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)

Dexrazoxane combined with doxorubicin (+ 5-fluorouracil + cyclophosphamide - the FAC regime) leads to a significant decrease in doxorubicin cardiotoxicity and a significant increase in median survival time for patients with advanced breast cancer responsive to FAC. The reason for this increase in survival may be due to interference with the mechanism involved in the emergence of multidrug resistance (MDR). In order to test this hypothesis, we induced resistance to doxorubicin in the K562 cell line by growing cells in increasing concentrations of doxorubicin (10-30 nM) in the presence and absence of dexrazoxane (20 nM). The doxorubicin sensitivity of all resultant sublines was measured using the MTT assay. Flow cytometry was used to assess the MDR1 phenotype, measuring P-glycoprotein expression with MRK 16 antibody and drug accumulation in the presence and absence of PSC 833 for functional P-glycoprotein. Long-term growth in doxorubicin increased the cellular resistance (IC(50)) of K562 cells in a concentration-dependent manner (r(2 )= 0.908). Doxorubicin resistance was not induced in the presence of dexrazoxane (P< 0.0001) for several months. In parallel, the expression of functional P-glycoprotein was delayed after concomitant addition of dexrazoxane to the selecting medium (P< 0.001). Dexrazoxane did not act as a conventional modulator of P-glycoprotein. These results suggest that dexrazoxane may delay the development of MDR1, thus allowing responders to the FAC regime to continue to respond.
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PMID:Dexrazoxane significantly impairs the induction of doxorubicin resistance in the human leukaemia line, K562. 1128 77

Resistance to doxorubicin based chemotherapy is a major therapeutic problem limiting advanced breast cancer treatment. 99mTc hexakis-2-methoxyisobutylisonitrile ((99m)Tc-MIBI) has been reported to be extruded from tumour cells by the P-glycoprotein and multidrug resistance protein encoded by MDR1 and MRP1 genes, respectively. These proteins are involved in the cellular efflux of several chemotherapeutic agents including doxorubicin. The aim of this study was to investigate the clinical value of a standard (99m)Tc-MIBI scintimammography technique in the prediction of response to chemotherapy in advanced breast cancer patients. Fifty-six lesions from 33 female patients with locally advanced (n=27) or recurrent breast cancer (n=6) were included in the study. MIBI scintigraphy was performed 2-8 days prior to chemotherapy (FAC regimen). Images were acquired 10 min and 1 h post-injection of 740-1110 MBq of (99m)Tc-MIBI. Tumour-to-normal background tissue uptake ratios were calculated on each lesion in the early (T/B(e)) and delayed phase of the study (T/B(d)). Both T/B(e) and T/B(d) ratios were significantly higher (P<0.0001) in responders (n=43) than nonresponders (n=13). Diagnostic values of (99m)Tc-MIBI in the prediction of chemotherapy response were evaluated using the arbitrary cut-off values of 1.5 for T/B(e) and 1.4 forT/B(d). Sensitivity, specificity, positive and negative predictive values were 88.4%, 92.3%, 97.4%, 70.6%; and 90.7%, 100.0%, 100.0%, 76.6%, for T/B(e) and T/B(d), respectively. We conclude that (99m)Tc-MIBI scintigraphy may be a clinically valuable tool for guiding chemotherapy in advanced breast cancer patients.
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PMID:Predictive value of (99m)Tc sestamibi scintigraphy in the evaluation of doxorubicin based chemotherapy response in patients with advanced breast cancer. 1212 82

Filamentous fungi are prolific producers of secondary metabolites with drug-like properties, and their genome sequences have revealed an untapped wealth of potential therapeutic leads. To better access these secondary metabolites and characterize their biosynthetic gene clusters, we applied a new platform for screening and heterologous expression of intact gene clusters that uses fungal artificial chromosomes and metabolomic scoring (FAC-MS). We leverage FAC-MS technology to identify the biosynthetic machinery responsible for production of acu-dioxomorpholine, a metabolite produced by the fungus, Aspergilllus aculeatus. The acu-dioxomorpholine nonribosomal peptide synthetase features a new type of condensation domain (designated CR) proposed to use a noncanonical arginine active site for ester bond formation. Using stable isotope labeling and MS, we determine that a phenyllactate monomer deriving from phenylalanine is incorporated into the diketomorpholine scaffold. Acu-dioxomorpholine is highly related to orphan inhibitors of P-glycoprotein targets in multidrug-resistant cancers, and identification of the biosynthetic pathway for this compound class enables genome mining for additional derivatives.
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PMID:Identification of the First Diketomorpholine Biosynthetic Pathway Using FAC-MS Technology. 2963 95