Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal cell carcinoma (RCC) displays strong resistance against many chemotherapeutic drugs. Overexpression of P-glycoprotein (Pgp) appears to be part of this resistance. The involvement of another resistance mechanism, involving the decreased activity of DNA topoisomerase II (topoII), remains uncertain. By culturing the human RCC lines RC2 and RC21 in the presence of increasing concentrations of etoposide, we derived the variant sublines RC2E, RC21A and RC21E, that had acquired approximately 30-, 60- and 90-fold resistance to this drug respectively. RC2E, RC21A and RC21E were approximately 50-, 5- and 400-fold cross-resistant to doxorubicin respectively. RC2E and RC21E also showed cross-resistance (approximately 200- and 3500-fold respectively) to vinblastine. Quantitative differences in MDR1 and Pgp expression (elevated in RC2E and RC21E) and topoII alpha (reduced in RC21E and RC21A) were demonstrated using Western blotting and the reverse transcriptase/polymerase chain reaction. Decreased amounts of topoII alpha were reflected in a reduced activity of RC21A and RC21E as measured by unknotting phage P4 DNA. Qualitative changes of the topoII alpha gene, such as point mutations in the motif B/DNBS and DNA-binding regions, or differences in methylation status of the promoter gene of RC21E, were not found. These cell lines represent a model of a solid tumor in which overexpression of Pgp, a combination of increased Pgp and decreased topoII alpha, and a decrease of topoII alpha are represented.
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PMID:Decreased levels of topoisomerase II alpha in human renal cell carcinoma lines resistant to etoposide. 939 88

Granzyme B is a protein thought to play a pivotal role in the cytolytic functions of T cells. In view of this, the inducibility of this gene in freshly isolated T cells (T-TILs) infiltrating human renal cell carcinoma (RCC) in vitro was examined by using the reverse transcriptase-polymerase chain reaction (RT-PCR). A reduction in granzyme B messenger RNA (mRNA) expression in stimulated T-TILs from five of nine patients with RCC compared with autologous peripheral blood T cells was noted. The reduced expression was observed after multiple stimuli including anti-CD3 antibody, interleukin-2 (IL-2), and phytohemagglutinin (PHA). Because CD8+ T cells represent the predominant cytotoxic population, the ability of this cell population to express granzyme B mRNA after stimulation also was examined. When compared with CD8+ peripheral blood lymphocytes (T-PBLs) from patients with RCC and normal donors, the induction of granzyme B mRNA was reduced in CD8+ T-TILs. CD8+ T-TILs also had lower non-major histocompatibility complex (MHC)-restricted cytotoxic activity than did CD8+ T-PBLs against both Daudi cells and allogeneic RCC cell lines. These results show that in a subset of patients with RCC, depressed lytic activity of CD8+ TILs compared with CD8+ PBLs is present. Reduced granzyme B mRNA expression also was noted in selected patients.
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PMID:Defective granzyme B gene expression and lytic response in T lymphocytes infiltrating human renal cell carcinoma. 940 54

Renal cell carcinoma (RCC) is a solid tumour of the kidney and is the most common renal neoplasm. Despite the presence of tumour infiltrating lymphocytes (TIL) in RCC, these tumours continue to progress in vivo suggesting a poor host immune response to the tumour, and the suppression of TIL effector function. Cytokines are key molecules that modulate the function of T cells. The possibility is investigated that the local production of cytokines in RCC contributes to immunosuppression of TIL. The expression of pro-inflammatory (IFN-gamma/IL-2) and immunosuppressive (IL-10/TGF-beta) cytokine mRNA transcripts was determined in RCC, normal kidney and peripheral blood of RCC patients using a semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) with cytokine-specific primers. Following Southern blot hybridization of the PCR products with internal radiolabelled oligonucleotide probes, cytokine transcript levels were measured by densitometry and expressed relative to the glyceraldehyde-3-phosphate dehydrogenase densitometry score. With the exception of IL-10, there were no differences in expression of cytokine mRNA transcripts between the peripheral blood of patients and normal healthy individuals. It was found that TGF-beta transcripts were well represented in normal kidney and RCC. In contrast, the expression of IFN-gamma transcripts, while low in the majority of samples, was significantly increased in RCC when compared to normal kidney (P=0.05). The IL-2 and IL-10 transcripts showed a more variable expression in normal kidney and RCC, with no significant differences in expression between the sample groups. The data demonstrating pro-inflammatory and immunosuppressive cytokine expression in RCC do not support a prominent immunosuppressive cytokine profile in these tumours.
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PMID:Expression of cytokine mRNA transcripts in renal cell carcinoma. 972 77

Degradation of the extracellular matrix is necessary for invasion and metastasis by cancer cells. Two gelatinolytic matrix metalloproteinase enzymes, MMP-2 and MMP-9, are supposed to be key enzymes in this process. The purpose of this study was to correlate the presence of MMP-2, MMP-9 and their inhibitors with the tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 RNA using reverse transcriptase PCR technique with tumor stage in 17 samples of renal cell carcinoma. The ratio of tissues expressing MMP-2 and MMP-9 to those expressing TIMP-1 and TIMP-2 was defined to be 1 in normal kidney tissue. This MMP:TIMP ratio was significantly increased to 2.43 (standard deviation, SD = 0.8) in locally confined renal cell carcinoma and to 4.86 (SD = 1.1) in advanced carcinoma (p <0.01). In primary tumor cell lines the ratio of MMP:TIMP expression was 3.44 (SD = 0.6). These data suggest that the balance of MMP-2 and MMP-9 to TIMP-1 and TIMP-2 expression is an essential factor in the aggressiveness of renal cell carcinoma.
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PMID:Expression of metalloproteinase 2 and 9 and their inhibitors in renal cell carcinoma. 978 85

Renal cell carcinoma (RCC) is the most common renal neoplasm. Despite being infiltrated by tumour infiltrating lymphocytes (TIL), these TIL are unable to control tumour growth in vivo, suggesting that the cytotoxic capacity of TIL against RCC is impaired, or that the tumour cells are resistant to killing and therefore escape detection by the immune system. It is postulated that the expression of apoptotic regulatory molecules in RCC favours tumour cell survival. The present study has therefore determined the expression of Fas (APO-1/CD95), Fas ligand (Fas L) and bcl-2 in these tumours. The expression of Fas, Fas L and bcl-2 mRNA transcripts was determined in RCC, normal kidney and peripheral blood by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), following RNA extraction and cDNA synthesis from tissues and cell samples. Transcript levels were measured by densitometry after Southern blot hybridization of PCR products with internal radio-labelled oligonucleotide probes; a densitometry score was assigned to each hybridizing DNA band and expressed as a ratio of the glyceraldehyde-3-phosphate dehydrogenase content. In peripheral blood, the expression of Fas L and bcl-2 transcripts was similar between patients and normal healthy individuals; however, Fas transcript expression was significantly down-regulated in the patients' versus normal peripheral blood (P = 0.026). Most interestingly, significantly up-regulated Fas L expression was observed in RCC compared to normal kidney (P = 0.041). In contrast, bcl-2 transcripts were well represented in normal kidney but markedly decreased in RCC (P = 0.021). The expression of Fas transcripts in normal kidney and RCC was variable. These data demonstrate elevated expression of Fas L transcripts in RCC, but the functional relevance of this remains to be investigated.
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PMID:Expression of apoptotic regulatory molecules in renal cell carcinoma: elevated expression of Fas ligand. 1010 81

Renal cell cancer is the main malignant tumour of the kidney and has an increasing incidence. This type of tumour has a poor prognosis and shows intrinsic resistance to several anti-cancer drugs. The CYP3A P450 family, which consists of three closely related forms, is involved in the oxidative activation and deactivation of a variety of carcinogens and several anti-cancer drugs. In this study the presence and cellular localization of CYP3A has been investigated using a combination of immunohistochemistry, immunoblotting and reverse transcriptase polymerase chain reaction (RT-PCR) in renal cell cancer and corresponding normal kidney. CYP3A was consistently expressed in both renal call cancer and in normal kidney. In renal cell cancer, CYP3A was localized to tumour cells and in normal kidney the predominant cellular localization of CYP3A was to proximal tubular epithelial cells. RT-PCR showed that both CYP3A5 mRNA and CYP3A7 mRNA were consistently present in both tumour and normal samples, while CYP3A4 mRNA was present in 65% of tumours and 90% of normal samples. This study indicates that individual members of the CYP3A family are expressed in renal cell cancer. The presence of CYP3A in renal cell cancer might be important in the metabolic potentiation as well as the detoxification of chemotherapeutic agents used to renal cancer.
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PMID:Cytochrome P450 CYP3A in human renal cell cancer. 1020 1

We have developed a highly sensitive technique to detect circulating renal cell carcinoma (RCC) cells in the blood using the reverse transcriptase-polymerase chain reaction (RT-PCR) with primers specific for the MN/CA9 gene. RT-PCR analysis of RCC specimens resulted in the clear detection of MN/CA9 mRNA signal in 93%. In contrast, no expression of MN/CA9 was observed in normal kidney specimens. Highly sensitive RT-PCR analysis of blood samples from RCC patients revealed the presence of circulating MN-positive cancer cells in the blood. Fifty samples obtained from the patients with RCC and 31 samples from healthy donors were investigated. The sensitivity and specificity of this RT-PCR analysis were 72% and 78%, respectively. These findings suggest that the MN antigen may be a potential diagnostic biomarker for early detection of RCC.
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PMID:[Molecular detection of circulating cancer cells in patients with renal cell carcinoma]. 1050 Sep 65

The monoclonal antibody G250 (mAbG250) raised against a human renal cell carcinoma (RCC) has been shown to react with a large number of RCCs. Recently, G250 antigen was isolated and found to be homologous to the MN/CA9 gene originally identified in HeLa cells. To determine whether G250 antigen (MN/CA IX/G250) could be a potential therapeutic target and a tumour marker, a total of 147 cases of RCC were investigated immunohistochemically as well as by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. In addition, total RNAs extracted from patients' peripheral blood samples were analysed for MN/CA9/G250 mRNA signals. Immunohistochemistry demonstrated strong expression in 128/147 (87.1%) of RCCs, in contrast to the lack of expression observed in normal tissues. RT-PCR analyses of frozen specimens resulted in the clear detection of MN/CA9/G250 mRNA signals in 137/147 (93.2%), and despite subtle differences the results were almost identical to those for immunohistochemistry. Although high-grade and -stage tumours exhibited significantly lower expression than low-grade and -stage tumours, a large proportion of tumours expressed MN/G250 protein as well as mRNA. RT-PCR analysis of patients' blood samples revealed the presence of circulating MN/CA9/G250 expressing cells. These findings suggest that this antigen may be a potential therapeutic target as well as diagnostic marker for RCCs.
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PMID:MN/CA IX/G250 as a potential target for immunotherapy of renal cell carcinomas. 1057 65

Activated cytolytic effector cells like lymphokine-activated killer (LAK) and the recently described bacillus-Calmette-Guerin-activated killer (BAK) cells are thought to mediate antitumor effects against metastatic renal cell carcinoma (RCC) and superficial bladder cancer respectively. Perforin and Fas ligand (FasL) have been described as the major lytic principles in cellular cytotoxicity. Using a radioactive-release assay and specific inhibitors, we investigated the molecular mechanisms used by LAK and BAK cells in the lysis of renal carcinoma cells. In addition, we evaluated the susceptibility of RCC cells to FasL-mediated cytotoxicity. LAK and BAK cells effectively lysed the renal cancer cell line SK-RC-35 upon cell-cell contact. Both effector cell populations were shown to produce perforin and FasL as determined by reverse transcriptase/polymerase chain reaction (RT-PCR). Using fluorescence-activated cell sorting analyses and RT-PCR, we detected a marked Fas receptor (Fas, CD95) expression on RCC cells. However, RCC cells were shown to be resistant to killing by recombinant FasL and lysis by BAK and LAK cells was not inhibited in the presence of anti-FasL antibody. In contrast, the cytotoxicity exerted by LAK and BAK cells was drastically reduced in the presence of the Ca2+-chelating agent EGTA as well as concanamycin A, a specific inhibitor of perforin-mediated lysis. These results demonstrate that cytolysis of FasL-resistant RCC cells by activated immune cells is mediated via perforin. Our findings give further insights into the molecular mechanisms involved in the elimination of RCC by cytotoxic lymphocytes activated with biological response modifiers.
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PMID:Killing of Fas ligand-resistant renal carcioma cells by interleukin-2- and BCG-activated effector cells. 1099 63

We compared the effects of paclitaxel (Taxol) in human renal cell carcinoma (RCC) of different histologic types. The growth inhibitory effects of paclitaxel on 34 human RCC cell lines of strictly defined different histologic types were determined by 3-[4,5-dimethylthiazolyl]-2,5-diphenyltetrazoliumbromide (MTT) assays. Paclitaxel-induced morphologic alterations were visualized by light and immunofluorescence and by transmission electron microscopy. The expression and function of P-glycoprotein and multidrug resistance-associated protein (MRP) were defined by reverse transcriptase polymerase chain reaction and fluorescence-activated cell sorting (FACS) analysis, respectively. Modulation of P-glycoprotein function was performed by verapamil or Cremophor EL. A significant (p < 0.05) dose-dependent paclitaxel-induced growth inhibition could be demonstrated in all cell lines, with the effects of paclitaxel dissolved in Cremophor EL/ethanol (= Taxol) exceeding the effects of paclitaxel dissolved in dimethyl sulfoxide. The extent of response markedly varied between the different cell lines, although chromophilic RCCs exhibited a more pronounced response to Taxol (IC50: 0.03-0.38 microM) than clear cell RCCs (IC50: 0.01-36.69 microM). Exposure to paclitaxel/Taxol induced an increase of microtubule bundles in the clear cell and the chromophobe RCCs but not in the chromophilic RCCs. The expression of the MRP was low in RCC cell lines and was not found to be related to paclitaxel/Taxol sensitivity. In contrast, the expression level of P-glycoprotein was much more pronounced and showed a positive correlation (p < 0.05) with the response to paclitaxel. Reversal of P-glycoprotein function by verapamil or Cremophor EL enhanced the growth inhibitory effects of paclitaxel and further supported the role of P-glycoprotein for paclitaxel sensitivity of human RCCs. Paclitaxel/Taxol effectively inhibits proliferation of human RCCs in vitro, irrespective of their histologic types. Moreover, expression and function of P-glycoprotein markedly contribute to paclitaxel responsiveness, although other as yet undefined drug resistance mechanisms are effective in human RCCs as well.
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PMID:Multidrug resistance phenotype and paclitaxel (Taxol) sensitivity in human renal carcinoma cell lines of different histologic types. 1103 69


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