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)

Screening programs for the detection of cancer in ulcerative colitis are inexact and not always successful in finding early, curable cancers. P-glycoprotein is a membrane-based, energy-dependent protein found in varying degrees within normal human tissue. P-glycoprotein is overexpressed in malignant tumors, particularly colorectal cancer, and is known to convey resistance to certain anticancer drugs by acting as a membrane "pump." The purpose of this study was to determine the expression of this protein in inflamed and premalignant colonic epithelium, compare its expression with normal controls, and assess its potential use as a screening tool for high-risk patients with ulcerative colitis. Using immunohistochemical techniques, the colons of 21 patients (10 with dysplasia) with ulcerative colitis were stained with monoclonal antibody C-219 (MAbC219) specific for P-glycoprotein. P-glycoprotein was expressed in 38 percent of normal areas, 71 percent of inflamed areas (P = 0.0156), and 70 percent of dysplastic areas. Comparing the level of expression when progressing from normal to inflamed areas within a given patient, 11 patients (52 percent) showed increased expression, 8 (38 percent) showed equal expression, and only 2 (10 percent) showed decreased expression (P = 0.0225). Comparing expression when progressing from inflamed to dysplastic areas (10 patients), 7 showed equal expression and 3 showed increased expression (P = 0.25). Increasing duration of disease was associated with a significant increase in P-glycoprotein expression, but only in histologically normal areas. Duration of disease had no effect on P-glycoprotein expression in inflamed or dysplastic areas. Similarly, when surgery was performed for elective reasons, there was a significant overexpression of P-glycoprotein, but only in histologically normal areas. Our findings suggest that the increase in P-glycoprotein expression from normal to inflamed and dysplastic areas reflects the premalignant nature of ulcerative colitis and occurs early in the course of the disease. Further research needs to be done to determine its role in cancer surveillance.
Dis Colon Rectum 1992 Aug
PMID:Variable expression of P-glycoprotein in normal, inflamed, and dysplastic areas in ulcerative colitis. 135 19

The effectiveness of liposome-encapsulated doxorubicin in overcoming multidrug resistance was studied in various human colon cancer cells. Colon-cancer cell lines SW403, HT29, SW620, and SW620/R overexpressed P-glycoprotein as determined by immunoflow cytometry, thereby confirming the presence of the multidrug-resistant phenotype. Important differences were observed in the cytotoxicity of free doxorubicin as represented by IC50 values of 0.168, 0.058, 0.023, and 9.83 microM for SW403, HT29, SW620, and SW620/R, respectively. Liposomally encapsulated doxorubicin provided an IC50 that was 1.4 times lower than that of the free drug in the doxorubicin-resistant SW 620/R cell line, whereas no difference was evident in the sensitive parental SW620 cells. In addition, liposome-encapsulated doxorubicin exhibited 1.31- and 2.33-fold cytotoxicity to HT-29 and SW403 cells, respectively. The intracellular drug accumulation in SW620/R cells was enhanced by liposomally encapsulated doxorubicin, whereas it was reduced in all other cell lines as compared with that of free drug. The colon-cancer cell lines demonstrated different degrees of doxorubicin-induced DNA strand breakage that correlated with their sensitivities to drug-induced cytotoxicity. However, no difference was observed between DNA breakage caused by the free drug and that induced by liposome-encapsulated doxorubicin in any of the cell lines. The results suggest that the enhanced cytotoxicity of liposomal doxorubicin to colon cancer cells was due to some secondary non-DNA target. However, liposomally encapsulated doxorubicin appears to be effective in diminishing the multidrug-resistant phenotype and may have clinical applications.
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PMID:Sensitization of multidrug-resistant colon cancer cells to doxorubicin encapsulated in liposomes. 167 95

Monoclonal antibody MRK16 was used to determine the location of P-glycoprotein, the product of the multidrug-resistance gene (MDR1), in normal human tissues. The protein was found to be concentrated in a small number of specific sites. Most tissues examined revealed very little P-glycoprotein. However, certain cell types in liver, pancreas, kidney, colon, and jejunum showed specific localization of P-glycoprotein. In liver, P-glycoprotein was found exclusively on the biliary canalicular front of hepatocytes and on the apical surface of epithelial cells in small biliary ductules. In pancreas, P-glycoprotein was found on the apical surface of the epithelial cells of small ductules but not larger pancreatic ducts. In kidney, P-glycoprotein was found concentrated on the apical surface of epithelial cells of the proximal tubules. Colon and jejunum both showed high levels of P-glycoprotein on the apical surfaces of superficial columnar epithelial cells. Adrenal gland showed high levels of P-glycoprotein diffusely distributed on the surface of cells in both the cortex and medulla. These results suggest that the protein has a role in the normal secretion of metabolites and certain anti-cancer drugs into bile, urine, and directly into the lumen of the gastrointestinal tract.
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PMID:Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. 244 83

Expression of the MDR1 (P-glycoprotein) gene confers resistance to several classes of chemotherapeutic drugs (multi-drug resistance). Colon carcinomas frequently express high levels of MDR1 mRNA and P-glycoprotein, presumably reflecting the origin of these tumors from MDR1-expressing normal colonic cells. In 4 colon carcinoma cell lines (SW 620, HCT-15, DLD-1, LS 180), MDR1 expression was reported in an earlier study to be elevated after exposure to a differentiating agent, sodium butyrate (NaB). In one of these cell lines (SW 620), increased MDR1 expression reportedly was not accompanied by a decrease in the accumulation or cytotoxicity of vinblastine, a P-glycoprotein-transported drug, suggesting a possible functional abnormality of NaB-induced P-glycoprotein. We have re-examined the effect of NaB on MDR1/P-glycoprotein expression and function in the same colon carcinoma cell lines. NaB treatment induced differentiation-related changes and increased expression of MDR1 mRNA in all 4 cell lines. A major increase in MDR1 mRNA and P-glycoprotein expression was observed in only one line, SW 620. This increase, however, was accompanied by a commensurate increase in the activity of P-glycoprotein, indicating that the induced protein was fully functional. NaB treatment caused a relatively minor increase in MDR1 mRNA expressed in the other 3 cell lines. Two of these lines showed a detectable increase in the P-glycoprotein expression and function, but in the third line (LS 180) P-glycoprotein was undetectable either before or after exposure to NaB. The magnitude of MDR1 induction by NaB showed no apparent correlation with differentiation-related changes induced by this agent.
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PMID:Variable effects of sodium butyrate on the expression and function of the MDR1 (P-glycoprotein) gene in colon carcinoma cell lines. 810 60

DNA topoisomerase II has been shown to be an important therapeutic target in cancer chemotherapy. Here, we describe studies on the antitumor activity of a novel topoisomerase II inhibitor, ER-37328 [12,13-dihydro-5-[2-(dimethylamino)ethyl]-4H-benzo[c]pyrimido[5,6,1- jk]carbazole-4,6,10(5H,11H)-trione hydrochloride]. ER-37328 inhibited topoisomerase II activity at 10 times lower concentration than etoposide in relaxation assay and induced double-strand DNA cleavage within 1 h in murine leukemia P388 cells, in a bell-shaped manner with respect to drug concentration. The maximum amount of DNA cleavage was obtained at 2 microM. Like etoposide, ER-37328 (2 microM) induced topoisomerase II-DNA cross-linking in P388 cells. A spectroscopic study of ER-37328 mixed with DNA demonstrated that ER-37328 has apparent binding activity to DNA. ER-37328 showed potent growth-inhibitory activity against a panel of 21 human cancer cell lines [mean (50% growth-inhibitory concentration) GI50 = 59 nM]. COMPARE analysis according to the National Cancer Institute screening protocol showed that the pattern of the growth-inhibitory effect of ER-37328 was similar to that of etoposide, but different from that of doxorubicin. Studies on etoposide-, amsacrine [4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA)]-, and camptothecin-resistant P388 cell lines showed that: (a) etoposide- and m-AMSA-resistant P388 cell lines were partially resistant to ER-37328 compared with the parental cell line; and (b) a camptothecin-resistant cell line showed no cross-resistance to ER-37328. In addition, ER-37328 overcame P-glycoprotein-mediated resistance. In vivo, ER-37328 produced potent tumor regression of Colon 38 carcinoma inoculated s.c., and its activity was superior to that of etoposide or doxorubicin. These results indicate that ER-37328 inhibits topoisomerase II activity through the formation of topoisomerase II-DNA cleavable complex and has potent antitumor activity both in vitro and in vivo.
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PMID:Antitumor activity of ER-37328, a novel carbazole topoisomerase II inhibitor. 1246 11

The purpose of the study was to determine whether the organ environment can influence the response of colon cancer cells to chemotherapy. The highly metastatic human colon cancer cell line KM12L4, previously selected for production of liver metastases in nude mice, was injected into the cecal wall and into the spleen to produce liver metastases, and into the subcutis of nude mice. Doxorubicin (DOX) at 10 mg/kg or saline (control) was injected intravenously on days 7 and 16 after tumor cell injection. The in vivo response of tumors growing in the cecum, liver, and subcutaneous (s.c.) sites as well as the DOX sensitivity of cell lines established from liver and s.c. tumors were compared. Colon cancers growing s.c. were more sensitive to DOX than tumors growing in the cecal wall or liver of nude mice. The difference in response to DOX between s.c. tumors (sensitive) and liver tumors (resistant) was not due to selection of cell populations with different sensitivity to DOX, or differences in DOX distribution. PKC activity was lower in tumors of the liver and the cecum than in s.c. tumors. The expression of P-glycoprotein as determined by flow cytometric analysis of tumor cells harvested from lesions in different organs correlated inversely with their sensitivity to DOX. Increased levels of P-glycoprotein correlated with mdr-1, mdr-3 mRNA expression as determined by Northern analysis. Collectively, the data show that the organ environment influences the response of human colon carcinoma cells to DOX and recommend that animal models of this disease for experimental therapeutic studies employ orthotopic implantation of tumor cells.
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PMID:Modulation of Doxorubicin sensitivity and level of p-glycoprotein expression in human colon-carcinoma cells by ectopic and orthotopic environments in nude-mice. 2157 80

We tried to overcome the paclitaxel (PTX) resistance of cancer cells due to P-glycoprotein (P-gp) overexpression in the in vivo anti-tumor chemotherapy by utilizing polyethylene glycol-modified liposomal paclitaxel (PL-PTX). First of all, established were PTX-resistant Colon-26 cancer cells (C26/PTX) overexpressing P-gp, which provided IC50 value of PTX solution about 30 times larger than that obtained for control C26 (C26/control) in the in vitro MTT assay. Western blot analysis confirmed P-gp expression in C26/PTX 10 times higher than that in C26/control, indicating that the resistance acquisition of C26/PTX to PTX would be ascribed to the enhanced efflux of PTX by P-gp overexpressed in C26/PTX. However, the in vivo anti-tumor effect of PL-PTX in C26/PTX-bearing mice was similar to that in C26/control-bearing mice. Double immunohistochemical staining of vascular endothelial cells and apoptotic cells within tumor tissues demonstrated that the apoptotic cell death was preferentially observed in vascular endothelial cells in C26/PTX tumors after intravenous administration of PL-PTX, while that was in tumor cells in C26/control tumors. These results suggest that the in vivo anti-tumor effect of PL-PTX in C26/PTX-bearing mice would be ascribed to the cytotoxic action of PTX pumped out of tumor cells by overexpressed P-gp to vascular endothelial cells in tumor tissues.
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PMID:A novel approach to overcome multidrug resistance: utilization of P-gp mediated efflux of paclitaxel to attack neighboring vascular endothelial cells in tumors. 2495 63