Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005684 (bladder cancer)
 16,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A cis-diamminedichloroplatinum (CDDP)-resistant cell line, CL-7/CDDP, has been established by chronic exposure of a parent human bladder cancer cell line, T24 (CL-7), to CDDP at progressively increased concentrations for 20 months. CL-7/CDDP was 2.7-fold more resistant to CDDP than CL-7 as determined by colony formation assay. Biological and biochemical characteristics were examined in CL-7/CDDP to compare with CL-7. There were no differences in doubling time and plating efficiency between the two cell lines, but a small one in the mode of chromosome numbers. Intra-cellular CDDP amounts after CDDP exposure showed no difference between the two cell lines, but CL-7/CDDP showed a higher glutathione (GSH) and metallothionein (MT) level. It is suggested that the mechanism of acquired resistance to CDDP is attributed to intra-cellular detoxication, but not to the efflux. CL-7/CDDP may be useful for elucidation of the mechanism of CDDP resistance in human bladder cancer.
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PMID:[Establishment and characterization of a cis-diamminedichloro platinum-resistant human bladder cancer cell line]. 189 16

The effect of systemic glutathione (GSH) depletion on sensitization of bladder cancer cells to various antineoplastic agents was investigated using murine model, MBT-2. Subcutaneous injection(s) of buthionine sulfoximine (BSO) significantly depleted the GSH content in the tumor and organs. BSO pretreatment produced significant enhancement in the antitumor effect of cyclophosphamide (CY), though it failed to sensitize the tumors to doxorubicin hydrochloride (Adriamycin), cisplatin, mitomycin C, JM-8, methotrexate, vinblastine, and tumor necrosis factor. Mice tolerated cytotoxic agents alone and in combination with BSO except for cisplatin in combination with BSO. A 29 percent (4/14) mortality rate was observed in mice treated with BSO and divided schedule of cisplatin.
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PMID:Effect of systemic glutathione depletion by buthionine sulfoximine on sensitivity of murine bladder cancer to cytotoxic agents. 259 83

Glutathione and its metabolizing enzymes were studied in erythrocytes of cattle suffering from urinary bladder cancer and associated hematuria. The concentration of glutathione (GSH) and GSH peroxidase activity were subnormal in the affected animals, whereas activities of GSH reductase and GSH S-transferase were not altered. Decreased GSH and GSH peroxidase are likely to make erythrocytes of the affected animals more susceptible to oxygen-induced injury and the radiomimetic effect of bracken fern.
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PMID:Erythrocyte glutathione and its metabolizing enzymes in bovine urinary bladder cancer. 281 1

Metallothionein (MT) in tumor cells has been implicated as one of the factors involved in mechanisms of resistance to anti-cancer drugs, including cis-diaminedichroloplatinum (CDDP) and adriamycin (ADM). The relationship between the expression of MT and chemotherapy with anti-cancer drugs was studied in CDDP- and ADM-resistant human bladder cancer cell lines and tissue samples from clinical cases. In drug-resistant cell lines (T-24/ADM, CI-7/CDDP) established in our laboratory, MT expression was studied by immunohistochemistry using the avidin-biotin peroxidase complex (ABC) method and radioimmunoassay (RIA), using anti-MT antibody. In addition, other potential mechanisms of drug resistance, such as P-glycoprotein expression were examined and the levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and glutathione-S-transferase (GST) determined in these cell lines. The results of these investigations demonstrate that the expression of MT in resistant cell lines increased 2.1- and 2.5-fold when compared with parent cell lines (CI-7, T-24). GSH, GSSG and GST levels were unchanged and P-glycoprotein was not over-expressed. A total of 120 tissue samples from 35 clinical cases of bladder cancer, before and after chemotherapy, were stained for MT which was detected in 10 of the 35 cases before chemotherapy. The incidence of MT expression was significantly higher (p < 0.05) in cases with lower pathological tumor grades.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Over-expression of metallothionein and drug-resistance in bladder cancer. 762 49

This study describes characteristics of a human bladder cancer cell line, SCaBER/R, selected for resistance to a mitomycin C (MMC) analogue BMY 25067. The SCaBER/R cell line was isolated by repeated 24 h exposures of the parental cells to 0.09 microM BMY 25067 (IC90, 24 h drug exposure) over a period of about 180 days. Approximately 2.2-fold higher concentration of BMY 25067 was required to kill 50% of the SCaBER/R cell line compared with parental cells (p < 0.001). The IC20 and IC90 values for BMY 25067 were also significantly higher in the SCaBER/R cell line than in SCaBER. Unlike most MMC resistant cell lines, the SCaBER/R cell line displayed a marked cross-resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and lacked cross-resistance to cisplatin, doxorubicin or VP-16. The SCaBER/R cell line also displayed a marked cross-resistance to the parent drug (MMC) and BMY 25282, another analogue of MMC. NADPH cytochrome P450 reductase activity, an enzyme implicated in bio-reductive activation of MMC, did not differ significantly in these cells. DT-diaphorase activity, another MMC activation enzyme, was significantly lower in the SCaBER/R cell line when compared to the SCaBER cells. These results suggest that relatively lower sensitivity of SCaBER/R cell line to MMC and BMY 25067 may result from impaired drug activation. Cellular levels of glutathione (GSH) and GSH-transferase (GST), which have been suggested to affect the cytotoxicity of MMC, were comparable in SCaBER and SCaBER/R cell lines. BMY 25067 induced DNA interstrand cross-links (DNA-ISC) could not be detected in either of the cell lines even at drug concentrations which produced a significant cell kill. These findings suggest that (a) cellular resistance to BMY 25067 in the SCaBER/R cell line may be due to impaired drug activation, and (b) the nature of the cytotoxic produced by BMY 25067 may be different from that of MMC.
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PMID:Characterization of a human bladder cancer cell line selected for resistance to BMY 25067, a novel analogue of mitomycin C. 765 43

This study was undertaken to elucidate the mechanism(s) of cross-resistance to cisplatin (CDDP) in a mitomycin C (MMC)-resistant human bladder cancer cell line, J82/MMC. The J82/MMC cell line displayed 2- to 3-fold cross-resistance to CDDP and carboplatin when compared to the parental J82/WT cells. Drug uptake studies revealed that cross-resistance to CDDP in the J82/MMC cell line was independent of reduced platinum accumulation. The J82/MMC cell line exhibited approximately a 1.5-fold resistance to cadmium chloride, an indicator for increased metallothionein (MT) content, when compared to the J82/WT cells. Northern blot analysis showed a 2.7-fold higher level of MT-IIA mRNA in the J82/MMC cell line compared with J82/WT. We have reported previously that, whereas glutathione (GSH) level is comparable in these cells, GSH transferase (GST) activity is significantly higher in the J82/MMC cell line compared with J82/WT. Results of the present study showed that the elevated GST activity in the J82/MMC cell line was due to an over-expression of pi-type GST protein. Although buthionine-S,R-sulfoximine (BSO)-induced GSH depletion significantly enhanced CDDP cytotoxicity in both cell lines, the magnitude of potentiation was markedly higher in J82/MMC cells (about 2.1-fold) relative to J82/WT (about 1.6-fold). Our results suggest that cross-resistance to CDDP in the J82/MMC cell line may be due to alterations in cellular thiols.
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PMID:Mechanism of cross-resistance to cisplatin in a mitomycin C-resistant human bladder cancer cell line. 772 58

This study describes characteristics of a human bladder cancer cell line J82/MMC that is 6-fold more resistant to mitomycin C (MMC) than the parental cells. The J82/MMC subline was isolated by repeated continuous exposures of the J82/WT cells to increasing concentrations of MMC. The J82/MMC cell line showed (1) collateral sensitivity to taxol, 5-FU and topoisomerase II inhibitors; and (2) cross-resistance to cisplatin, melphalan and MMC analogues BMY 25282 and BMY 25067. Levels of two key MMC activation enzymes, NADPH cytochrome P450 reductase and DT-diaphorase, were significantly lower in J82/MMC cells compared with J82/WT, suggesting that lower sensitivity of J82/MMC cells to MMC may result from deficient drug activation. Further support is indicated by: 1) reduction in the differential in toxicity between the 2 cell lines by BMY 25282; and 2) a higher effect of DT-diaphorase inhibitor dicumarol on the wild-type cells compared with J82/MMC. Although glutathione (GSH) levels did not differ in these cells, a small but significant increase in GSH transferase (GST) activity was noticed in J82/MMC cells. GST inhibitor ethacrynic acid significantly enhanced MMC cytotoxicity in the J82/MMC cell line. A small but significant increase in the level of anti-oxidative enzyme catalase, but not GSH peroxidase, was also observed in J82/MMC cell line compared with J82/WT. Thus, the possibility that relatively lower sensitivity of J82/MMC cells to MMC may result from reduced oxygen radical generation cannot be ruled out. MMC-induced DNA interstrand cross-linking was markedly lower in the J82/MMC cell line compared with J82/WT. Our results suggest that the MMC resistance in the J82/MMC cell line may be multifactorial.
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PMID:Characterization of a human bladder cancer cell line selected for resistance to mitomycin C. 807 54

In this study, we have examined the relationship between sensitivity to mitomycin C (MMC) and glutathione (GSH) and glutathione transferase (GST) levels using a panel of three unrelated human bladder cancer cell lines. J82, HT-1197, and SCaBER. Cell lines HT-1197 and SCaBER were about 2- and 4.5-fold more resistant to MMC as compared to J82. Although the GSH level did not differ significantly in these cell lines, GST activity in HT-1197 and SCaBER cells were higher by about 2.3- and 6.0-fold, respectively, as compared to J82. Similar to GST activity, GST pi content was highest in the most insensitive cell line and lowest in J82 cells. The cytotoxicity of MMC was increased significantly in these cells by a 1-h pretreatment with a nontoxic concentration of ethacrynic acid (EA), an inhibitor of GST activity. EA pretreatment resulted in a marked GSH depletion as well as GST activity inhibition in both of these cells. Although pretreatment of J82 and SCaBER cells with a nontoxic concentration of D,L-buthionine-S,R-sulfoximine (BSO) caused similar GSH depletion, the cytotoxicity of MMC was enhanced only in SCaBER cells. The differential effect of BSO on MMC cytotoxicity in these cell lines appeared to be due to the differences in the extent of GSH regeneration after removal of BSO. While a marked GSH regeneration occurred in J82 cells within 1 h after BSO removal, such an effect was not observed in SCaBER cells. Combined treatment of these cells with BSO and EA produced a greater potentiation of MMC cytotoxicity in both the cell lines when compared to BSO or EA treatment alone. We conclude that GSH/GST levels may affect the sensitivity of human bladder cancer cells to MMC.
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PMID:Mitomycin C sensitivity in human bladder cancer cells: possible role of glutathione and glutathione transferase in resistance. 831 48

This study describes characteristics of a mitomycin C (MMC)-resistant human bladder cancer cell line, J82/MMC-2, which was established by repeated in vitro exposures of a 6-fold MMC-resistant variant (J82/MMC) to 18 nM MMC. A 9.6-fold higher concentration of MMC was required to kill 50% of the J82/MMC-2 sub-line compared with parental cells (J82/WT). NADPH cytochrome P450 reductase and DT-diaphorase activities were significantly lower in J82/MMC-2 cells compared with J82/WT, suggesting that reduced sensitivity of J82/MMC-2 cells to MMC resulted from impaired drug activation. Consistent with this hypothesis, the formation of MMC-alkylating metabolites was significantly lower in J82/MMC-2 cells compared with J82/WT. Furthermore, DT-diaphorase activity in J82/MMC-2 cells was significantly lower compared with the 6-fold MMC-resistant variant. Glutathione (GSH) levels were comparable in all 3 cell lines. Although GSH transferase (GST) activity was significantly higher in the J82/MMC-2 cells compared with J82/WT, this enzyme activity did not differ between 6- and 9.6-fold MMC-resistant variants. Whereas DNA polymerase alpha mRNA expression was comparable in these cell lines, levels of DNA ligase I mRNA were slightly lower in both MMC-resistant variants relative to J82/WT. However, the DNA polymerase beta mRNA level was markedly higher in the J82/MMC-2 cell line compared with either J82/WT or J82/MMC. Thus, emergence of a higher level of resistance to MMC in J82/MMC-2 cells compared with J82/MMC may be attributed to (i) impaired drug activation through further reduction in DT-diaphorase activity and (ii) enhanced DNA repair through over-expression of DNA polymerase beta.
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PMID:Biochemical characterization of a mitomycin C-resistant human bladder cancer cell line. 863 3

In contrast to most other types of cancer, metastatic testicular germ cell tumours (TGCT) are cured in most patients using cisplatin-based combination chemotherapy. The biochemical mechanisms underlying this sensitivity have not been defined. Drug detoxification can modulate response to chemotherapy in vivo and in vitro, and therefore we measured levels of glutathione (GSH), glutathione-S-transferase (GST) and both constitutive and cisplatin- and dexamethasone-induced levels of metallothionein (MT) in five human testis tumour cell lines. The levels were compared with those in five human bladder cancer cell lines and two cell lines with cisplatin resistance acquired in vitro. GSH levels were relatively low in the testis tumour cell lines, as might be expected in drug-sensitive cells, and there was a 77-fold increase in GSH levels in the cisplatin-resistant testis tumour cell line. GST levels were similar in the two cell types, while metallothionein levels were relatively high in the testis tumour cell lines. These data indicate that GSH may contribute to the sensitivity of TGCT to chemotherapy, and that GSH expression may be involved in the acquisition of cisplatin resistance in these tumours.
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PMID:Sensitivity of testis tumour cells to chemotherapeutic drugs: role of detoxifying pathways. 875 61


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