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)

Detection of P-glycoprotein and other multidrug resistance protein activity is currently under investigation to identify subgroups of cancer patients with tumors resistant to chemotherapy. Application of a test that reliably evaluates the phenomenon in vivo would not only serve as a predictor for responses to chemotherapy but would also be of use in testing the efficacy of multidrug resistance reversers in humans. Tc-99m radiolabeled hexakis-2-methoxy-isobutyl-isonitrile (Tc-sestamibi) has been recently shown to be extruded from cells through P-glycoprotein activity. In the present study, we examined the uptake and extrusion rate of the radiotracer in 25 patients with advanced non-small cell lung cancer undergoing chest radiotherapy, using a novel scintigraphic technique based on simulation-guided pinhole imaging. Five-min tumor images were taken 10, 60, and 120 min postinjection of 20 mCi of Tc-sestamibi. Six of 25 (24%) of tumors showed a 1.3-1.7 times higher extrusion rate as compared to that of normal lung tissue. Increased tumor clearance of Tc-sestamibi significantly correlated with resistance to radiotherapy (P = 0.05) as well as the existence of distant metastasis (P = 0.008). Patients with known resistance to chemotherapy had a higher extrusion rate as compared to chemotherapy-naive patients (P = 0.01). Moreover, increased Tc-sestamibi tumor capture was seen in patients with distant metastasis (P = 0.09). We concluded that functional imaging of lung cancer with Tc-sestamibi may have a role in predicting responses to cytotoxic treatment and in identifying tumors with aggressive behavior. Additional clinicopathological trials are required to investigate whether Tc-sestamibi kinetics correlates with P-glycoprotein expression, intratumoral angiogenesis, or other mechanisms.
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PMID:Non-small cell lung cancer functional imaging: increased hexakis-2-methoxy-isobutyl-isonitrile tumor clearance correlates with resistance to cytotoxic treatment. 981 45

Acrolein (AC) and chloroacetaldehyde (CHA) are metabolites of the non-multidrug resistance cytotoxic drugs cyclophosphamide and ifosfamide. It has previously been reported that both metabolites can induce extensive depletion of glutathione (GSH) in vitro and in vivo and that this depletion occurs at drug concentrations in the micromolar range. A link between the function of the multidrug resistance-associated protein (MRP) and the intracellular concentration of GSH has also been demonstrated. To determine whether AC and CHA can modulate the function of MRP by inducing GSH depletion, we used two human lung cancer cell lines overexpressing MRP: the large cell carcinoma cell line COR-L23/R and the adenocarcinoma cell line MOR/R0.4, along with their respective sensitive parental lines, COR-L23/P and MOR/P. We showed that micromolar concentrations of AC and millimolar concentrations of CHA are able to deplete GSH concentrations in the cell lines studied. In addition, concentrations of 50 micrometer AC and 5 mm CHA could completely reverse the daunorubicin (DNR) and vinblastine accumulation deficit present in COR-L23/R and partially reverse the DNR accumulation deficit in MOR/R0.4. In contrast, AC and CHA did not reverse the drug accumulation deficit in the P-glycoprotein-overexpressing lung cancer cell line H69/LX4. The effect of CHA and AC on drug accumulation was related to the GSH depletion, as we found a concentration-dependent relationship between the GSH levels and the reversal of the accumulation deficit for both AC and CHA. To substantiate further this correlation, we increased cellular GSH content in AC- and CHA-treated cells with the GSH ethyl ester. An increase in cellular GSH levels in CHA- and AC-treated COR-L23/R cells was accompanied by a restoration of the DNR accumulation deficit. No significant effect of the GSH ethyl ester was detected on DNR accumulation in COR-L23/P parental cells. In conclusion, treatment with AC or CHA can reverse the drug accumulation deficit of MRP-overexpressing cells, and this effect appears to be mediated by GSH depletion.
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PMID:Modulation by acrolein and chloroacetaldehyde of multidrug resistance mediated by the multidrug resistance-associated protein (MRP). 981 3

While resistance to chemotherapy is a major problem in lung cancer treatment, there is no useful predictor of treatment response. We thus designed this study to determine the utility of p53 and P-glycoprotein expression in predicting the response to chemotherapy in patients with primary lung cancer, retrospectively. We evaluated transbronchial biopsy (TBB) specimens from 60 patients with lung cancer, who were previously untreated. Formalin-fixed, paraffin-embedded TBB specimens were immunostained using anti-p53 antibody (DO-1) and anti-P-glycoprotein antibody (JSB-1). The positivity of p53 was 63%, and that of P-glycoprotein was 17%. No correlation was observed between p53 and P-glycoprotein immunostaining. Positivity of p53 correlated significantly (P = 0.004) with a lack of response to chemotherapy in non-small cell lung cancer (NSCLC), but not in small cell lung cancer (SCLC). In contrast, positivity of P-glycoprotein was correlated with chemotherapy resistance in SCLC (P = 0.003), but not in NSCLC. Multiple logistic regression analysis revealed that positive immunostaining for p53 was a significant risk factor for chemotherapy resistance in NSCLC. These results suggest that immunostaining of p53 and P-glycoprotein for TBB specimens may help to predict response to chemotherapy in NSCLC and SCLC, although the results should be confirmed in a larger, more homogeneous series.
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PMID:Immunohistochemically detected p53 and P-glycoprotein predict the response to chemotherapy in lung cancer. 984 16

Distant metastases and multidrug resistance are critical problems in the therapy of human small cell lung cancer (SCLC). In this study, we investigated whether transduction of the monocyte chemoattractant protein-1 (MCP-1) gene into multidrug-resistant (MDR) human lung cancer cells affected the formation of metastases or their inhibition by the anti-P-glycoprotein (P-gp) monoclonal antibody (MAb) MRK16. MDR human SCLC (H69/VP) cells were transduced with the human MCP-1 gene inserted into the expression vector BCMGSNeo. MCP-1 gene transduction had no effect on drug sensitivity, the expression of surface antigens or the in vitro proliferation of H69/VP cells. Using the metastatic model of NK cell-depleted SCID mice, H69/VP cells transduced with the MCP-1 gene were inoculated intravenously (i.v.) and formed metastatic colonies in the liver, kidneys and lymph nodes, similar to those formed by parent or mock-transduced cells. However, systemic treatment of the mice with MRK16 reduced the metastases of H69/VP cells in the liver, kidneys and lymph nodes, and was significantly more effective in inhibiting the metastases of MCP-1 producing H69/VP than those of mock-transduced cells. MCP-1 gene transduction significantly prolonged the survival of tumor-bearing mice treated with MRK16. Our findings suggest that local production of MCP-1 in the tumor site increases the anti-P-gp antibody-dependent cell-mediated cytotoxicity, and the MCP-1 gene-induced modification of MDR human SCLC cells thereby enhances the antimetastatic effect of therapy with anti-P-gp antibody. Thus, the accumulation of effector cells in the tumor site is a very important factor in the therapy using the anti-P-gp antibody.
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PMID:Monocyte chemoattractant protein-1 gene modification of multidrug-resistant human lung cancer enhances antimetastatic effect of therapy with anti-P-glycoprotein antibody in SCID mice. 1004 81

Lung cancer is a major cause of cancer deaths, most of which can be attributed to distant multiorgan metastases. To examine the cellular and molecular mechanisms of lung cancer metastasis to distant organs, we have established novel models of human lung cancer (small cell and non-small cell lung cancer) metastasis in natural killer cell-depleted severe combined immunodeficient (SCID) mice. We investigated whether local production of the cytokines responsible for regulation of macrophage function at tumor growth sites affects the pattern of lung cancer metastasis in distant organs. Several lung cancer cell lines were genetically engineered to produce human macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein-1 (MCP-1), and their metastatic potentials were assessed. Interestingly, M-CSF gene transduction had an antimetastatic effect for the liver and lymph nodes, but not the kidneys. In contrast, MCP-1 gene-modified lung cancer cells and their parent cells had identical metastatic potentials. These findings indicate a possible role for cytokines and suggest that lung cancer has metastatic heterogeneity. Examining ways of controlling human lung cancer metastases, we investigated the antimetastatic effect of chimeric monoclonal antibodies (MAbs) against P-glycoprotein and ganglioside GM2 (MH162 and KM966, respectively). Both MAbs, when given on days 2 and 7, inhibited the development of distant metastases of lung cancer in a dose-dependent fashion. Combined use of anti-P-glycoprotein MAb with M-CSF or MCP-1 gene transduction caused complete inhibition of metastasis of H69/VP cells. The antimetastatic effect of these MAbs in vivo was mainly due to an antibody-dependent cell-mediated cytotoxicity reaction mediated by mouse macrophages. These findings suggest that the mouse-human chimeric MAb in combination with cytokine gene transduction may be useful for the eradication of lung cancer metastases in humans.
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PMID:Heterogeneity of multiorgan metastases of human lung cancer cells genetically engineered to produce cytokines and reversal using chimeric monoclonal antibodies in natural killer cell-depleted severe combined immunodeficient mice. 1035 55

In a series of 40 neuroblastomas we analyzed the relative mRNA levels of the MDR associated genes encoding MDR1/P-glycoprotein (MDR1), multidrug resistance associated protein (MRP), lung cancer resistance related protein (LRP) and topoisomerase IIalpha (TOPO IIalpha) by cDNA-PCR. Cyclin A (CYCA) was included to examine cellular proliferation activity. MYCN gene expression was analyzed as it was recently shown to be associated with enhanced MRP gene expression in neuroblastomas. We found that tumors with MYCN gene amplification exhibit significantly increased MYCN and MRP gene expression levels. Tumors with an allelic loss of the chromosomal 1p region showed significant (P<0.05) lower MDR1 gene expression (MDR1: 50+/-29, n=4) than tumors without (MDR1: 117+/-81, P<0.05, n=36). Moreover, significant positive correlations were found for MYCN/TOPO IIalpha (P<0.0001), MYCN/CYCA (P<0.05), TOPO IIalpha/CYCA (P<0.01), MRP/CYCA (P<0.0001) and MRP/LRP (P<0.05). Our results give evidence that MDR in neuroblastomas might be caused by multiple resistance factors and that a higher proliferation rate of neuroblastoma cells possibly based on altered MYCN gene expression is associated with enhanced MRP, CYCA and TOPO IIalpha gene expression.
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PMID:Expression analysis of multidrug resistance associated genes in neuroblastomas. 1042 16

The most well-characterized mechanism of multidrug resistance (MDR) involves P-glycoprotein (Pgp), a transmembrane protein acting as an ATP-dependent drug efflux pump. The recognition of 99mTc-Sestamibi and other lipophilic cations as transport substrates for Pgp provided the necessary tool for the clinical assessment of Pgp function in patients with cancer. Many clinical studies from different institutions and trials including a variety of malignancies indicate that both tumor uptake and clearance of 99mTc-Sestamibi are correlated with Pgp expression and may be used for the phenotypic assessment of multidrug resistance. Although both parameters may predict tumor response to chemotherapy, the extraction of efflux rate constants appeared to provide a more direct index of Pgp function as compared to tracer uptake ratio allowing to trace a continuous spectrum of drug transport activity. Preliminary studies reported the use of MDR imaging agents to monitor the modulating ability of revertant compounds. Although the results support the feasibility of this approach, the alteration of tracer pharmacokinetics induced by the modulators certainly constitutes a challenge in the development of a simple functional test suitable in clinical practice. The extension of the acquired imaging methodology to tumors with redundant intrinsic resistant mechanisms such as lung cancer requires further investigations on the relative contribution and clinical relevance of each mechanism. Due to the multifactorial nature of the phenomenon, the development of new tracers with substrate specificity for other known drug transporters would hopefully help to dissect the complex array of cellular mechanisms contributing to treatment failure.
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PMID:Clinical imaging of multidrug resistance in cancer. 1042 7

Human lung cancer leads the mortality of cancers and the chemotherapy is often uneffective because of drug resistance. In order to study the role of mdr-1 gene in resistant lung cancer, the fully length mdr-1 cDNA was transferred into a sensitive lung cancer cell line GLC. The mdr-1 cDNA was constructed in a retroviral vector, pDORneo. The transfection of recombinant plasmid was carried out by lipofectin. Supernatant containing infective viruses derived from a G418 resistant clone of package cell PA317 was used to infect GLC cell which is sensitive to chemotherapeutic agents. After G418 and adriamycine selections, three P-glycoprotein positive clones were isolated and the integration of mdr-1 cDNA was demonstrated by PCR of genomic DNA. The relative resistance of 3 clones to adriamycine as and elevated by 5.4, 6.0 respectively 7.8 times compared with the untransfected cell and the transcription of mdr-1 gene in these transfected cells as obviously enhanced by in situ hybridization. This results suggest that the mdr-1 gene plays a role in increasing drug resistance of human lung cancer.
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PMID:[Fully length MDR1 cDNA transfer conferring resistance to adriamycine on sensitive cells GLC]. 1045 56

Resistance to cytotoxic drugs is an important cause of treatment failure. The causes are complex and may be determined by a combination of the tumour characteristics, such as the proportion of resting cells, adequacy of blood supply, and specific cellular mechanisms, as in the multidrug resistance phenotype. In lung cancer four types of multidrug resistance have been defined on the basis of the cellular drug targets involved, i.e., classical multidrug resistance (MDR), non-P-glycoprotein MDR (also called MRP), atypical MDR (mediated through altered expression of topoisomerases II) and lung resistance-related protein. In lung cancer the role of the different forms of multidrug resistance is complex and only partially understood.
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PMID:Multidrug resistance in non-small-cell lung cancer. 1058 46

J-107088 (6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13-dihydro-2,10-dihydroxy- 13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo [3,4-c]carbazole-5,7(6H)-dione) is a derivative of NB-506, an indolocarbazole compound previously reported as an anti-tumor agent targeting topoisomerase I. The optimal administration schedule of J-107088 was found to be intermittent injections. The GID75 (75% growth inhibiting total dose) values of J-107088 against LX-1 lung cancer and PC-3 prostate cancer when given by intermittent injection (twice a week for 2 consecutive weeks) were 200 and 15 mg/m2, respectively, whereas the 10% lethal dose (LD10) values of J-107088 against LX-1- and PC-3-bearing mice were 578 and 1200 mg/m2. The ratio of LD10/GID75 indicates the therapeutic window of an anti-tumor agent. Although the ratios of doxorubicin, paclitaxel and cisplatin against PC-3 were <0.3, <0.5 and <0.2, J-107088 showed the widest therapeutic window among the anti-tumor drugs tested. J-107088 was also effective on cells that had acquired resistance related to P-glycoprotein. Furthermore, J-107088 was found to be highly effective in inhibiting proliferation of micro-metastases of tumors to the liver in mice. Therefore, J-107088 is considered to be a promising candidate as an anti-tumor drug for treatment of solid tumors in humans.
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PMID:In vivo anti-tumor activity of a novel indolocarbazole compound, J-107088, on murine and human tumors transplanted into mice. 1059 46


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