Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of P-glycoprotein in primary and recurrent human breast cancer was investigated by means of immunohistochemistry, using a monoclonal antibody (C219) and the streptavidin-biotin-peroxidase method. Twelve patients received no chemotherapeutic treatment. The other 11 patients were treated with chemotherapy, and all developed clinical resistance to it. No or only minimal reactivity was found in specimens coming from the untreated patients (12 cases) or from patients treated with substances not involved in the multidrug resistance phenomenon (four cases). In contrast, three out of seven tumours from patients treated with multidrug resistance related substances showed clear reactivity (positive staining in more than 20% of the tumour cells). In one of these cases, where specimens of the tumour could be studied before and after treatment, an association between the latter and expression of P-glycoprotein was suggested. Finally, this marked expression of P-glycoprotein only took place in tumours treated over a longer space of time (five courses or more of multidrug resistance related chemotherapy).
Br J Cancer 1989 Dec
PMID:P-glycoprotein expression in treated and untreated human breast cancer. 257 87

The sensitivity of eight cell lines established from treated and untreated patients with small cell carcinoma of the lung (SCCL) was tested in the clonogenic assay with 1 h and continuous exposure to aclarubicin (ACLA), adriamycin (ADR), daunorubicin (DAU) and mitoxantrone (MITO). The sensitivity to ADR, DAU and MITO covariated, and varied with a factor of five. The sensitivity to ACLA was independent of the sensitivity to ADR and varied only within a factor of two. Only ACLA showed pronounced increased potency with continuous incubation, and ACLA was the most potent drug in the three cell lines least sensitive to ADR. Two resistant cell lines were selected by treating NCI-H69 in vitro with DAU. One cell line (9-fold resistant to DAU) expressed large amounts of P-glycoprotein, the other cell line (4-fold resistant to DAU) had barely detectable glycoprotein. Both lines acquired resistance to ADR, ACLA and MITO. The cross-resistance to ACLA and MITO was only partial and ACLA was still the most potent drug on these lines. The sensitivity to ACLA of the cell lines least sensitive to ADR suggest that ACLA partially circumvents mechanisms of multidrug resistance. Together with the pronounced increase in potency with prolonged exposure, these results suggest that ACLA has a mechanism of action different from the 'classical' anthracyclines. In this context mitoxantrone is more similar to the classical anthracyclines although its structure is more dissimilar.
Br J Cancer 1989 Dec
PMID:In vitro evaluation of the potential of aclarubicin in the treatment of small cell carcinoma of the lung (SCCL). 257 88

A series of CCRF-CEM sublines selected for extreme resistance to methotrexate has been shown previously to exhibit cross resistance to a number of agents belonging to the multidrug resistance phenotype (J.Natl.Cancer Inst.1989; 81, 1250-1254). The role of the mdr1 gene and its product (P-glycoprotein) in this atypical pattern of multidrug resistance has now been investigated. Southern and Northern analyses failed to demonstrate any amplification, rearrangement or over-expression of the mdr1 gene in the drug-resistant cells. Similarly, monoclonal antibodies MRK16 and JSB1 revealed no increase in the amount of P-glycoprotein present. By contrast, monoclonal antibody C219 detected a 170 kDa protein in all sublines, and in highest concentration in the most resistant cells. The results raise the possibility that a novel, C219-reactive protein may mediate resistance to both methotrexate and members of the multidrug resistance family.
Biochem Biophys Res Commun 1989 Dec 29
PMID:Atypical multidrug resistance in CCRF-CEM cells selected for high level methotrexate resistance: reactivity to monoclonal antibody C219 in the absence of P-glycoprotein expression. 257 83

The cephalosporins are a family of semisynthetic antibiotics, some of which have structural features associated with substrates for the multidrug transporter, P-glycoprotein. The activity of a series of six cephalosporins in reversing multidrug resistance (MDR) was examined in MDR variants (Dx5 cells) of the human sarcoma line MES-SA. Dx5 cells express high levels of the mdr1 gene product P-glycoprotein and are 25- to 30-fold resistant to doxorubicin (DOX), etoposide (VP-16), and vinblastine (VBL). Cytotoxicity was measured by the MTT assay. Cefoperazone (1.0 mM) was the most effective modulator of MDR, lowering the IC50 for VP-16 by 29-fold (29x), for VBL by 16x, and for DOX by 14x. Ceftriaxone at 1.0 mM produced 10x modulation of VP-16 cytotoxicity, 8x for DOX, and 2x for VBL. The reversal of resistance was concentration dependent, decreasing to 4x and 5x, respectively, for DOX with 0.25 mM cefoperazone and ceftriaxone. No modulation of cytotoxicity was observed in the parental MES-SA cells, which do not express mdr1. Cefazolin, cefotetan, cephradine, and ceftazidime were ineffective, producing less than 5x modulation of DOX at 1.0 mM. Among these cephalosporins, cefoperazone and ceftriaxone were the most highly protein bound in the media (30 and 52%), and the most lipid soluble, with octanol/water partitioning coefficients of -0.49 and -0.60. Varying the serum concentration in medium from 5 to 50% had less than a two-fold effect on the modulation of MDR by ceftriaxone. The ability to reverse MDR among these agents is associated with lipid solubility, high protein binding, a polycyclic planar geometry, and the presence of the piperazine group in cefoperazone. These data and the potential for achieving high tissue concentrations indicate that cefoperazone merits further study as a modulator of MDR.
Cancer Res 1989 Dec 15
PMID:Reversal by cefoperazone of resistance to etoposide, doxorubicin, and vinblastine in multidrug resistant human sarcoma cells. 258 32

The multidrug resistance (MDR) phenotype is presumed to be mostly dependent on changes in the resistant cell plasma membrane, notably the emergence of a 170 kDa glycoprotein called P-glycoprotein, which facilitate increased drug efflux. We have previously demonstrated that ATP-enhanced binding of vincristine (VCR) to plasma membrane vesicles is much greater in MDR than in wild type cells. The present study has shown that VCR binding to MDR Ehrlich ascites tumour cell plasma membrane vesicles is inhibited 50% most efficiently by quinidine (0.5 microM) followed by verapamil (4.1 microM) and trifluoperazine (23.2 microM). This is the reverse order of the effect on whole cells where a ranking of efficiency in terms of enhancement of VCR accumulation, inhibition of VCR efflux, DNA perturbation and modulation of resistance in a clonogenic assay, was trifluoperazine greater than or equal to verapamil much greater than quinidine. The detergent Tween 80 inhibited VCR binding to plasma membrane vesicles at 0.001% v/v which agreed with the level which modulated resistance and increased VCR accumulation in whole cells. No effect was observed on daunorubicin binding to MDR plasma membrane vesicles after incubation with either Tween 80 (up to 0.1% v/v) or verapamil (up to 25 microM). We conclude that the effect of a modulating drug in reversing resistance to VCR correlates with its ability to raise intracellular VCR levels but not with its capability to inhibit VCR binding to the plasma membrane. Thus, enhancement of VCR accumulation in MDR cells is hardly solely due to competition for a drug binding site on P-glycoprotein. Furthermore, the lack of a demonstrable effect on daunorubicin binding to the plasma membrane by modulators points to transport mechanisms which do not utilise specific drug binding to the plasma membrane.
Br J Cancer 1989 Dec
PMID:Inhibition of vincristine binding to plasma membrane vesicles from daunorubicin-resistant Ehrlich ascites cells by multidrug resistance modulators. 260 92

Interest in DNA-intercalating ligands as anti-cancer drugs has developed greatly since the clinical success of doxorubicin. However, despite a great deal of 'rational design' of synthetic DNA-intercalators, only a few such compounds have proved clinically useful. This review briefly surveys the history of DNA-intercalators as clinically-used anti-cancer drugs, summarizes the known structure-experimental activity relationships and modes of action, and concludes that a factor in the slow progress is that much of the work on these compounds has been carried out by chemists, who were generally more interested in ligand/DNA interactions than drug development. Future development of the class rests on a careful consideration of the biochemical reasons behind the common limitations of the present drugs. The most important are: the inherent resistance of non-cycling cells, the rapid development (even by cycling cells) of resistance by the expression of both P-glycoprotein and altered topoisomerase II, limitations on drug distribution to and transport into tumours, low extravascular pH in tumours and the cardiotoxic side-effects of quinonoid chromophores. These considerations provide a set of constraints on physicochemical properties which must be considered in future design. However, within these constraints, there are useful future avenues for the development of DNA-intercalators as anti-cancer drugs. These include: (i) the production of improved topoisomerase inhibitors (by consideration of drug/protein as well as drug/DNA interactions); (ii) the development of reductively-activated chromophores as hypoxia-selective agents; and (iii) the use of DNA-intercalators of known DNA binding orientation as 'carriers' for the delivery of other reactive functionality specifically (sequence-, regio- and site-specifically) to DNA.
Anticancer Drug Des 1989 Dec
PMID:DNA-intercalating ligands as anti-cancer drugs: prospects for future design. 269 99

Double minutes (DM) have been associated with gene amplification in drug-resistant cells and tumor cells. However, the mechanisms by which DM are formed have not been elucidated. We present here a model to describe a possible mechanism of DM formation based on the observations made in two independent early drug-selected multidrug-resistant cell lines and from in vitro somatic cell fusion experiments between synchronized S- and M-phase cells. The multidrug-resistant cell lines contain both DM and amplified mdr (P-glycoprotein) gene. Cytogenetic analyses of cells at early stages of selection revealed the presence of a number of micronuclei in a subpopulation of these cells. These micronuclei were often asynchronous in their progression through the cell cycle. As a result, premature condensation of micronuclear chromatin was often observed in metaphase plates. The pulverized chromatin pattern seen in certain instances of S-phase prematurely condensed chromosomes displays a striking resemblance to DM structures. These DM-like structures are linked by replicating DNA as revealed by DNA labeling experiments. Somatic cell hybrids between S- and M-phase cells when grown in vitro demonstrated that S-phase prematurely condensed chromatin indeed gives rise to extra chromosomal structures in the successive cell generations. It is hypothesized that distinct DM-like structures may arise from the partially replicated and prematurely condensed S-phase chromosomes following their liberation as extra chromosomal entities after replication and/or recombination in the succeeding division cycle(s). The enrichment for DM containing specific genes in drug-resistant cells may result from the subsequent drug selections.
Cancer Res 1989 Dec 01
PMID:Model for the formation of double minutes from prematurely condensed chromosomes of replicating micronuclei in drug-treated Chinese hamster ovary cells undergoing DNA amplification. 281 18

At least five linked genes are amplified in the multidrug-resistant Chinese hamster ovary cell line CHRC5, selected with colchicine (A. M. Van der Bliek, T. Van der Velde-Koerts, V. Ling, and P. Borst, Mol. Cell. Biol. 6:1671-1678, 1986). We report here that only a subset of these, encoding the 170-kilodalton P-glycoprotein, are consistently amplified in three different multidrug-resistant Chinese hamster lung cell lines, selected with vincristine, daunorubicin, or actinomycin D. Within each cell line, genomic sequences homologous to the P-glycoprotein cDNA probe were amplified to different levels. The pattern of differential amplification was consistent with the presence of at least two and possibly three P-glycoprotein genes. In the actinomycin D-selected cell line, these genes were disproportionately overexpressed relative to the associated levels of amplification. These results underline a central role for P-glycoprotein in multidrug resistance. In the daunorubicin-selected cell line, another, as yet uncharacterized, gene was amplified but disproportionately underexpressed. Its amplification was therefore fortuitous. We present a tentative map of the region in the hamster genome that is amplified in the multidrug-resistant cell lines which were analyzed.
Mol Cell Biol 1986 Dec
PMID:Differential amplification and disproportionate expression of five genes in three multidrug-resistant Chinese hamster lung cell lines. 287 24

The development of simultaneous resistance to multiple drugs in cultured cells occurs after selection for resistance to single agents. This multidrug-resistance phenotype is thought to mimic multidrug-resistance in human tumors treated with chemotherapy. Both the expression of a membrane protein, termed P170 or P-glycoprotein, and the expression of a cloned DNA fragment, termed mdr1, have been shown independently to be associated with multidrug-resistance in cultured cells. In this work, we show that human KB carcinoma cells which express the mdr1 gene also express P-glycoprotein, and that cDNAs encoding P-glycoprotein cross-hybridize with mdr1 cDNAs. Thus, the mdr1 gene codes for P-glycoprotein.
Biochem Biophys Res Commun 1986 Dec 30
PMID:The mdr1 gene, responsible for multidrug-resistance, codes for P-glycoprotein. 288 May 83

Primary resistance to vincristine (VCR) has been selected in rhabdomyosarcoma xenograft HxRh12 by sequential administration of VCR at 1.5 and subsequently 3 mg/kg/passage. The resistant tumor (HxRh12/VCR-3) was approximately 4-fold resistant to VCR and resistance was stable in the absence of selecting pressure (greater than 2 yr). HxRh12/VCR-3 was 2- to 3-fold cross-resistant to L-phenylalanine mustard (L-PAM) but only slightly cross-resistant to ifosfamide. To determine whether selection for primary resistance to L-PAM conferred cross-resistance to VCR we selected an L-PAM-resistant subline of rhabdomyosarcoma xenograft HxRh28 (HxRh28/L-PAM-13). This tumor was 2- to 3-fold resistant to L-PAM and 3-(p-fluorophenyl)-L-alanyl-3-[m-bis-(2-chloroethyl)-aminophenyl]-L- alanyl-L-methionine ethoxyhydrochloride, cross-resistant to cyclophosphamide and ifosfamide, and completely resistant to VCR under in vivo conditions. Pharmacokinetic studies in HxRh12/VCR-3 showed decreased retention of [G-3H]VCR but not alteration in metabolism. Expression of mdr1, a gene that encodes P-glycoprotein, associated with the multiple drug resistance phenotype, was examined. Expression of mdr1 was detected in both HxRh12 and HxRh28 tumors, sensitive to VCR, but there was no increase in expression in tumors selected for primary resistance to VCR or L-PAM. Data suggest that mechanisms other than those associated with "classical" multiple drug resistance confer resistance in these tumors. In clinical evaluation against childhood rhabdomyosarcoma, L-PAM has demonstrated only slight activity in patients relapsing on conventional therapy (including VCR) but demonstrated marked activity in patients with advanced previously untreated disease. It appears likely, therefore, that cross-resistance between VCR and L-PAM as demonstrated in this model may have clinical significance.
Cancer Res 1987 Dec 01
PMID:Reciprocal cross-resistance in human rhabdomyosarcomas selected in vivo for primary resistance to vincristine and L-phenylalanine mustard. 289 Apr 32


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>