Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P33527 (ABCC1)
 1,164 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to investigate the relationship between Technetium-99m (Tc-99m) tetrofosmin accumulation in tumors which may represent the expression of multidrug resistance (MDR)--mediated P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) as well as response to chemotherapy in patients with untreated small cell lung cancers (SCLC). Twenty patients with SCLC were studied with Tc-99m tetrofosmin lung scintigraphy before chemotherapeutic induction. Tc-99m tetrofosmin lung scans were interpreted both visually and quantitatively. Response was evaluated upon completion of chemotherapy. Patients with good chemotherapy response had a significantly higher incidence (93%) of positive Tc-99m tetrofosmin lung single photon emission computed tomography (SPECT) findings than patients with poor response (33%) (p value < 0.05). The tumor/background ratios (T/B) were 1.8 +/- 0.4 and 1.2 +/- 0.3, for patients with good response and poor response, respectively (p < 0.05). However, other prognostic factors (tumor size and stage) were not significantly related to Tc-99m tetrofosmin lung scan findings and chemotherapy responses. Tc-99m tetrofosmin lung scintigraphy can predict chemotherapy response in patients with SCLC.
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PMID:Evaluation of chemotherapy response in patients with small cell lung cancer using Technetium-99m-tetrofosmin. 1047 50

Pyrazoloacridine (PZA) is the first of a new class of rationally synthesized acridine derivatives to undergo clinical testing as an anticancer agent. Recent studies suggest that PZA might be a dual inhibitor of DNA topoisomerase I and DNA topoisomerase II that exerts its effects by diminishing the formation of topoisomerase-DNA adducts. Consistent with this unique mechanism of action, PZA exhibits broad spectrum antitumor activity in preclinical models in vivo. In addition, this agent displays several unique properties including solid tumor selectivity, activity against hypoxic cells, and cytotoxicity in noncycling cells. PZA also retains full activity against cells that are resistant to other agents on the basis of overexpression of P-glycoprotein or the multidrug resistance-associated protein (MRP). PZA has been studied in phase I trials in adults and children, and is currently undergoing broad phase II trials in a number of tumor types. No significant anti-tumor activity has been seen in gastrointestinal malignancies and prostate cancer. Results from ongoing or recently completed trials are awaited before the utility of this agent in our current armamentarium can be defined. Because of its unique properties, combination studies with other antineoplastic agents are warranted.
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PMID:Current status of pyrazoloacridine as an anticancer agent. 1055 21

Malignant cystosarcoma phyllodes (MCSP) is a rare breast tumor. Chemotherapeutic regimens for treatment of MCSP have not been established. We previously established an MCSP xenograft line MC-3-JCK. In this study, we established a new MCSP xenograft line, MC-10-JCK, by serial transplantation in nude mice. We studied the chemosensitivity of these two MCSP tumor xenografts to anticancer drugs in vivo. We also examined the expression of multidrug resistance-related proteins such as p-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) by immunohistochemical analysis. These two xenografts were sensitive to doxorubicin, vincristine and cyclophosphamide in vivo. Immunohistochemically, clinical specimens and xenografts were negative for Pgp and MRP expression. These results are consistent with the chemosensitivity of human MCSP to lipophilic anticancer compounds.
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PMID:In vivo chemosensitivity of human malignant cystosarcoma phyllodes xenografts. 1067 67

The overexpression of P-glycoprotein (P-gp) and the multidrug resistance-associated protein (MRP) have been shown to confer broad drug resistance in tumor cells. We have demonstrated previously direct binding between MRP and a quinoline-based photoreactive drug (iodo-azido-amino quinoline, IAAQ) (Vezmar et al., Biochem Biophys Res Commun 241: 104-111, 1997). In this report, we show the reversal of multidrug resistance in two MRP-overexpressing cell lines, HL60/AR and H69/AR, with four quinoline-based drugs. Non-toxic concentrations (5-20 microM) of chloroquine, quinine, quinidine, and primaquine potentiated the toxicity of doxorubicin in a concentration-dependent manner. These quinoline-based drugs showed a 5- to 10-fold decrease in the IC(50) of doxorubicin in H69/AR and HL60/AR cells. Primaquine was the most active, with modulation ratios of 10- and 5-fold versus 8- and 3-fold with MK-571 for H69/AR and HL60/AR, respectively. Moreover, using IAAQ, we showed that molar excesses of chloroquine, quinine, quinidine, and MK-571 inhibit the photoaffinity labeling of MRP. Primaquine and vinblastine showed lesser inhibition of MRP photoaffinity labeling by IAAQ. Taken together, the results of this study demonstrated the reversal of doxorubicin resistance with several quinoline-based drugs. Moreover, these drugs have been shown to reverse P-gp-mediated MDR and are clinically well tolerated.
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PMID:Reversal of MRP-mediated doxorubicin resistance with quinoline-based drugs. 1073 25

A 66-year-old female patient underwent left upper lobectomy and dissection of the mediastinal lymph nodes. The pathological diagnosis was well-differentiated papillary adenocarcinoma of the lung with metastasis to the mediastinal lymph nodes, p-T2N2MO, stage IIIA. After the operation, she was treated by chemotherapy including lipophilic anticancer compounds (carboplatin and VP-16). The patient unexpectedly showed long survival for 6 years and 2 months without obvious recurrence or metastasis of the cancer. The anticancer compounds were not effective on the recurrent lesions and then she died due to respiratory failure 8 months after recurrence. The autopsy revealed pleural dissemination and intrapulmonary metastasis. Immunohistochemical analysis showed increased multidrug resistance-associated protein (MRP)-positive tumor cells in the recurrent and metastatic lesions, while few MRP-positive cells were apparent in the primary lesion. The MRP-positive cells were accompanied by p53 nuclear accumulation in the carcinoma. This was a case of pulmonary adenocarcinoma with acquired multidrug resistance caused by MRP overexpression and aberrant p53 after chemotherapy.
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PMID:A case of pulmonary adenocarcinoma with overexpression of multidrug resistance-associated protein and p53 aberration. 1092 27

Multidrug resistance may be conferred by P-glycoprotein (Pgp, ABCB1) or the multidrug resistance associated protein (MRP). These membrane proteins are members of the ATP binding cassette transporter superfamily and are responsible for the removal from the cell of several anticancer agents including doxorubicin. Modulators can inhibit these transporters. LY335979 is among the most potent modulators of Pgp with a Ki of 59 nM. LY335979 is selective for Pgp, and does not modulate MRP-mediated resistance by MRP1 (ABCC1) and MRP2 (ABCC2). LY335979 significantly enhanced the survival of mice implanted with Pgp-expressing murine leukemia (P388/ADR) when administered in combination with either daunorubicin, doxorubicin or etoposide. Coadministration of LY335979 with paclitaxel compared to paclitaxel alone significantly reduced the tumor mass of the Pgp-expressing UCLA-P3.003VLB lung carcinoma in a xenograph model and delayed the development of tumors in mice implanted with the parental drug-sensitive UCLA-P3 tumor. LY335979 was without significant effect on the pharmacokinetics of these anticancer agents. This may be due impart to its poor inhibition of four major cytochrome P450 isozymes important in metabolizing doxorubicin and other oncolytics. The selectivity and potency of this modulator allows the clinical evaluation of the role of Pgp in multidrug resistance. LY335979 is currently in clinical trials.
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PMID:Reversal of multidrug resistance by the P-glycoprotein modulator, LY335979, from the bench to the clinic. 1117 91

Malignant gliomas are largely resistant to current chemotherapeutic strategies often displaying a multidrug-resistant phenotype. Mechanisms involved in drug resistance are reduced cellular drug accumulation through membrane efflux pumps, drug detoxification as well as alterations in drug target specificity. In 27 primary and 17 secondary glioblastomas and their astrocytic precursor tumors, we studied the immunohistochemical expression profile of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), metallothionein, and topoisomerase II alpha. Glial tumor cells in all glioblastomas showed constant up-regulation of LRP, MRP, and topoisomerase II alpha. P-gp was found in 90% of the primary and 60% of the secondary glioblastomas. In precursor tumors, these drug resistance-related factors were expressed in varying proportions. Metallothionein, also found in normal and activated astrocytes, was retained in all neoplastic phenotypes. Furthermore, metallothionein, P-gp, LRP, and topoisomerase II alpha were strongly expressed by normal and neoplastic vessels which may confer to impaired penetration of therapeutic agents through the blood-brain and blood-tumor barrier. However, the expression profiles of drug resistance-related proteins neither differed between primary and secondary glioblastomas nor revealed any correlation to precursor or recurrent tumors. Nevertheless, inhibition of these factors may be promising approaches to the management of malignant gliomas.
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PMID:Drug resistance-associated factors in primary and secondary glioblastomas and their precursor tumors. 1126 2

Multidrug resistance protein 1 (MRP1/ABCC1) is an ATP-binding cassette (ABC) polytopic membrane transporter of considerable clinical importance that confers multidrug resistance on tumor cells by reducing drug accumulation by active efflux. MRP1 is also an efficient transporter of conjugated organic anions. Like other ABC proteins, including the drug resistance conferring 170-kDa P-glycoprotein (ABCB1), the 190-kDa MRP1 has a core structure consisting of two membrane-spanning domains (MSDs), each followed by a nucleotide binding domain (NBD). However, unlike P-glycoprotein and most other ABC superfamily members, MRP1 contains a third MSD with five predicted transmembrane segments with an extracytosolic NH(2) terminus. Moreover, the two nucleotide-binding domains of MRP1 are considerably more divergent than those of P-glycoprotein. In the present study, the first structural details of MRP1 purified from drug-resistant lung cancer cells have been obtained by electron microscopy of negatively stained single particles and two-dimensional crystals formed after reconstitution of purified protein with lipids. The crystals display p2 symmetry with a single dimer of MRP1 in the unit cell. The overall dimensions of the MRP1 monomer are approximately 80 x 100 A. The MRP1 monomer shows some pseudo-2-fold symmetry in projection, and in some orientations of the detergent-solubilized particles, displays a stain filled depression (putative pore) appearing toward the center of the molecule, presumably to enable transport of substrates. These data represent the first structural information of this transporter to approximately 22-A resolution and provide direct structural evidence for a dimeric association of the transporter in a reconstituted lipid bilayer.
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PMID:The structure of the multidrug resistance protein 1 (MRP1/ABCC1). crystallization and single-particle analysis. 1127 22

Meningiomas, commonly benign tumors, rarely display aggressive behavior by recurrences and invasion. In addition to surgery, irradiation is beneficial for recurrent, atypical, and malignant meningiomas. The role of chemotherapy, however, remains controversial, although there is evidence that meningiomas respond well to adjuvant chemotherapy. A major obstacle in chemotherapy remains drug resistance with reduced cellular drug accumulation through membrane efflux pumps, drug detoxification, and alterations in drug target specificity. In 84 classic, atypical, and malignant meningiomas, the immunohistochemical expression profile of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), metallothionein, and topoisomerase IIalpha were studied. All types of meningiomas showed constant expression of P-gp, LRP, MRP, and topoisomerase IIalpha; metallothionein was found in 67% of the tumors, especially in atypical and malignant meningiomas. Furthermore, metallothionein. P-gp, LRP, and topoisomerase IIalpha were strongly expressed by normal and neoplastic vessels, which may confer to impaired penetration of therapeutic agents through the blood-brain and blood-tumor barrier. Neither recurrent nor previously irradiated meningiomas revealed any significant difference to primary tumors. These intrinsic drug resistances indicate that successful chemotherapy may require additional inhibition of these factors to be a promising approach in the management of meningiomas.
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PMID:Intrinsic expression of drug resistance-associated factors in meningiomas. 1155 52

In contrast to the parent triptycene (code name TT0), triptycene bisquinone (code name TT2) is cytostatic (IC50: 300 nM) and cytotoxic (IC50: 230 nM) in wild-type (WT), drug-sensitive HL-60 cells (HL-60-S) at day 4. Therefore, the effects of this new quinone antitumor drug were assessed and compared to those of daunorubicin (DAU, daunomycin) in the multidrug-resistant (MDR) HL-60-RV and HL-60-R8 sublines, which respectively overexpress P-glycoprotein (P-gp) or multidrug resistance-associated protein (MRP). In contrast to DAU, which loses its cytostatic [resistance factors (RFs): 22.9-35.7] and cytotoxic (RFs: 23.8-31.3) activities in MDR sublines, TT2 decreases tumor cell proliferation (RFs: 0.9-1.3) and viability (RFs: 0.9-1.5) as effectively in HL-60-S as in HL-60-RV and HL-60-R8 cells at days 2 and 4. Similarly, DAU inhibits the rate of DNA synthesis less effectively in MDR than in parental HL-60 cells (RFs: 8.1-11.9) but TT2 decreases the incorporation of 3[H]-thymidine into DNA to the same degree in HL-60-S, HL-60-RV and HL-60-R8 cells (RFs: 1.2). In contrast to DAU, which is inactive, the advantage of TT2 is its ability to block the cellular transport of purine and pyrimidine nucleosides in WT tumor cells, an effect which persists in both MDR sublines (RFs: 1.0-1.2). Moreover, the concentrations of DAU which induce maximal DNA cleavage in HL-60-S cells at 24 h lose all or most of their DNA-damaging activity in HL-60-RV and HL-60-R8 cells, whereas treatments with 4 microM TT2 produce similar peaks of DNA fragmentation in all WT and MDR cell lines. Since TT2 not only mimics the antitumor effects of DAU but also blocks nucleoside transport and retains its effectiveness in MDR cells that have already developed different mechanisms of resistance to DAU, this new quinone antitumor drug might be valuable to develop new means of polychemotherapy.
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PMID:A synthetic triptycene bisquinone, which blocks nucleoside transport and induces DNA fragmentation, retains its cytotoxic efficacy in daunorubicin-resistant HL-60 cell lines. 1171 86


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