Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The resistance of small cell lung cancer (SCLC) to anticancer drugs is a serious clinical problem often encountered during chemotherapy. Therefore, how to prevent this drug resistance need to be investigated. Multidrug resistance 1 (MDR1) gene and multidrug resistance-related protein (MRP) gene, two genes known to be associated with the development of drug resistance, are very common in SCLC. The purpose of this study was to evaluate retrospectively the relationship between chemotherapy responses to MDR1 gene encodes 170 kDa P-glycoprotein (Pgp) expression or MRP gene encodes 190 kDa MRP expression in SCLC. Before chemotherapy, multiple nonconsecutive sections of the bronchoscopy biopsy specimens of SCLC from 50 patients were analyzed immunohistochemically to detect Pgp and MRP expressions. Chemotherapy responses of the 50 patients were evaluated in the third month after completion of treatment by clinical and radiological methods. Of the 23 SCLC patients with poor response to chemotherapy, 11 had positive Pgp and MRP expressions, 2 had positive Pgp but negative MRP expressions, 6 had positive MRP but negative Pgp expressions, and 4 patients had negative Pgp and MRP expressions. All 27 SCLC patients with good response had negative Pgp and MRP expression. Immunohistochemical analyses of Pgp or MRP expression are potential tools for predicting patients' chemotherapy response in SCLC.
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PMID:Relationship between chemotherapy response of small cell lung cancer and P-glycoprotein or multidrug resistance-related protein expression. 1217 31

RLIP76 functions as an ATP-dependent transporter of amphiphilic chemotherapeutic drugs such as doxorubicin (DOX, adriamycin), as well as of glutathione-conjugates of endogenous electrophilic toxins such as 4-hydroxynonenal (4HNE). RLIP76 couples transport and ATP-hydrolysis with a 1:1 stoichiometry, making the ATPase activity of RLIP76 an excellent surrogate for its transport activity. Present studies were performed to determine the relationship of the RLIP76 ATPase activity with DOX and 4HNE resistance in a panel of 13 native human lung cancer cell lines. RLIP76 was purified from each cell line and homogeneity demonstrated by SDS-PAGE and amino acid composition analysis. Anti-RLIP76 antibodies were shown by Ouchterlony double immunodiffusion tests to be non-cross-reactive with any other proteins including P-glycoprotein (Pgp) or multidrug resistance associated protein (MRP). These antibodies completely immunoprecipitated ATPase activity of purified RLIP76 fractions, further confirming homogeneity of purified RLIP76. RLIP76 ATPase purified from NSCLC cell lines was about 2-fold more active than that from SCLC in the absence of the stimulator dinitrophenyl S-glutathione (206+/-47, n=7 vs. 94+/-22, n=6, nmol/min/mg protein, respectively), or in its presence (340+/-60, n=7 vs. 186+/-32, n=6, nmol/min/mg; p<0.01). Partial tryptic digest revealed a 44 kDa internal fragment of RLIP76 beginning at Thr-294 in NSCLC cell lines. This fragment was absent from all SCLC, suggesting the possibility that the activity of RLIP76 in SCLC and NSCLC is differentially regulated through post-translational modifications. Taken together, these findings suggest that RLIP76 activity is a general determinant of 4HNE and DOX resistance, and that its activity contributes to the drug-resistant phenotype of NSCLC.
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PMID:Role of RLIP76 in lung cancer doxorubicin resistance: I. The ATPase activity of RLIP76 correlates with doxorubicin and 4-hydroxynonenal resistance in lung cancer cells. 1252 36

Two human small cell lung cancer (SCLC) subpopulations, CPH 54A, and CPH 54B, established from the same patient tumor by in vitro cloning, were investigated. The tumor was classified as intermediate-type SCLC. The cellular sensitivity to ionizing radiation (IR) was previously determined in the two sublines both in vivo and in vitro. Here we measured the etoposide (VP16) sensitivity together with the induction and repair of VP16- and IR-induced DNA double-strand breaks (DSBs). The two subpopulations were found to differ significantly in sensitivity to VP16, with the radioresistant 54B subline also being VP16 resistant. In order to explain the VP16 resistant phenotype several mechanisms where considered. The p53 status, P-glycoprotein, MRP, topoisomerase IIalpha, and Mre11 protein levels, as well as growth kinetics, provided no explanations of the observed VP16 resistance. In contrast, a significant difference in repair of both VP16- and IR-induced DSBs, together with a difference in the levels of the DSB repair proteins DNA-dependent protein kinase (DNA-PK(cs)) and RAD51 was observed. The VP16- and radioresistant 54B subline exhibited a pronounced higher repair rate of DSBs and higher protein levels of both DNA-PK(cs) and RAD51 compared with the sensitive 54A subline. We suggest, that different DSB repair rates among tumor cell subpopulations of individual SCLC tumors may be a major determinant for the variation in clinical treatment effect observed in human SCLC tumors of identical histological subtype.
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PMID:DNA repair rate and etoposide (VP16) resistance of tumor cell subpopulations derived from a single human small cell lung cancer. 1271 Nov 16

Etoposide (VP16) is a potent inducer of DNA double-strand breaks (DSBs) and is efficiently used in small cell lung cancer (SCLC) therapy. However, acquired VP16 resistance remains an important barrier to effective treatment. To understand the underlying mechanisms for VP16 resistance in SCLC, we investigated DSB repair and cellular VP16 sensitivity of SCLC cells. VP16 sensitivity and RAD51, DNA-PK(cs), topoisomerase IIalpha and P-glycoprotein protein levels were determined in 17 SCLC cell lines. In order to unravel the role of RAD51 in VP16 resistance, we cloned the human RAD51 gene, transfected SCLC cells with RAD51 sense or antisense constructs and measured the VP16 resistance. Finally, we measured VP16-induced DSBs in the 17 SCLC cell lines. Two cell lines exhibited a multidrug-resistant phenotype. In the other SCLC cell lines, the cellular VP16 resistance was positively correlated with the RAD51 protein level. In addition, downregulation or overexpression of the RAD51 gene altered the VP16 sensitivity. Furthermore, the levels of the RAD51 and DNA-PK(cs) proteins were related to VP16-induced DSBs. The results suggest that repair of VP16-induced DSBs is mediated through both RAD51-dependent homologous recombination and DNA-PK(cs)-dependent nonhomologous end-joining and may be a determinant of the variation in clinical treatment effect observed in human SCLC tumors of identical histologic subtype. Finally, we propose RAD51 as a potential target to improve VP16 efficacy and predict tumor resistance in the treatment of SCLC patients.
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PMID:The role of RAD51 in etoposide (VP16) resistance in small cell lung cancer. 1271 36

Our preliminary studies found technetium-99m tetrofosmin (Tc- TF) chest imaging was related to Pgp or MRP1 expression and successfully predict chemotherapy response and in SCLC in human. However, there was no published literature to study relationship of Tc-TF chest images and LRP expression in SCLC patients. Therefore, the aim of this study was to investigate the relationships among Tc- TF accumulation in untreated small cell lung cancer (SCLC), the expression of P-glycoprotein (Pgp), multidrug resistance related protein-1 (MRP1), and lung resistance-related protein (LRP), as well as the response to chemotherapy in patients with untreated SCLC. Thirty patients with SCLC were studied with chest images 15 to 30 minutes after intravenous injection of Tc-TF before chemotherapeutic induction. Tumor-to-background (T/B) ratios were obtained on the static and plantar Tc-TF chest images. The response to chemotherapy was evaluated upon completion of chemotherapy by clinical and radiological methods. These patients were separated into 15 patients with good response and 15 patients with poor response. No significant differences of prognostic factors (Karnofsky performance status, tumor size, or tumor stage) were found between the patients with good and poor responses. Immunohistochemical analyses were performed on multiple nonconsecutive sections of biopsy specimens to detect Pgp, MRP1, and LRP expression. The difference in T/B ratios on the Tc-TF chest images of the patients with good versus poor response was significant. The differences in T/B ratios of the patients with positive versus negative Pgp expression and with positive versus negative MRP1 expression were significant. The difference in T/B ratios of the patients with positive versus negative LRP expression was not significant. We concluded that Tc-TF chest images could accurately predict chemotherapy response of patients with SCLC. In addition, The Tc-TF tumor uptake was related to Pgp or MRP1 but not LPR expression in SCLC.
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PMID:To predict response chemotherapy using technetium-99m tetrofosmin chest images in patients with untreated small cell lung cancer and compare with p-glycoprotein, multidrug resistance related protein-1, and lung resistance-related protein expression. 1290 Feb 88

The purpose of this study was to predict chemotherapy response by technetium-99m methoxyisobutylisonitrile (Tc-99m MIBI) lung single-photon-emission computed tomography (SPECT) and compare P-glycoprotein (Pgp) expression in patients with untreated small cell lung cancer (SCLC). Before chemotherapy, 40 patients with untreated SCLC underwent Tc-99m MIBI lung SPECT. Immunohistochemical analyses were performed using multiple nonconsecutive sections of the biopsy specimens to detect Pgp expression. Chemotherapy response was evaluated in the third month after completion of treatment by clinical and radiological methods. Based on quantitative analyses, the tumor uptake ratios (TUR) of the 20 patients with good response (1.89 +/- 0.28) were significantly higher than that of the 20 patients with poor response (1.21 +/- 0.28) (p value < 0.05). Based on visual interpretation, all of the 20 patients (100%) with good response had positive Tc-99m TF lung SPECT findings and negative Pgp expression. Five of the other 20 patients (25%) with poor response had positive Tc-99m MIBI lung SPECT findings, and 12 of the other 20 patients (60%) with poor response had negative Pgp expression (p value < 0.05). Negative Tc-99m MIBI lung SPECT findings could predict poor response. Therefore, we concluded that Tc-99m MIBI lung SPECT can accurately predict the chemotherapy response, and Tc-99m MIBI lung SPECT findings can be partially compatible with Pgp expression in patients with untreated SCLC.
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PMID:Using technetium-99m methoxyisobutylisonitrile lung single-photon-emission computed tomography to predict response to chemotherapy and compare with P-glycoprotein expression in patients with untreated small cell lung cancer. 1451 74

The multidrug resistance gene 1 encoding human P-glycoprotein (Pgp) is thought to play an important role in the multidrug resistance of lung cancer. The purpose of this study was to predict chemotherapy response by technetium-99m tetrofosmin (Tc-99m TF) lung single photon emission computed tomography (SPECT) and compare Pgp expression in patients with untreated small cell lung cancer (SCLC). Forty patients with untreated SCLC received Tc-99m TF lung SPECT prior to chemotherapy. The chemotherapy response was evaluated in the 3rd month after completion of treatment. Immunohistochemical staining of Pgp expression was performed on multiple nonconsecutive sections of biopsy specimens. By quantitative analyses, tumor to background ratios were 1.86 +/- 0.27 and 1.17 +/- 0.26 for patients with a good and poor response, respectively (p < 0.05). All of the 20 patients with a good chemotherapy response also had a positive Tc-99m TF lung SPECT and negative Pgp expression. In contrast, only 4 of the 20 patients with a poor chemotherapy response had a positive Tc-99m TF lung SPECT. Moreover, 10 of the 20 patients with a poor chemotherapy response also had negative Pgp expression (p < 0.05). Therefore, we concluded that Tc-99m TF lung SPECT can accurately predict the chemotherapy response, and Tc-99m TF lung SPECT findings can be partially compatible with Pgp expression in patients with untreated SCLC.
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PMID:Technetium-99m tetrofosmin SPECT predicts chemotherapy response in small cell lung cancer. 1461 Mar 19

Etoposide is a derivative of podophyllotoxin widely used in the treatment of several neoplasms, including small cell lung cancer, germ cell tumours and non-Hodgkin's lymphomas. Prolonged administration of etoposide aims for continuous inhibition of topoisomerase II, the intracellular target of etoposide, thus preventing tumour cells from repairing DNA breaks. However, the clinical advantages of extended schedules as compared with conventional short-term infusions remain unclear. Oral administration of etoposide represents the most feasible and economic strategy to maintain effective concentrations of drug for extended times. Nevertheless, the efficacy of oral etoposide therapy is contingent on circumventing pharmacokinetic limitations, mainly low and variable bioavailability. Inhibition of small bowel and hepatic metabolism of etoposide with specific cytochrome P450 inhibitors or inhibition of the intestinal P-glycoprotein efflux pump have been attempted to increase the bioavailability of oral etoposide, but the best results were obtained with daily oral administration of low etoposide doses (50-100 mg/day for 14-21 days). Saturable absorption of etoposide was reported for doses greater than 200 mg/day, whereas lower doses were associated with increased bioavailability, although they were characterised by high inter- and intrapatient variability. Pharmacokinetic parameters such as plasma trough concentration between two oral administrations (C(24,trough)), drug exposure time above a threshold value and area under the plasma concentration-time curve have been correlated with the pharmacodynamic effect of oral etoposide. Pharmacokinetic-pharmacodynamic relationships indicate that severe toxicity is avoided when peak plasma concentrations do not exceed 3-5 mg/L and C(24,trough) is under the threshold limit of 0.3 mg/L. To maintain effective etoposide plasma concentrations during prolonged oral administration, pharmacokinetic variability must be monitored in each patient, taking account of factors from many pharmacokinetic studies of etoposide, including absorption, distribution, protein binding, metabolism and elimination. Dosage reduction is generally useful to avoid haematological toxicity in patients with renal dysfunction (creatinine clearance <50 mL/min). The need for dosage adjustment based on liver function in patients with liver dysfunction is not completely defined, but generally is not indicated in patients with minor liver dysfunction. Adaptive dosage adjustment based on individual pharmacokinetic parameters, estimated using limited sampling strategies and population pharmacokinetic models, is more appropriate. This approach has been used with success in different clinical trials to increase the etoposide dosage, without significantly increasing toxicity. Various pharmacodynamic models have been proposed to guide etoposide oral dosage. However, they lack precision and accuracy and need to be refined by considering other predictor variables in order to extend their application in current clinical practice.
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PMID:Pharmacokinetic optimisation of treatment with oral etoposide. 1513 94

The aim of this study was to investigate the expression of P-glycoprotein (Pgp), multidrug resistance-related protein-1 (MRP1), and lung resistance-related protein (LRP) in response to chemotherapy in untreated small cell lung cancer (SCLC). Immunohistochemical analyses were performed on multiple nonconsecutive sections of biopsy specimens to detect Pgp, MRP1, and LRP expression in 40 patients with SCLC before chemotherapeutic induction. Response to chemotherapy was evaluated by clinical and radiological methods. The patients were divided into a good response group (n = 20) and a poor response group (n = 20). No significant differences in prognostic factors (Karnofsky performance status, tumor size, or tumor stage) were found between the two groups of patients. The difference in positive Pgp and MRP1 expressions between the good and poor response groups was significant. However, the difference in LRP expression was not significant. We conclude that chemotherapy response of patients with SCLC was related to either Pgp or MRP1 but not LPR expression.
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PMID:Comparison of chemotherapy response with P-glycoprotein, multidrug resistance-related protein-1, and lung resistance-related protein expression in untreated small cell lung cancer. 1607 39

In this paper, a shear force scanning near-field fluorescence microscope combined with a confocal laser microspectrofluorometer is described. The shear force detection is realized based on a bimorph cantilever, which provides a very sensitive, reliable, and easy to use method to control the probe-sample distance during scanning. With the system, high-quality shear force imaging of various samples has been carried out. Furthermore, simultaneous shear force and near-field fluorescence imaging of biological cells has also been realized. As an example, we especially present the result on the distribution of P-glycoprotein in the plasma membrane of human small cell lung cancer cells, suggesting that the system would be a promising tool for biological applications.
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PMID:Development of a shear force scanning near-field fluorescence microscope for biological applications. 1608 Dec 14


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