reaction (PCR) were obtained from 100 children attending the Bandim Health Centre in Bissau with symptoms compatible with malaria. Furthermore, a stool sample was collected from the same children and cultured for E. coli. Of the cultured E. coli, 67% were resistant both to sulfonamides and trimethoprim, 4% to sulfonamides alone, 3% to trimethoprim alone while 26% were fully sensitive to both drugs. PCR was successfully performed in 97 blood samples. Of these, 41% had triple mutations at the dhfr-gene (at codons 51, 59 and 108), and 15% had triple mutations plus mutation at codon 437 in the dhps-gene. Only 45% harboured the wild-type dhfr-gene. Thus both bacterial resistance and mutations in the parasitic genes were common, but not linked in the individual child. As sulphadoxine-pyrimethamine has only been used as a second line treatment for chloroquine resistant malaria in Guinea-Bissau for a few years, it is worrying to find a high prevalence of mutations in the parasitic genes coding for resistance to these drugs. Therefore, restricting the use of sulphadoxine-pyrimethamine for the treatment of chloroquine resistant malaria might not be sufficient to prevent the development of resistance in the parasites as long as antifolate drugs are used extensively.

Adolescent↗