Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of the protooncogene encoded proteins (c-erbB1, c-erb B2, c-myc, c-fos) and the suppressor gene product p53 was analyzed in 81 human squamous cell carcinomas of the lung and correlated with clinical parameters of the patients (patient survival, presence of metastases and tumor stage) and with biological characteristics of the tumors (tumor growth in nude mice, DNA-ploidy, proliferative activity, drug-resistance and P-glycoprotein or gluathione S-transferase expression). By means of immunohistochemistry, expression of c-erbB1 oncoprotein (EGF-receptor) was detected in 79% of the tumors, c-erbB2 (c-neu) proteins in 35%, c-myc proteins in 48%, c-fos proteins in 41%, and p53 in 43% of the tumors. Patients with c-erbB1 positive tumors had a poor prognosis (p = 0.021). In addition, these tumors were more frequently drug resistant (p = 0.0067). A significant correlation between the growth of the squamous lung carcinomas in nude mice and c-fos oncoprotein expression was demonstrated (p = 0.017). Therefore, EGF-receptor and c-fos products may serve as prognostic factors for the aggressiveness of squamous cell carcinomas of the lung and for the response of these tumors to chemotherapy. No significant correlation was found between the expression of the c-erbB1 or c-fos gene products and stage, metastasis and DNA-ploidy. In contrast to these results, no relationship was found between c-neu or c-myc gene products expression and any of the clinical or biological parameters examined. Aneuploid squamous cell carcinomas of the lung expressed p53 more frequently than diploid tumors (p = 0.027). However, there was no significant difference between p53 expression and stage, survival of patients, metastasis, growth of the tumors in nude mice, proliferative activity and drug-resistance of the tumors.
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PMID:Oncoprotein (c-myc, c-erbB1, c-erbB2, c-fos) and suppressor gene product (p53) expression in squamous cell carcinomas of the lung. Clinical and biological correlations. 134 20

PANC02 is a ductal adenocarcinoma of the pancreas that is resistant to every known class of clinically active antitumor agent. To study the mechanism(s) underlying the intrinsic drug resistance of this tumor, a mammary adenocarcinoma (CA-755) that also grows in C57/BL mice and is known to be drug sensitive was used for comparison. PANC02 resistance and CA-755 sensitivity to several antitumor agents and to X-ray therapy was confirmed in mice, and PANC02 also demonstrated relative resistance in tissue culture. Relative to Chinese hamster ovary (CHO) and CA-755 cells, PANC02 did not appear to show a higher rate of mutation to drug resistance in culture as based on the 6-thioguanine resistance marker. Although P-glycoprotein characteristic of the multidrug resistance (MDR) phenomenon could be demonstrated at the mRNA level using a sensitive RNAse protection assay, the level of expression found was several orders of magnitude lower than that observed in phenotypic MDR cell lines. Furthermore, quinidine failed to increase the sensitivity of PANC02 cells to Adriamycin under conditions that clearly potentiated the toxicity of the drug to a CHO cell line exhibiting classic MDR traits. The heterogeneity in the distribution of drugs was inferred as being significantly greater in PANC02 versus CA-755 cells in vivo as based on measurements of within-animal, within-tumor variance in the distribution of the marker compounds inulin and antipyrine. Although it may not be the only mechanism involved, this greater intratumor heterogeneity in drug distribution could theoretically play a major role in the intrinsic drug resistance of PANC02 in vivo.
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PMID:Intrinsic resistance to anticancer agents in the murine pancreatic adenocarcinoma PANC02. 134 74

Upon exposure to chemotherapeutic drugs, mammalian cells can acquire resistance to structurally and functionally unrelated compounds, a property known as multidrug resistance (MDR). One MDR mechanism, i.e. by the overexpression of a plasma membrane protein, P-glycoprotein (P-gp), has been identified at the molecular level. The mdr1 gene-encoded P-gp acts as a drug efflux pump, lowering intracellular drug concentration by active extrusion of drugs from the cell. The role of P-gp in determining clinical resistance to multiple anticancer drugs is likely to be largely different for various tumor types. Recently we selected a monoclonal antibody (mAb LRP56) for strong, granular cytoplasmic reactivity with MDR tumor cell lines without P-gp (over)expression. None or weak reactivity was observed with parental and P-gp positive cell lines. We hypothesize that as yet-undefined drug transport-mediating proteins are inserted in intracellular membranes lining the exocytotic compartment and thus may contribute to clinical multidrug resistance.
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PMID:Drug-transporter proteins in clinical multidrug resistance. 134 70

To investigate the possible role of the multidrug resistance phenotype to chemoresistance in human ovarian carcinoma, we have analyzed human multidrug resistance gene (mdr 1) expression in 8 human ovarian adenocarcinoma cell lines. An increase in P-glycoprotein level specific to multidrug-resistant tumor cells was not apparently associated with the increase in resistance to vincristine (VCR) or doxorubicin (Adriamycin). Mdr 1 transcripts (4.5 kilobases) were observed in the RNA preparation obtained from only one cell line (SHIN-3) that showed the highest resistance to both drugs in vitro and in vivo. No cell lines showed mdr 1 DNA amplification. These results suggest that the insensitivity of human ovarian carcinoma to chemotherapy could be partly explained by the expression of mdr 1.
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PMID:Expression of a human multidrug resistance gene in human ovarian carcinoma cell lines. 134 3

Disease-oriented panels of human tumor cell lines used by the National Cancer Institute for large-scale in vitro anticancer drug screening were evaluated for multidrug-resistant phenotype at the functional (in vitro drug sensitivity) and molecular levels. The cell line panels manifested a broad range of sensitivities to drugs typically associated with multidrug resistance (MDR) as well as to drugs not associated with MDR. Individual cell lines displayed unique and characteristic profiles of response. Patterns of correlated response were observed among, but not between, MDR and non-MDR drugs. Strong evidence of correlated response was limited to drugs sharing an intracellular mechanism of action. Several tumor cell lines exhibited a high degree of resistance to MDR drugs and relative sensitivity to non-MDR drugs, contained high levels of MDR-1 mRNA, and expressed cell surface P-glycoprotein detectable with one or more monoclonal antibodies. Parallel expression of all of these features representing the classic MDR phenotype was observed among members of the colon and renal tumor panels. Certain individual cell lines among other panels (lung, ovarian, melanoma, and central nervous system) also manifested some aspects of the MDR phenotype to various extents. Identification of MDR cell lines used for large-scale in vitro anticancer drug screening will facilitate interpretation of data in a way which may allow identification of new drug leads of potential value in treatment of MDR tumor cell populations.
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PMID:Multidrug-resistant phenotype of disease-oriented panels of human tumor cell lines used for anticancer drug screening. 135 May 7

P-glycoprotein plays a key role in multidrug resistance of tumor cells. In order to elucidate the possible quarternary structure/function relationship of P-glycoprotein, we treated multidrug-resistant human leukemia K562/ADM cells with the crosslinking reagent, disuccinimidyl suberate. In addition to 180K P-glycoprotein, a 340K protein was immunoprecipitated with an anti-P-glycoprotein monoclonal antibody, MRK-16. The 340K protein is most probably a dimeric P-glycoprotein, since only the 180K P-glycoprotein was immunoprecipitated with MRK-16 when K562/ADM cells were treated with the cleavable crosslinking reagent, dithiobis(succinimidylpropionate), and analysed under reduced conditions. The dimeric P-glycoprotein was photolabeled with [3H]azidopine like the 180K monomeric P-glycoprotein and the photolabeling was inhibited by excess amount of vincristine and verapamil. The dimeric P-glycoprotein could be a functionally active form of the protein involved in the transport of antitumor agents.
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PMID:Functionally active homodimer of P-glycoprotein in multidrug-resistant tumor cells. 135 Sep 3

K1 is a murine monoclonal antibody (MAb) derived from a hybridoma generated by the fusion of splenocytes of BALB/c mice immunized with a human ovarian tumor cell line, OVCAR-3. This antibody reacts strongly with epithelial ovarian tumors and mesotheliomas. The antigen recognized by MAb K1, designated CAK1, has recently been characterized as a 40-kDa protein probably anchored to the cell surface by glycosyl-phosphatidylinositol. Using immunoperoxidase histochemical methods, we examined 37 squamous-cell carcinoma (SqCC) samples from cervix, lung, esophagus and other origins, and 12 normal squamous epithelia of the cervix and esophagus for their reactivity with MAb K1. Of the SqCC specimens, 81% showed K1 reactivity with variable intensity, but none of 12 normal tissue samples of squamous epithelia did so. Two patterns of CAK1 expression in tumor samples were found, i.e., a heterogeneous pattern with strong intensity, and a homogeneous pattern with weak intensity. Three carcinomas in situ of the larynx, vulva and esophagus were moderately positive with K1, suggesting that CAK1 antigen may occur in the early stage of carcinogenesis of SqCC. The expression of CAK1 was also compared with expression of CA125, HER-2/neu, p53 and P-glycoprotein, and MAb K1 was found to react most consistently with SqCC. Since K1 reacts with a majority of cervical and esophageal carcinomas but has no detectable reactivity in normal epithelia of the cervix uteri and esophagus, MAb K1 could be of value as a reagent to help distinguish between normal and neoplastic cells on sections as well as in cytological samples.
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PMID:Frequent expression of the tumor antigen CAK1 in squamous-cell carcinomas. 135 Oct 45

The apical surface of the proximal tubular epithelium is the site of both P-glycoprotein localization and postulated active secretion of organic cations in the mammalian kidney. P-glycoprotein has been shown to act as a pleiotropic drug efflux pump across the cell membrane of tumor cells expressing the multidrug resistance phenotype, whereas the renal organic anion and organic cation secretory systems serve the function of pleiotropic drug transport across the proximal tubule epithelium. Because most known substrates for P-glycoprotein are organic cations, we tested the hypothesis that the physiological function of this protein in the kidney is to mediate renal organic cation secretion. In one approach, we compared the postnatal development of organic cation transport with that of kidney mdr gene expression. Cimetidine-sensitive uptake of classical substrates for renal secretion (N-methyl nicotinamide and tetraethylammonium) into kidney slices developed gradually in neonate mice, reaching adult capacity in 4 to 6 weeks. P-glycoprotein and its mRNA, as estimated by immunohistochemical methods and RNAse protection analysis, were undetectable at birth and were expressed abruptly at the adult level between 2 and 3 weeks of age. In another approach, classical inhibitors of renal organic cation secretion (cimetidine and cyanine 863) failed to reverse resistance to adriamycin in Chinese hamster ovary and P388 cell lines, which possess the phenotypic traits of multidrug resistance. These results suggest that the cimetidine-sensitive component of organic cation secretion is mediated by a protein other than the P-glycoprotein in the mammalian kidney.
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PMID:Postnatal development of organic cation transport and mdr gene expression in mouse kidney. 135 Oct 97

Small cell lung cancer (SCLC) is one of the most sensitive tumors to drug therapy; however, the majority of patients eventually relapse within a few years. Emergence of drug resistance is thought to play a major role in the dismal course of this disease. However, the mechanism of drug resistance in SCLC still remains obscure. Based on the clinical observation that a significant proportion of patients with relapsing tumor show an elevated serum carcinoembryonic antigen (CEA) concentration while serum neuron-specific enolase (NSE) concentration remains normal, we attempted to determine whether the tissue of CEA is indicative of a clonal change in SCLC, in contrast with the tissue expression of NSE and P-glycoprotein (P-gp). We examined 22 SCLC patients with tumor specimens available both at diagnosis and at relapse. Of the 22 patients, two had CEA expression at diagnosis, and a further three patients showed CEA expression at relapse. It is of note that there were two patients whose tumors expressed NSE alone at diagnosis but expressed CEA alone at relapse. Serum CEA concentration was concordant with the tissue expression of CEA; however, serum NSE concentration was not concordant with the tissue expression of NSE. Tumors with CEA expression at relapse were generally resistant to salvage chemotherapy, while there was no close relationship between the tissue expression of P-gp and refractoriness to drugs at relapse. These findings indicate that the tissue expression of CEA in SCLC is a marker of a clonal change during chemotherapy, and such a clonal change would play a role in the emergence of drug resistance in SCLC.
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PMID:[Immunohistochemical detection of carcinoembryonic antigen and P-glycoprotein in small cell lung cancer at diagnosis and relapse, with special reference to the tissue expression of CEA and response to chemotherapy]. 135 Nov 8

We have developed a mouse-human chimeric antibody MH171, in which the antigen-recognizing variable regions of the mouse monoclonal antibody MRK17 are joined with the constant regions of human IgG1 antibodies. The MRK17 recognizes specifically the multidrug transporter P-glycoprotein and inhibits the growth of human multidrug resistant (MDR) tumor cells in vitro and in the xenograft nude mouse model system. The established chimeric MH171 antibody forms an apparently intact IgG composed of heavy and light chains covalently assembled via disulfide bonds in sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis and is specific to MDR cell lines with a similar affinity to the original mouse MRK17. MH171 also displays strong antibody-dependent cell-mediated cytotoxicity to the target cells in vitro, when human mononuclear cells are used as effector cells. The chimeric antibody against P-glycoprotein, MH171, should be a useful agent in the treatment of human drug-resistant tumors.
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PMID:Mouse-human chimeric antibody MH171 against the multidrug transporter P-glycoprotein. 135 81


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