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PubMedDate not supplied

New TFO conjugates containing a carminomycinone-derived chromophore.

Conjugates obtained by linking the anthracycline intercalating chromophore to triple helix forming oligonucleotides (TFOs) have been used in a physicochemical study of the stability of triple helices with DNA sequences of pharmacological relevance. The intercalating moiety is represented by carminomycinone derivatives obtained upon O-demethylation and hydrolysis of the glycosidic linkage of daunomycin followed by the introduction of an alkylating residue at two different positions. Results of experiments with a polypurinic region present in the multidrug resistance (MDR) gene indicate that the stability of the triple helix is significantly enhanced by replacement of C's with (5-Me)C's in the TFO sequences tested. The stability is not changed when a 3'-TpT is present in place of a 3'-CpG at the presumed intercalation site of the anthraquinone chromophore. The same carminomycinone derivatives were used for the preparation of conjugates able to form triple helices with the polypurine tract (PPT) present in the human integrated genome of HIV-1 infected cells. Three different TFOs (T(4)(Me)CT(4)(Me)CC, C2; T(4)(Me)CT(4)(Me)CC(Me)CC(Me)CCT, C6; and T(4)(Me)CT(4)G(6), G6) were designed and linked to the anthraquinone moiety. These conjugates showed a significantly enhanced ability to bind the PPT region of HIV with respect to the nonconjugated TFOs.

Anthracyclines↗
PubMed2000

Effects of multidrug resistance gene expression in acute erythroleukemia.

Acute erythroleukemia is a relatively rare disorder of a multilineal nature. Patients with this type of leukemia traditionally have been treated with a standard myeloid protocol, with a wide variation in prognosis between M6a, which has a similar prognosis to acute myelogenous leukemias, and M6b, with an extremely poor outcome despite aggressive therapy. Forty-eight archival cases of acute erythroleukemia, subtypes M6a (the traditional FAB-M6), M6b (pure erythroleukemia), and M6c (>30% myeloblasts and >30% pronormoblasts by FAB exclusion criteria), were evaluated for multidrug resistance gene (MDR-1) status. Findings were correlated with clinical course and karyotypes. Immunohistochemical stain for the protein product of MDR-1, P-glycoprotein, was variably positive in 11 of 23 patients with M6a, as well as in all of the patients with M6b (strongly positive) and M6c (weakly positive). P-glycoprotein expression positively correlated with unfavorable cytogenetic aberrations, poor response to chemotherapeutic agents, and short survival. Most significant was that P-glycoprotein expression demonstrated a negative additive effect on response to treatment and prognosis with unfavorable cytogenetic anomalies. P-glycoprotein expression and multiple cytogenetic anomalies most probably contribute to the resistance to chemotherapy and poor survival characteristic of the patients with M6b (mean survival, 3.15 +/- 4.2 mo) and M6c (mean survival, 10.5 +/- 12.7 mo). Because patients with M6b and M6c have increased numbers of pronormoblasts in their bone marrow and past chemotherapeutic attempts have failed, chemotherapy directed at these cells is appropriate. Additional therapy directed toward the MDR-1 gene and its protein product seems indicated from our findings.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Chemopreventive effects of tea extracts and various components on human pancreatic and prostate tumor cells in vitro.

Pancreatic and prostate cancers pose serious problems to human health. To determine the potential for chemopreventive intervention against pancreatic and prostate cancers, black and green tea extracts and components of these extracts were examined in vitro for their effect on tumor cell growth. Components included a mixture of polyphenols from green tea (GTP), mixtures of polyphenols (BTP) and of theaflavins (MF) from black tea, and the purified components epicatechin-3-gallate (ECG) and epigallocatechin-3-gallate (EGCG). Two human cell lines, pancreatic adenocarcinoma (HPAC) and prostate tumor (LNCaP), were exposed to these agents for 24 hours. Results showed inhibition (approx 90%) of cell growth in pancreatic tumor cells by black and green tea extracts (0.02%). GTP (10 micrograms/ml) and MF (100 micrograms/ml) significantly inhibited growth (approx 90%); ECG and EGCG inhibited growth as well (approx 95%). Black and green tea extracts, GTP, and EGCG decreased the expression of the K-ras gene, as determined by reverse transcription-polymerase chain reaction. Green and black tea extracts decreased the multidrug-resistant gene (mdr-1), although GTP and EGCG increased expression. Similar data were obtained in the prostate cell line LNCaP. All agents significantly inhibited growth. These agents increased expression of the mdr-1 gene. This study suggests that components from black and green tea extracts can modulate the expression of genes known to play a role in the carcinogenesis process and, therefore, may be potential agents for chemoprevention against pancreatic cancer.

Anticarcinogenic Agents↗
PubMed2006

Multidrug resistance in amoebiasis patients.

BACKGROUND & OBJECTIVES: Amoebiasis, caused by Entamoeba sp. a protozoan parasite, is a major public health problem in tropical and subtropical countries. The symptomatic patients are treated by specific chemotherapy. However, there are reports of treatment failure in some cases suggesting the possibility of drug resistance. The present study was therefore planned to assess the presence and expression of mRNA of multidrug resistance (MDR) gene in clinical isolates of Entamoeba histolytica and E. dispar. METHODS: Forty five clinical isolates of Entamoeba sp. [E. histolytica (15) and E. dispar (30)] were maintained in polyxenic followed by monoxenic medium. DNA and total RNA were extracted from clinical isolates of Entamoeba sp. and from sensitive strain of E. histolytica (HM1: IMSS) and subjected to polymerase chain reaction (PCR) and multiplex reverse transcription (RT)-PCR techniques. RESULTS: The 344 bp segment of E. histolytica DNA was seen by PCR using primers specific to EhPgp1 in all clinical isolates and sensitive strain of E. histolytica. Over expression of EhPgp1 was observed only in resistant mutant of E. histolytica; however, transcription of EhPgp1 was not seen in any clinical isolates and sensitive strain of E. histolytica. INTERPRETATION & CONCLUSION: The findings of the present study indicate that, so far, drug resistance in clinical isolates of E. histolytica does not seem to be a major problem in this country. However, susceptibility of clinical isolates of E. histolytica against various antiamoebic drugs needs to be investigated for better management.

Animals↗
PubMed2004

Flow cytometric analysis of DNA indices, expression of p53 and multidrug resistance genes in multiple myeloma patients.

OBJECTIVE: To perform a quantitative analysis of DNA ploidy, S-phase fraction % (SPF%), p53 and multidrug resistance (MDR) gene expression as independent prognostic parameters and to compare these parameters with stage of the disease in multiple myeloma (MM) patients. STUDY DESIGN: Peripheral blood bone marrow samples were analyzed for DNA ploidy and SPF% using a FACScan flow cytometer (Becton Dickinson). Detection of p53 and MDR gene expression was done using immunocytochemistry. RESULTS: Aneuploidy was found in 5/48 (10.42%) total myeloma patients, all of whom revealed hyperdiploidy. High SPF% was noted in 18/37 (48.65%) newly diagnosed MM patients and 5/11 (45.45%) follow-up cases of myeloma. p53 Gene product was noted in 8/48 (16.66%) myeloma patients, 6 newly diagnosed and 2 on follow-up. MDR gene expression was detected in 4/27 (10.81%) newly diagnosed patients and in 1/11 (9.09%)follow-up patients. CONCLUSION: All myeloma patients with aneuploidy revealed hyperdiploidy. The majority of cases with high SPF% were at advanced stages, indicating the prognostic significance of SPF%. Although, there was no statistical significance of DNA ploidy, SPF%, p53 and MDR gene product expression, they are important prognostic parameters. Our results can provide baseline data for comparison with future studies since these parameters have not been reported earlier from the Indian subcontinent.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1991

Newly formed chromosome-like structures in independent mouse P388 sublines with developed in vivo mdr1 gene amplification.

Mouse leukemia P388 sublines that acquired the resistance to multiple drugs as a result of treatment in vivo with anthracyclines (rubomycin, ruboxyl) and/or vincristine were studied. The mdr gene amplification was found in all tested cell lines: in four of five sublines all three members of the mdr gene family showed increased copy numbers, and in one cell line, developed after treatment with ruboxyl, mdr1a and mdr1b genes were amplified to the same degree, whereas the mdr2 gene was not amplified at all. The levels of amplification of mdr genes varied in different cell lines from 30-fold to 50-fold. Unusual cytological manifestations--relatively large newly formed chromosomelike structures, were revealed in four of five long-term independent sublines. Some of these structures did not contained C blocks; the others, in contrast, were enriched by C-heterochromatin. In situ hybridization showed the presence of mdr genes in newly formed bodies. In the majority of cases, the formation of chromosomelike structures was preceded by the appearance of other, smaller size, structures: the so-called "small chromatin bodies" (minichromosomes) and/or homogeneously G-positive small ring chromosomes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Wild-type p53-mediated induction of rat mdr1b expression by the anticancer drug daunorubicin.

The expression of P-glycoproteins encoded by the mdr gene family is associated with the emergence of the multidrug resistance phenotype in animal cells. mdr expression can be induced by many extracellular stimulants including cytotoxic drugs and chemical carcinogens. However, little is known about the mechanisms involved. Here, we report that the expression of the rat mdr1b can be induced by anticancer drug daunorubicin. Further analysis identified a bona fide p53-binding site spanning from base pairs -199 to -180 (5'-GAACATGTAGAGACATGTCT-3') in the rat mdr1b promoter that is essential for basal and daunorubicin-inducible promoter activities. In addition, our results show that wild-type p53 can up-regulate not only the promoter function but also endogenous expression of the rat mdr1b. To the best of our knowledge, this is the first report showing that a specific p53-binding site is involved in the transcriptional regulation of mdr gene by wild-type p53. Since p53 is a sensor for a wide variety of genotoxic stresses, our finding has broad implications for understanding the mechanisms involved in the inducible expression of mdr gene by anticancer drugs, chemical carcinogens, UV light, and other DNA-damaging agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Appearance and detection of multiple copies of the mdr-1 gene in clinical samples of mammary carcinoma.

To examine the presence of multiple copies of the mdr-I gene in clinical tumor samples we have developed an approach where the cells are obtained by fine-needle biopsies and the number of gene copies determined by PCR. The temporal appearance of amplified mdr-I was examined in 20 breast-cancer patients with clinical stage-IV disease receiving endocrine treatment. Tumor samples were obtained every 2nd to 3rd month from the same tumor lesion. None of the initial samples from each patient contained multiple copies of mdr-I. Of 16 patients who showed increased tumor size, 4 developed multiple gene copies, showing that the event occurs without cytotoxic selection of cells with chemotherapy.

Aged↗
PubMed1990

Is the mdr 1 gene relevant in chronic lymphocytic leukemia?

Chronic lymphocytic leukemia (CLL) is a progressive disease in which chemotherapy may result in temporary suppression of the peripheral blood lymphocyte count, but cure is not usually possible. Drug resistance mechanisms and the multidrug resistant (MDR) phenotype may be relevant to the therapeutic response. We have studied 34 patients with CLL (seven untreated, 27 treated), screening both DNA and RNA with the mdr 1 gene probe. In pure lymphocyte populations from 10 normal subjects, low levels of mdr 1 RNA expression were found. Eighteen CLL patients (four untreated, 14 treated) had levels of mdr 1 RNA expression above the normal range. No evidence of mdr 1 gene amplification could be found in these patients. Sequential estimations of RNA levels in three patients suggest that malignant lymphocytes in CLL can increase mdr 1 expression in response to chemotherapy and return to basal levels on withdrawal of the treatment. Such data raise important questions about the type of timing of cytotoxic therapy in CLL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Regulation of the multidrug resistance gene in regenerating rat liver.

The MDR1 gene encodes an Mr 170,000 energy-dependent drug efflux pump (P-glycoprotein) which transports hydrophobic agents such as Adriamycin, colchicine, the Vinca alkaloids, and actinomycin D out of cells. Increased expression of the mdr gene has been observed in preneoplastic and neoplastic carcinogen-induced rat liver nodules as well as in regenerating rat liver, suggesting that the mdr gene is regulated in response to liver injury. To determine whether the increased levels of mdr mRNA seen in regenerating liver are the result of an increased rate of transcription or a posttranscriptional event, nuclear run-on assays were performed on nuclei isolated from regenerating rat livers 4-72 h after partial hepatectomy. Whereas Northern blot analysis of regenerating rat liver demonstrated a greater than 20-fold increase in mdr mRNA levels, there was little or no increase in mdr gene transcription as measured by nuclear run-on analyses. beta-Actin and metallothionein gene transcription levels, known to increase transiently in regenerating liver, both showed increased nuclear run-on activity 4 h posthepatectomy, indicating that the nuclei were functional. Failure to demonstrate a substantial increase in mdr gene transcription suggests that the observed increase in mdr mRNA levels may result from a posttranscriptional event such as message stabilization. The sequence of the 3' noncoding region of the MDR1 gene shares strong homology with other unstable mRNAs, suggesting that RNA stabilization could account for the rise of mdr mRNA after partial hepatectomy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Feasibility of multidrug resistance (MDR-1) gene transfer in patients undergoing high-dose therapy and peripheral blood stem cell transplantation for lymphoma.

We have performed a pilot study of MDR-1 gene transfer in patients receiving CD34-selected peripheral blood stem cell (PBSC) transplant for lymphoma. To ensure minimum engraftment thresholds and facilitate CD34 purification, mobilisation of > 2 x 10(6) CD34 cells/kg was a condition for recruitment. Of 11 patients counselled for study entry, only five achieved this target in a single apheresis. In three consenting patients, purified CD34 cells were exposed to A12M1 MDR-1 retroviral supernatant for 6 h, cryopreserved then thawed and readministered following ablative chemotherapy. No delay in engraftment was observed, although one patient received additional back-up cells. Gene transfer was demonstrated by polymerase chain reaction (PCR) for vector-derived MDR-1 cDNA sequence in all cases. Analysis of peripheral blood and bone marrow cells after transplant has, however, shown no evidence of in vivo gene transfer with a follow-up of 12, 15 and 18 months. The effect of MDR-1 substrate drugs has not yet been tested as all patients remain in clinical and radiological remission of their lymphoma. These results confirm the difficulty of achieving in vivo gene transfer in human haemopoietic cells and indicate major logistical constraints in PBSC mobilisation in patients with relapsed and resistant disease in whom initial studies are appropriate.

Adolescent↗
PubMed1987

Expression of the multidrug-resistant gene in hepatocarcinogenesis and regenerating rat liver.

Preneoplastic and neoplastic liver nodules and hepatocytes isolated from regenerating rat liver have been shown to be resistant to a broad range of carcinogenic agents. This phenomenon was studied by measuring the expression of the multidrug-resistant (mdr) gene in normal liver cells and in preneoplastic and neoplastic nodules and regenerating liver. Levels of messenger RNA for the mdr gene, which encodes P-glycoprotein, were elevated in both preneoplastic and neoplastic lesions. Expression of the mdr gene also reached high levels in regenerating rat liver 24 to 72 hours after partial hepatectomy. These results show that the expression of the mdr gene can be regulated in liver and is likely to be responsible for part of the multidrug-resistance phenotype of carcinogen-initiated hepatocytes and regenerating liver cells.

Animals↗
PubMed1994

Identification of two nuclear protein binding sites and their role in the regulation of the murine multidrug resistance mdr1a promoter.

Multidrug resistance genes (mdr) that encode P-glycoproteins (P-gp) are transcriptionally regulated in normal tissues and in some multidrug-resistant (MDR) cells. Several lines of evidence suggest that regulation of P-gp overexpression at the transcriptional level is also important in human tumors. In murine MDR cells, mdr1a and/or mdr1b genes are overexpressed and P-gp isoforms are overproduced. To identify the mdr1a promoter regions that are required for transcription, the promoter has been linked to the chloramphenicol acetyltransferase (CAT) gene in transient expression vectors. 5'-Deletions of the promoter sequences have demonstrated that the region between -155 to +89 bp is crucial for basal activity of the mdr1a gene. DNase I footprinting, methylation interference, and gel retardation assays identified two nuclear protein binding sites within these sequences. One of the nuclear protein binding sites contains an 11-bp DNA sequence that interacts with nuclear protein(s) and is conserved in the promoters of the murine mdr1a and mdr1b, hamster pgp1, and human MDR1 genes. The conserved SP1 site (5'-GGGCGGG-3') that is present further downstream was shown to interact with its nuclear factor. These observations suggest that at least part of mdr gene transcriptional regulation is mediated by conserved mdr cis-regulatory elements and common nuclear factors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Activation of distinct multidrug-resistance (P-glycoprotein) genes during rat liver regeneration and hepatocarcinogenesis.

The multidrug transporter P-glycoproteins are encoded by three multidrug-resistance (mdr) genes in rodents, designated mdr1a (mdr3), mdr1b (mdr1), and mdr2. Only the first two genes are functionally related to multidrug resistance. Activation of rodent mdr genes during liver regeneration and hepatocarcinogenesis has been reported. In mice, mdr1a is activated in hepatocellular carcinomas (HCCs) produced by various carcinogenic protocols, whereas both mdr1a and mdr2 are activated during liver regeneration. In this communication, we report isolating three gene-specific probes for the rat mdr homologues, which were used as probes in an RNase protection assay to demonstrate that mdr1b mRNA was expressed in HCCs induced by two different protocols. Furthermore, high levels of hepatic mdr1b mRNA but only moderate levels of mdr1a and mdr2 mRNA were seen in preneoplastic lesions in rats treated with 2-acetylaminofluorene. Likewise, highly elevated levels of hepatic mdr1b mRNA but only moderately increased levels of mdr1a and mdr2 mRNA were seen after partial hepatectomy. Nevertheless, the general patterns of tissue-specific expression of these three mdr genes were similar in rats and mice. These results reveal a complex hepatic gene expression pattern during hepatocarcinogenesis and hepatic proliferation for this conserved gene family in rodents.

2-Acetylaminofluorene↗
PubMed2002

Regional expression of multidrug resistance genes in genetically epilepsy-prone rat brain after a single audiogenic seizure.

PURPOSE: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood-brain barrier. Recent evidence suggests that P-gp-mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR) brain after a single audiogenic seizure. METHODS: Three groups of adult male GEPRs (n = 5/group) were exposed to a seizure-inducing audiogenic stimulus and killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a stimulus-naïve control. Expression of mdr1a and mdr1b in distinct anatomic brain regions (cortex, midbrain, pons/medulla, hippocampus) was determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in the presence of competitive internal standards. RESULTS: When compared with control, mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at 24 h after a single audiogenic seizure. Cortical mdr1a expression remained elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla and hippocampus was unchanged. The mdr1b isoform was quantifiable in hippocampus alone and not influenced by seizure activity. CONCLUSIONS: These findings suggest that acute seizures in the GEPR can induce the expression of mdr genes. The pattern of increased expression appears to follow the anatomic pathway of audiogenic seizures in these animals, with initiation in the midbrain and propagation to the cortex. Further studies are required to investigate the effects of recurrent seizure activity and to characterise mdr expression in other experimental seizure models.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1993

MDR-1 gene expression, anthracycline retention and cytotoxicity in human lung-tumor cells from refractory patients.

Lung-tumor cells from pleural effusion of four refractory patients and in cell lines established from them were analyzed for anthracycline retention, cytotoxicity, and MDR-1 gene and P-glycoprotein expression. Murine leukemic P388 and doxorubicin-resistant P388/R84 lines were used as controls. The 50% growth-inhibitory concentration (IC50) for doxorubicin among lung-tumor lines varied from 0.16 to 0.31 microM in soft agar. Heterogeneity in doxorubicin or daunorubicin retention and response to the efflux-blocking action of 25 microM prochlorperazine was noted in pleural effusion of FCCL-1, -4, and -8. Among the cell lines established, an efflux-blocking effect in a subpopulation was noticed only in FCCL-1 and -4. Although the MDR-1 gene was present in all cell lines, including P388, its expression was pronounced only in P388/R84 and FCCL-1. In situ hybridization of antisense RNA probe to tumor cells showed high heterogeneity for MDR-1 message in the human lung-tumor cells as compared with the murine cells. Northern and slot blot hybridization confirmed in situ hybridization in lines with high levels of MDR-1 expression. The synthesis of MDR-1 mRNA and P-glycoprotein in tumor lines was correlated. The results suggest that because of extensive tumor-cell heterogeneity in human tumors, monitoring of MDR expression by in situ hybridization, quantitation of P-glycoprotein content by laser flow cytometry (and/or immunohistochemical methods), and drug efflux (by laser flow cytometry) may be the best ways to monitor multidrug resistance in human tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross.

Chloroquine is thought to act against falciparum malaria by accumulating in the acid vesicles of the parasite and interfering with their function. Parasites resistant to chloroquine expel the drug rapidly in an unaltered form, thereby reducing levels of accumulation in the vesicles. The discovery that verapamil partially reverses chloroquine resistance in vitro led to the proposal that efflux may involve an ATP-driven P-glycoprotein pump similar to that in mammalian multidrug-resistant (mdr) tumor cell lines. Indeed, Plasmodium falciparum contains at least two mdr-like genes, one of which has been suggested to confer the chloroquine resistant (CQR) phenotype. To determine if either of these genes is linked to chloroquine resistance, we performed a genetic cross between CQR and chloroquine-susceptible (CQS) clones of P. falciparum. Examination of 16 independent recombinant progeny indicated that the rapid efflux phenotype is controlled by a single gene or a closely linked group of genes. But, there was no linkage between the rapid efflux, CQR phenotype and either of the mdr-like P. falciparum genes or amplification of those genes. These data indicate that the genetic locus governing chloroquine efflux and resistance is independent of the known mdr-like genes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

An MDR-EGFP gene fusion allows for direct cellular localization, function and stability assessment of P-glycoprotein.

In cancer and AIDS, overexpression of the MDR1 gene has important implications in the design of chemotherapy protocols because of the ability of its product, the ATP-dependent drug efflux pump P-glycoprotein (Pgp), to confer selective advantage to tumor and HIV-infected cells in the form of multidrug resistance. To study Pgp expression and physiology, we designed a translational fusion between the MDR1 and enhanced green fluorescent protein (EGFP) genes. The chimeric protein, Pgp-EGFP, was concentrated mainly in the plasma membrane and in the Golgi when expressed in drug-sensitive KB-3-1 cells. Doxorubicin, daunorubicin and rhodamine-123 efflux assays confirmed function of the chimeric pump. Also, at the single-cell level, an inverse relationship between Pgp-EGFP expression and nuclear doxorubicin accumulation was demonstrated. Polarized Pgp expression on the apical cell surface was confirmed by transfection of the MDR-EGFP fusion gene into MDCK cells. However, after colchicine selection, Pgp-EGFP was also detectable in the lateral domain of the transfected MDCK monolayers. These results indicate that drug selection affects not only expression, but cellular localization of Pgp. Furthermore, using a tet-based inducible expression system for Pgp-EGFP, we confirmed the stable nature of Pgp (t(1/2 total Pgp-EGFP) = 2.2 days), but revealed that surface-Pgp acquires extra stability as an active pump (t(1/2 surface Pgp-EGFP) = 3.7 days).

ATP Binding Cassette Transporter, Subfamily B, Mem↗