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)

Although combination chemotherapy has had a significant impact on survival for malignancies such as Hodgkin's disease, testicular cancer, and childhood acute leukemias, the majority of cancers are either initially resistant to chemotherapy (renal, colon, etc.) or are initially chemosensitive but acquire resistance during treatment, such as lymphoma and breast cancer. Resistance to chemotherapy remains an obstacle to the successful treatment of human cancer and has been the subject of numerous investigations aimed at identifying the molecular mechanisms of resistance in cancer cells. An improved understanding of the mechanisms by which tumor cells develop resistance to chemotherapy may not only enhance the activity of cytotoxic therapy in advanced malignancies but may ultimately improve the impact of adjuvant therapy, potentially resulting in prolonging disease-free intervals and survival. In this review, therefore, we discuss our current understanding of the MDR1 gene, encoding P-glycoprotein, which is responsible for one mechanism of multidrug resistance (MDR). We also review the evidence supporting the clinical relevance of the MDR1 gene and clinical trials aimed at reversing MDR-mediated resistance. Although MDR-mediated drug resistance has been well characterized in preclinical models, its role in clinical drug resistance is not as well characterized and requires further investigation. Prospective studies are necessary to establish the role of MDR1 gene expression in the clinical resistance. The ability to identify tumors with increased MDR1 gene expression has several potential applications (for example, the prediction of response to chemotherapy and the design of studies aimed at reversal of resistance with agents that inhibit MDR-mediated drug efflux). The initial goal of such trials is to demonstrate the ability to reverse MDR1-mediated drug resistance in the appropriate advanced refractory malignancies. Ultimately, it will be important to incorporate these reversal strategies in the treatment of early-stage disease, at which time the tumor burden is smaller and fewer mechanisms of resistance may be present. Prospective phase I, II, and III clinical trials using reversing agents in conjunction with chemotherapy in malignancies that express the MDR1 gene, such as the hematologic malignancies and breast cancer, are necessary before routine use of agents such as verapamil, quinidine, and cyclosporine, which carry innate toxicities. MDR is a mechanism of drug resistance that provides the potential for an alteration in drug efflux, which may have a significant impact on response and possibly result in improved survival for some cancer patients.
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PMID:Clinical reversal of drug resistance. 760 Aug 45

Chemotherapy is the principal strategy to systemically challenge metastasized cancers of genitourinary origin. Unfortunately, the efficacy of chemotherapy is often hampered by multidrug resistance, the resistance to a variety of structurally and functionally distinct cytotoxic agents. Multidrug resistance can be either intrinsic or acquired, and can be caused by several mechanisms. The so-called classical multidrug resistance, mediated by the MDR1 gene product P-glycoprotein, has been held mainly responsible for inferring the multidrug resistance phenotype on urologic malignancies. However, several other multidrug resistance pathways have been identified. Multidrug resistance can be caused by the membrane-bound multidrug-resistance-associated protein, the detoxifying glutathione metabolism, the antiapoptotic protein BCL2, and changes in levels or activity of the topoisomerase enzymes. Strategies to overcome multidrug resistance of genitourinary tumors have arisen from the better understanding of the biologic and molecular mechanisms of multidrug resistance, and have been studied in experimental and clinical settings. However, attempts to modulate multidrug resistance in clinical renal cell, bladder, prostate, and testicular cancer have not been very rewarding so far, despite the optimism that had arisen from experimental data. Nevertheless, application of novel therapies to reverse multidrug resistance and to increase efficacy of chemotherapy for urologic cancers should be further pursued, within the setting of controlled clinical trials, to improve on current strategies.
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PMID:Circumvention of multidrug resistance in genitourinary tumors. 953 94

Germ cell testicular cancers are well-curable neoplasms, because total remission can be achieved in about 80% of the cases. However, 15-20% of the patients die due to drug resistance (DR). A number of mechanisms of the multidrug resistance phenotype are known, including MDR/P-glycoprotein (P-gp) and the so-called multidrug resistance associated protein (MRP). Lung Resistance Protein (LRP) is an ATP dependent membrane transporter protein associated with MDR. In our present work we studied the expression of LRP in testicular cancers. LRP expression was determined by immunohistochemistry (IH), Western blot (WB) and RT-PCR techniques. Clinical resistance was defined in accordance with the clinical oncologic rules. In 29 (41%) of 70 primary testicular tumours and in 22 (63%) of 35 cases, elevated LRP levels were established by IH and WB, respectively. In the latter 63%, the LRP mRNA levels were elevated as well. Six cases of the 15 seminomas and 23 cases of the nonseminomatous germ cell tumours (NSGCT) proved to be positive. No relationship was demonstrated between LRP expression and the stage of the disease. Despite the LRP positivity of 6 tumour samples, all of the seminomas proved sensitive. Of the 39 sensitive NSGCT, 27 cases were LRP-negative, whereas 11 tumour samples of 16 patients belonging to the resistant group proved LRP-positive (p=0.04). The authors concluded that the expression of LRP is responsible for clinical drug resistance in non-seminomatous testicular cancer patients.
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PMID:[Lung resistance protein analysis in testicular cancer]. 1256 57

The overexpression of reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in human prostatic and testicular cancer cells. The aim of this study is to examine the potential of REIC/Dkk-3 as a therapeutic target against breast cancer. First, the in vitro apoptotic effect of Ad-REIC treatment was investigated in breast cancer cell lines and the adenovirus-mediated overexpression of REIC/Dkk-3 was thus found to lead to apoptotic cell death in a c-Jun-NH(2)-kinase (JNK) phosphorylaion-dependent manner. Moreover, an in vivo apoptotic effect and MCF/Wt tumor growth inhibition were observed in the mouse model after intratumoral Ad-REIC injection. As multidrug resistance (MDR) is a major problem in the chemotherapy of progressive breast cancer, the in vitro effects of Ad-REIC treatment were investigated in terms of the sensitivity of multidrug-resistant MCF7/ADR cells to doxorubicin and of the P-glycoprotein expression. Ad-REIC treatment in MCF7/ADR cells also downregulated P-glycoprotein expresssion through JNK activation, and sensitized its drug resistance against doxorubicin. Therefore, not only apoptosis induction but also the reversal of anticancer drug resistance was achieved using Ad-REIC. We suggest that REIC/Dkk-3 is a novel target for breast cancer treatment and that Ad-REIC might be an attractive agent against drug-resistant cancer in combination with conventional antineoplastic agents.
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PMID:REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer. 1865 8