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

Screening programs for the detection of cancer in ulcerative colitis are inexact and not always successful in finding early, curable cancers. P-glycoprotein is a membrane-based, energy-dependent protein found in varying degrees within normal human tissue. P-glycoprotein is overexpressed in malignant tumors, particularly colorectal cancer, and is known to convey resistance to certain anticancer drugs by acting as a membrane "pump." The purpose of this study was to determine the expression of this protein in inflamed and premalignant colonic epithelium, compare its expression with normal controls, and assess its potential use as a screening tool for high-risk patients with ulcerative colitis. Using immunohistochemical techniques, the colons of 21 patients (10 with dysplasia) with ulcerative colitis were stained with monoclonal antibody C-219 (MAbC219) specific for P-glycoprotein. P-glycoprotein was expressed in 38 percent of normal areas, 71 percent of inflamed areas (P = 0.0156), and 70 percent of dysplastic areas. Comparing the level of expression when progressing from normal to inflamed areas within a given patient, 11 patients (52 percent) showed increased expression, 8 (38 percent) showed equal expression, and only 2 (10 percent) showed decreased expression (P = 0.0225). Comparing expression when progressing from inflamed to dysplastic areas (10 patients), 7 showed equal expression and 3 showed increased expression (P = 0.25). Increasing duration of disease was associated with a significant increase in P-glycoprotein expression, but only in histologically normal areas. Duration of disease had no effect on P-glycoprotein expression in inflamed or dysplastic areas. Similarly, when surgery was performed for elective reasons, there was a significant overexpression of P-glycoprotein, but only in histologically normal areas. Our findings suggest that the increase in P-glycoprotein expression from normal to inflamed and dysplastic areas reflects the premalignant nature of ulcerative colitis and occurs early in the course of the disease. Further research needs to be done to determine its role in cancer surveillance.
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PMID:Variable expression of P-glycoprotein in normal, inflamed, and dysplastic areas in ulcerative colitis. 135 19

A mouse-human chimeric monoclonal antibody (mAb), MH162, against P-glycoprotein was previously found to be more effective than an all-mouse mAb (MRK16) in lysis of multidrug-resistant (MDR) tumor cells by blood mononuclear cells. The present study was performed to identify the effector cells responsible for the chimeric mAb-dependent cell-mediated cytotoxicity (ADCC) against MDR cells. The ADCC reaction was assessed by a 6-h 51Cr release assay. Highly purified lymphocytes (greater than 99%), monocytes (greater than 99%) and neutrophils (greater than 96%) were obtained from peripheral blood of the same healthy donors. A comparison of these three effector cell populations showed no difference between MH162 and its all-murine counterpart MRK16 in MDR cell lysis by monocytes or neutrophils. But MH162 was more effective than MRK16 in lymphocyte-mediated lysis of the MDR cells. The lymphocytes responsible for this ADCC had CD16+ Fc receptors. Pretreatment of monocytes with colony-stimulating factors (IL-3, GM-CSF and M-CSF) caused significant increase in their MH162-mediated lysis of MDR cells. Another anti-P-glycoprotein chimeric mAb (MH171) was also more effective than its murine counterpart MRK17 in lymphocyte-mediated lysis of MDR cells. These findings suggest that mouse-human chimeric mAbs may be useful therapeutically for in vivo destruction of MDR cancer cells by the ADCC reaction.
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PMID:Effector cell analysis of human multidrug-resistant cell killing by mouse-human chimeric antibody against P-glycoprotein. 135 55

The presence of an endogenous P-glycoprotein substrate in rat urine was examined by testing the ability of a hydrophobic extract to reverse multidrug resistance in CHO cells and to inhibit [3H]azidopine photolabelling. The accumulation of several hydrophobic drugs and dyes, known to be transported by P-glycoprotein, was dramatically enhanced in multidrug-resistant CHO cells (CHRC5) by a component contained in a hydrophobic extract prepared from rat urine by octadecyl (C18) reverse phase chromatography. The biological action of this urinary component involves a direct interaction with P-glycoprotein since it blocked photolabelling of the protein with [3H]azidopine. The effective concentration of the substance required to enhance drug accumulation and inhibit photolabelling was similar and within the range of its urinary content. These results suggest that a hydrophobic substance in urine may be an endogenous substrate of kidney P-glycoprotein.
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PMID:Interaction of P-glycoprotein with a hydrophobic component of rat urine. 135 59

Multi-drug-resistant cells overproduce a 130-180-kDa integral membrane phosphoglycoprotein known as P-glycoprotein which acts as an energy-dependent drug efflux pump. While P-glycoprotein has been shown to transport hydrophobic anti-tumor drugs out of multi-drug-resistant cells in tissue culture, its endogenous substrates remain unknown. This report shows that 3H-corticosterone can specifically photoaffinity label P-glycoprotein. Furthermore, corticosterone is effluxed from multi-drug-resistant cells by P-glycoprotein. These data suggest that corticosterone may be an endogenous substrate for P-glycoprotein.
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PMID:P-glycoprotein transports corticosterone and is photoaffinity-labeled by the steroid. 135 2

An etoposide-resistant subline, SBC-3/ETP, from a human small cell lung cancer cell line, SBC-3, was developed by continuous exposure to increasing concentrations of etoposide in culture. The SBC-3/ETP was 52.1-fold more resistant to etoposide than the parent cell line. The SBC-3/ETP was highly cross-resistant to teniposide, adriamycin, vinca alkaloids, 4-hydroperoxycyclophosphamide, CPT-11 and mitomycin C, and marginally cross-resistant to cisplatin, while the subline showed a collateral sensitivity to bleomycin. Topoisomerase I activity in the SBC-3/ETP was reduced to an extent of one half and topoisomerase II activity to an extent of one eighth in comparison with those of the SBC-3. Intracellular accumulation of [3H]-etoposide in the SBC-3/ETP was significantly lower in comparison to the SBC-3. An overexpression of MDR1 mRNA, and the presence of its product, P-glycoprotein, were detected in the SBC-3/ETP by Northern blotting and flowcytometry using a monoclonal antibody of the protein, MRK16. These results indicate that a decreased activity of topoisomerase II is the major factor for the development of etoposide resistance, and that an overexpression of the MDR1 gene is responsible, in part, for the development of resistance to the drug and some structurally unrelated compounds such as adriamycin and vinca alkaloids.
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PMID:Establishment and characterization of an etoposide-resistant human small cell lung cancer cell line. 135 8

Thirty human renal cell carcinomas and 94 non-small cell lung carcinomas of previously untreated patients were analyzed for the presence of P-glycoprotein, glutathione S-transferase-pi and topoisomerase II by means of immunohistochemistry. In the renal cell carcinomas investigated, two resistance markers were seen in 53% and three resistance markers in 36% of the cases. In only three tumors was one resistance mechanism observed. In the 94 non-small cell lung carcinomas 34% had two and 20% three resistance mechanisms, whereas 24% of the tumors revealed only one resistance mechanism. For determining the resistance of the tumors against drugs an in vitro short-term test was used. Only 12% of the sensitive lung tumors had more than one resistance mechanism, whereas 70% of the resistant tumors did. Thus a significant relationship exists between the resistance measured in vitro and the overexpression of P-glycoprotein or glutathione S-transferase-pi and the down-regulation of topoisomerase II.
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PMID:Expression of several resistance mechanisms in untreated human kidney and lung carcinomas. 135 30

In the process of assessing the effect of anthracycline drugs on cellular membrane function in cultured multidrug resistant (MDR) and its parental cells, experiments were undertaken to investigate the kinetics of neutral amino acid membrane transport (the sodium dependent A and ASC systems). P-glycoprotein, a high molecular weight energy requiring integral membrane protein responsible for actively pumping drugs out of cells, has been shown to be overexpressed in MDR cells. It was our hypothesis that its presence might affect other membrane energy requiring systems such as amino acid transport. On establishing the concentrations of P-glycoprotein by western blotting in the two cell lines to be studied, the kinetics of membrane transport of the neutral amino acids alpha-aminoisobutyric acid (AIB) and serine (SER) were investigated using the CHRC5 multidrug resistant and AUX B1 parental Chinese hamster ovary (CHO) cells. In CHRC5 cells, the amount and rate (Vmax) of accumulated amino acids, was significantly depressed when compared to AUX B1 cells, however, there was no difference in the rates of amino acid efflux between these two cell lines. Using 1,6-diphenyl 1,3,5-hexatriene (DPH) polarization to evaluate the state of membrane fluidity in the two cell lines studied, it was seen that CHRC5 cells showed a slightly lower degree of polarization than that observed in AUX B1 cells. These results suggest, that the P-glycoprotein does not alter amino acid transport directly but may modify the activity or numbers of functional transport carriers.
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PMID:Amino acid transport in multidrug-resistant Chinese hamster ovary cells. 135 38

A bispecific F(ba')2 was constructed that was composed of two Fab fragments, one derived from anti-CD3 monoclonal antibody (mAb) (OKT3) and the other from anti P-glycoprotein mAb (MRK 16). This bispecific F(ab')2 enhanced the binding and cytotoxicity of human peripheral blood mononuclear cells (PBMCs) on P-glycoprotein-positive human kidney cancer cells (ADMHK/E). It had no effect on the cytotoxicity of PBMCs on P-glycoprotein-negative HK/E cells [long-term cultured HK/E (LCHK/E)]. Control F(ab')2 composed of OKT3 or MRK16 alone did not influence the cytotoxicity of PBMCs on ADMHK/E cells. These findings suggest that the MRK16-OKT3 bispecific F(ab')2 may be therapeutically beneficial in treatment of human multidrug-resistant cancers.
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PMID:Augmentation by bispecific F(ab')2 reactive with P-glycoprotein and CD3 of cytotoxicity of human effector cells on P-glycoprotein positive human renal cancer cells. 135 68

N-(5,5-Diacetoxypent-1-yl)doxorubicin (DAPDOX) (3), a new, water-soluble analogue of doxorubicin, has been synthesized by coupling doxorubicin with 5-oxopentane-1,1-diacetate in the presence of NaBH3CN. This analogue was designed to be converted to the corresponding aldehyde, N-(5-oxopent-1-yl)doxorubicin, in the presence of carboxylate hydrolases, enzymes that are ubiquitous in tissue. DAPDOX had a half-life of several days in 0.05 M phosphate or 0.05 M acetate buffer solution at pH 4.0. However, in 0.05 M phosphate buffer at pH 7.4 in the presence of 20 unit equiv of porcine liver carboxylate esterase, the half-life of DAPDOX was less than 1 min. N-(5-acetoxypent-1-yl)doxorubicin (4), which should give rise to N-(5-hydroxypent-1-yl)doxorubicin on esterase-mediated hydrolysis, and N-(pent-1-yl)doxorubicin (5), were also prepared for comparative biological studies. DAPDOX was 150 times more potent than doxorubicin at inhibiting the growth of Chinese hamster ovary (CHO) cells in culture. The compound retained the same degree of potency against a CHO subline 100-fold resistant to doxorubicin (CHO/DOX) that expressed elevated levels of P-glycoprotein. Compounds 4 and 5, on the other hand, were no more effective than doxorubicin at inhibiting the growth of CHO cells and were 4-7-fold less potent against the CHO/DOX subline. DAPDOX is representative of a new structural class of doxorubicin analogues with unique chemical and biological properties.
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PMID:N-(5,5-diacetoxypent-1-yl)doxorubicin: a new intensely potent doxorubicin analogue. 135 50

Two new fused indoles were found to overcome multidrug resistance in P388/Adr cells in vitro. These agents potentiated the cytotoxicity of the antitumor drugs Adriamycin, vinblastine, and vincristine in multidrug-resistant cells with no effect on drug-sensitive parent P388 cells. They significantly increased the ATP-dependent accumulation of [3H]-vinblastine and inhibited efflux of the labeled drug from resistant cells. These compounds also inhibited photoaffinity labeling of P-glycoprotein by [3H]azidopine in P388/Adr cells and membranes isolated from these cells. In addition, the calcium antagonist activity of these compounds was very weak compared with that of verapamil. These data suggest that the compounds reported here may specifically overcome multidrug resistance without the serious hypotensive effects associated with calcium antagonists and that this activity may be independent of their ability to block calcium transport.
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PMID:Reversal of multidrug resistance by two novel indole derivatives. 135 8


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