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)

Using an in situ kinase assay we have identified kinases that are elevated in some multidrug resistant cells. Kinases were detected by measurement of 32P incorporation in proteins that were renatured after being subjected to SDS-polyacrylamide gel electrophoresis and transferred to polyvinylidene difluoride membranes [Ferrell and Martin: J Biol Chem 264:20723-20729, 1989; Mol Cell Biol 10:3020-3026, 1990]. Kinases at 79, 84, and 92 kDa showed increased activity in the multidrug resistant human KB-V1 cells as compared to the sensitive parental KB-3-1 cells. The KB-V1 multidrug resistant cell line exhibited a 170 kDa membrane associated kinase activity that was not present in the parental drug sensitive line. The 170 kDa kinase activity was not affected by Ca++, phosphatidylserine, or cAMP, but was diminished after incubation in the presence of the kinase inhibitors staurosporine, K252a and KT5720. The 170 kDa kinase activity phosphorylated mainly threonine, with no evidence of tyrosine phosphorylation, and was not identical to either the multidrug resistance associated P-glycoprotein or the EGF receptor. Other multidrug resistant cell lines also showed elevated 170 kDa kinase activity, such as the human breast cancer MCF-7/Adr(R) and murine melanoma B16/Adr(R) cells, but the activity was not present in murine leukemia P-388 sensitive or multidrug resistant cells.
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PMID:Identification of a 170 kDa membrane kinase with increased activity in KB-V1 multidrug resistant cells. 769 26

The phosphorylation of P-glycoprotein has been appreciated for many years, yet little is known about the factors that initiate this post-translational modification. To determine whether the activation of P-glycoprotein phosphorylation could occur in response to cellular stress and to investigate the possible signal pathways involved, we studied the effect of heat shock on the phosphorylation of P-glycoprotein in sensitive and resistant MCF-7 human breast cancer cells. Treatment of multidrug resistant MCF-7/AdrR cells with heat shock increased the phosphorylation of P-glycoprotein. The response was not seen in the sensitive MCF-7 line, which does not express this drug transporter. Phosphorylation of P-glycoprotein induced by heat shock was not dependent on synthesis of new proteins, since phosphorylation was not inhibited by cycloheximide and the content of P-glycoprotein, as measured by immunoblotting, did not change after heat shock. The activation of P-glycoprotein phosphorylation by heat shock may be initiated through activation of phospholipase C, since heat shock stimulated the activity of this enzyme, as evidenced by increased formation of inositol trisphosphate and diacylglycerol and by phosphorylation of phospholipase C-gamma. U-73122, an inhibitor of phospholipase C and staurosporine, an inhibitor of protein kinase C, both decreased the heat-shock-induced phosphorylation of P-glycoprotein. These results suggest that heat shock induces phosphorylation of P-glycoprotein through the activation of the phospholipase C/protein kinase C pathway.
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PMID:Involvement of phospholipase C in heat-shock-induced phosphorylation of P-glycoprotein in multidrug resistant human breast cancer cells. 774 43

Paclitaxel is a highly active single agent as therapy for previously untreated as well as doxorubicin-refractory metastatic breast cancer, with associated response rates of 62% and 20-48%, respectively. Complete responses with paclitaxel occur chiefly in breast cancer patients whose metastatic disease has not been previously treated with chemotherapy. Early data suggest a possible dose-response relationship for paclitaxel in metastatic breast cancer, but the optimal dose has not yet been defined. The optimal duration of infusional paclitaxel treatment is also not yet known. A study of 96-hour infusional paclitaxel in the treatment of doxorubicin- or mitoxantrone-refractory metastatic breast cancer patients has demonstrated a 48% response rate suggesting that prolonged exposures to paclitaxel may offer a therapeutic advantage. Randomized trials of 3- vs 96-hour paclitaxel are ongoing or planned. The relative efficacy of paclitaxel versus standard chemotherapy as front-line or salvage therapy for metastatic breast cancer is currently under study. In addition, two randomized trials are under way in node positive breast cancer patients to study whether treatment with paclitaxel following standard or high dose doxorubicin and cyclophosphamide adjuvant therapy results in improved patient benefit. Combining paclitaxel with other active agents in the treatment of metastatic breast cancer is an area of active investigation. Combined paclitaxel and doxorubicin, administered concurrently or sequentially, is associated with modest complete response rates in metastatic breast cancer patients. Sequential paclitaxel-->doxorubicin administration is associated with more mucositis than is doxorubicin-->paclitaxel when paclitaxel is administered over 24 hours. High doses of cyclophosphamide can be combined with 24- or 72-hour infusional paclitaxel, and phase II studies of this combination are warranted. Early data suggest that administering biweekly paclitaxel and cisplatin to previously untreated metastatic breast cancer patients is associated with high response rates, and confirmatory studies of this combination and schedule are planned. Preclinical data suggest that cell cycle considerations may be important in combining doxorubicin and possibly other agents with paclitaxel. Paclitaxel is an excellent substrate for P-glycoprotein, the protein product of the multidrug resistance-1 (mdr-1) gene, and phase I trials are under way combining paclitaxel with several known blockers of Pgp function. Finally, pilot studies are under way to determine whether the radiation sensitizing effects of paclitaxel can be exploited as part of radiation therapy for patients with locally advanced breast cancer.
Breast Cancer Res Treat 1995
PMID:Current status of paclitaxel in the treatment of breast cancer. 774 30

Paraffin-embedded, formalin-fixed tissue (PEFFT) specimens from a subset of breast cancer patients were analyzed by immunohistochemistry to determine whether or not the presence of P-glycoprotein identified chemotherapy resistance. Two antibodies, C219 (monoclonal) and Ab1 (polyclonal), demonstrated appropriate immunostaining. Retrospectively and prospectively, P-glycoprotein expression was determined from PEFFT of 20 breast cancer biopsies (19 patients with locally advanced or metastatic disease). Immunohistochemical staining was graded for number of positive cells (N0 to N4) and intensity (I0 to I3). The immunostaining N and I of both antibodies were similar. There was no correlation between N, (P = 0.13) or I, (P = 0.67) and chemotherapy response or between N, (P = 0.63) or I, (P = 0.89) and survival. Five patients had residual cancer at repeat biopsy after systemic chemotherapy for locally advanced disease. These specimens had similar N and I as the primary cancer. This assay accurately identifies P-glycoprotein expression in PEFFT and revealed no correlation between expression and chemotherapy response or survival.
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PMID:Immunohistochemical analysis of P-glycoprotein expression in breast cancer: clinical correlations. 776 69

We have shown previously that preactivated merocyanine 540 (pMC540) and merodantoin appear to mediate their cytotoxic effects via interaction with Topo II. Now, we demonstrate a correlation between DNA Topo II activity and drug-sensitive (MCF-7) and -insensitive (MDA-MB-231) breast cancer cell lines. Further studies indicate that MDA-MB-231 cells are insensitive to the cytotoxic and DNA cleavage effects of pMC540 and merodantoin. This loss of sensitivity is not associated with M(r) 170,000 P-glycoprotein over expression. However, in drug insensitive cells, the Topo II catalytic activity in crude nuclear extract was reduced two- to-three-fold and in cellular extracts was virtually absent as determined by decatenation of kDNA. Topoisomerase I activities appeared similar in extracts from MCF-7 and MDA-MB-231 cell lines. Drug-induced DNA cleavage was reduced two-to-threefold in nuclear extracts from MDA-MB-231. m-AMSA was more effective in inhibiting the decatenation activity in the nuclear extracts from MDA-MB-231 as compared to MCF-7 cells. Western blot analysis of whole-cell lysates revealed undetectable immunoreactivity of Topo II in the drug-insensitive cells. These data indicate that insensitivity of MDA-MB-231 to pMC540 and merodantoin is in part due to the reduced drug-induced formation of the cleavage complex and Topo II (170 kD) enzyme content.
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PMID:Correlation between DNA topoisomerase II activity and cytotoxicity in pMC540 and merodantoin sensitive and resistant human breast cancer cells. 776 97

In a retrospective study, liquid nitrogen preserved specimens from 50 women with primary breast cancer, who underwent surgery at the Beijing Institute for Cancer Research between June, 1986 and September, 1988, were investigated. All patients under this study were staged in TNM II or later, involved with axillary lymph node metastasis, and treated with systemic postoperative adjuvant chemotherapy. The median length of follow-up was 69 months. The expression of P-glycoprotein was investigated by means of immunohistochemistry, using a monoclonal antibody C219 specifically against P-glycoprotein and avidin-biotin peroxidase method. Positive staining for P-glycoprotein was found in 23 (46%) of the 50 patients. The P-glycoprotein expression negative group fared better than the group that was P-glycoprotein positive in overall survival curves (p = 0.0008, by the generalized Wilcoxon test). The prognostic effect of P-glycoprotein expression remained statistically significant (p = 0.0007) after adjustment by multivariate analysis (Cox's model) for other prognostic factors. It is demonstrated that P-glycoprotein expression is a significant and independent predictor of postoperative survival in breast cancer patients. The results of the present study suggest that P-glycoprotein expression might also influence the biological behavior of breast cancers.
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PMID:P-glycoprotein expression in primary breast cancer. 778 Jan 10

Tamoxifen is an anti-oestrogen which is currently being assessed as a prophylactic for women at high risk of breast cancer. Taxoxifen has also been shown to reverse multidrug resistance in P-glycoprotein (P-gp)-expressing cells, although the mechanism of action is unknown. In this study we demonstrate that tamoxifen interacts directly with P-gp. Plasma membranes from P-gp-expressing cells bound [3H]tamoxifen in a specific and saturable fashion. A 180 kDa membrane protein in these membranes, labelled by the affinity analogue tamoxifen aziridine and azidopine, was shown to be P-gp. Tamoxifen reduced the binding of vinblastine and azidopine to P-gp, and tamoxifen increased [3H]vinblastine accumulation in P-gp-expressing cells to levels approaching those in non-P-gp-expressing cells. However, the cellular accumulation of [3H]tamoxifen itself was not influenced by the presence of P-gp. Thus, tamoxifen appears to reverse multidrug resistance by binding to P-gp and inhibiting the transport of cytotoxic drugs, but does not itself appear to be transported by the protein.
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PMID:Interaction of tamoxifen with the multidrug resistance P-glycoprotein. 784 Oct 43

The search for new active agents and strategies to improve the prognosis for patients with stage IV breast cancer has led to examination of paclitaxel. Several clinical trials have been undertaken to determine its optimal use and clarify its role in the treatment of breast cancer and other malignancies. Several phase II trials involving breast cancer patients with limited prior therapy have yielded overall response rates (complete response and partial response) of 44% to 62% among women receiving paclitaxel. Treatment was generally well tolerated, with febrile neutropenia the most common side effect. An interim analysis of the European-Canadian Randomized Trial in Metastatic Breast Cancer demonstrated safety and efficacy of paclitaxel in a multicenter setting. Among the 234 patients evaluable for response, 29% (34/117) responded at 175 mg/m2 paclitaxel and 22% responded (26/117) at 135 mg/m2. Treatment was well tolerated at both dose levels; responses continue to evolve in patients who remain on study. Among patients with extensive prior therapy (> 2 prior regimens for stage IV disease), paclitaxel also has demonstrated safety and efficacy. At Memorial Sloan-Kettering Cancer Center, responses were noted among 36% of patients who had received two prior treatments and 21% of those who had received 3 or more. Paclitaxel was administered at 200 mg/m2 plus G-CSF. Other studies involving heavily pretreated patients yielded overall response rates as high as 53%. The concerns about cross-resistance between paclitaxel and doxorubicin (or other agents for which resistance is thought to be at least partly due to P-glycoprotein-mediated pleiotropic drug resistance) also are addressed.
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PMID:Single-agent use of Taxol (paclitaxel) in breast cancer. 786 28

Tamoxifen (TAM), a widely used agent in the hormonal therapy of breast cancer, is also an antagonist of P-glycoprotein (P-gp), a cell surface protein which confers drug resistance to cells. Here we report that in an estrogen receptor-deficient multidrug-resistant subline of MCF-7 human breast carcinoma cells (MCF-7/MDR), but not in the parent drug-sensitive cells (MCF-7/WT), clinically relevant concentrations (1-5 microM) of TAM inhibited the uptake and phosphorylation of ethanolamine and choline. These inhibitory effects resulted in decreased synthesis of the corresponding phospholipids. In view of the known dependence of P-gp function on phosphatidylethanolamine (PtdEtn), inhibition of PtdEtn synthesis may represent an additional mechanism by which TAM inhibits P-gp-mediated drug efflux.
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PMID:Tamoxifen inhibits uptake and metabolism of ethanolamine and choline in multidrug-resistant, but not in drug-sensitive, MCF-7 human breast carcinoma cells. 787 22

The development of cross-resistance to many natural product anticancer drugs, termed multidrug resistance (MDR), is one of the major reasons why cancer chemotherapy ultimately fails. This type of MDR is often associated with over-expression of the MDR1 gene product, P-glycoprotein (Pgp), a multifunctional drug transporter. The expression of MDR in breast tumors is related to their origination from a tissue that constitutively expresses Pgp as well as to the development of resistance during successive courses of chemotherapy. Therefore, understanding the mechanisms that regulate the transcriptional activation of MDR1 may afford a means of reducing or eliminating MDR. We have found that MDR1 expression can be modulated by type I cAMP-dependent protein kinase (PKA), opening up the possibility of modulating MDR by selectively down-regulating the activity of PKA-dependent transcription factors which upregulate MDR1 expression. High levels of type I PKA occurs in primary breast carcinomas and patients exhibiting this phenotype show decreased survival. The selective type I cAMP-dependent protein kinase (PKA) inhibitors, 8-Cl-cAMP and Rp8-Cl-cAMP[S] may be particularly useful for downregulating PKA-dependent MDR-associated transcription factors, and we have found these compounds to downregulate transient expression of a reporter gene under the control of several MDR1 promoter elements. Thus, investigations of this nature should not only lead to a greater understanding of the mechanisms governing the expression of MDR, but also provide a focus for pharmacologic intervention by a new class of inhibitors.
Breast Cancer Res Treat 1994
PMID:Transcriptional regulation of multidrug resistance in breast cancer. 788 Nov 4


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