Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cisplatin-resistant KCP-4 cells were 12.4- and 31.6-fold more resistant to CPT-11 and SN-38 than parental KB-3-1 cells, respectively. We studied the mechanism of cross-resistance to CPT-11 and SN-38. Our previous study showed that multidrug resistance protein (MRP), canalicular multispecific organic anion transporter (cMOAT) and P-glycoprotein (P-gp) were not expressed in KCP-4 cells (Chen, Z.-S. et al., Exp. Cell Res., 240 (1998) 312-320, and Chuman, Y. et al., Biochem. Biophys. Res. Commun., 226 (1996) 158-165). The accumulation of both CPT-11 and SN-38 in KCP-4 cells was lower than that in KB-3-1 cells. The ATP-dependent efflux of CPT-11 and SN-38 from KCP-4 cells was enhanced compared with that from KB-3-1 cells. DNA topoisomerase (topo) I expression, topo I activity, topo I-mediated cleavable complex, and the sensitivity to SN-38 of DNA topo I in KCP-4 were similar to those in KB-3-1 cells. Furthermore, the conversion of CPT-11 to SN-38 in the two cell lines was also similar. The transport of LTC4 in KCP-4 membrane vesicles was competitively inhibited by bis-(glutathionato)-platinum (II) (GS-Pt), CPT-11 and SN-38. These findings suggested that an unknown transporter distinct from P-gp, MRP or cMOAT is expressed in KCP-4 cells and transports CPT-11 and SN-38.
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PMID:An enhanced active efflux of CPT-11 and SN-38 in cisplatin-resistant human KB carcinoma cells. 1037 68

We examined the expression levels of mRNA for multidrug resistance 1 (MDR1), multidrug resistance-associated protein (MRP), human canalicular multispecific organic anion transporter (cMOAT), lung resistance-related protein (LRP), topoisomerase IIalpha, beta (Topo IIalpha, beta) and topoisomerase I (Topo I) genes in human head and neck squamous cell carcinoma (HNSCC) specimens and mucosa (HNM) specimens, to elucidate their roles in relation to the biological characteristics and drug resistance in vivo. Fifty-eight samples (45 head and neck carcinomas and 13 head and neck mucosa) obtained during surgical resection or biopsy from 38 patients were analyzed using the quantitative reverse transcription-polymerase chain reaction (RT-PCR) method. MDR1, MRP, LRP, Topo IIalpha, Topo IIbeta, and Topo I gene transcripts were detected in all the samples tested, but cMOAT mRNA was not detected in them. Comparisons of the expression levels in HNSCC with those in HNM showed that the Topo IIalpha gene expression level was higher in HNSCC than in HNM (P=0.0298). Moreover, the Topo IIalpha mRNA level was significantly higher in metastatic lymph node samples of HNSCC than in HNM samples (P=0.0205). There were no significant differences in the six genes' expression levels between samples exposed to platinum drugs and those not exposed to platinum drugs. These results suggest that it may be effective in anticancer therapy to use topoisomerase-targetting drugs against HNSCC, especially metastatic neck tumors, and that the expression of these genes in HNSCC is not associated with platinum drug exposure.
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PMID:Expression of drug resistance-related genes in head and neck squamous cell carcinomas and normal mucosa. 1074 48

We investigated the mechanism of intrinsic resistance to cisplatin in human transitional cell cancer (TCC) using 7 human bladder cancer cell lines, which were derived from untreated TCC of the urinary bladder. The sensitivity to cisplatin was different from cell line to cell line, and a 15-fold difference was observed between the most sensitive line and the most resistant line. No significant correlation was observed between the content of intracellular glutathione and the resistance to cisplatin. In contrast, a positive correlation was seen between intracellular cisplatin accumulation and cisplatin resistance. The expression of drug resistance-related genes including glutathione S-transferase pi, gamma-glutamyl-cysteine synthetase, multidrug resistance-1, multidrug resistance-associated protein, DNA topoisomerase I, topoisomerase II, human canalicular multispecific organic anion transporter, and thioredoxin was not significantly related to cisplatin resistance. These data suggest that intracellular cisplatin may contribute to intrinsic cisplatin resistance and may therefore be a useful biomarker to predict cisplatin sensitivity in human untreated TCC.
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PMID:Accumulation of intracellular platinum is correlated with intrinsic cisplatin resistance in human bladder cancer cell lines. 1076 37

The cell lines described in the present study were isolated as part of an effort to understand resistance to topoisomerase (topo) II inhibitors. To that end, 50 sublines were isolated from four human breast cancer cell lines, i.e., MCF-7, T47D, MDA-MB-231, and ZR-75B. As an initial step, a concentration that would be lethal to the majority of cells (IC99) was selected for both VP-16 and mAMSA, for each cell line. The identification of an increasing number of putative drug resistance-related proteins provided the opportunity to examine expression of the corresponding genes in the selected cell lines. Northern blot analysis revealed different responses to the selecting agents in the different cell lines. Previous studies examining expression of multidrug resistance (MDR)-1 in resistant cell lines had found undetectable levels in all cells. In the ZR-75B sublines, increased expression of MDR-associated protein (MRP) and canalicular multispecific organic anion transporter (cMOAT) was observed, and when the relative levels of overexpression were compared, a high correlation was found. In contrast, increased expression of MRP was observed in some of the MDA-MB-231 sublines, without a concomitant increase in cMOAT expression. Finally, in both T47D and MCF-7 sublines, increased expression of cMOAT or MRP was observed infrequently, and where it occurred, was of a much smaller magnitude. In the analysis of expression of MRP, the highest levels were found in the ZR-75B and MDA-MB-231 sublines, with lower levels in the MCF-7 and T47D clones. Similarly, differences in the expression of topo IIalpha were observed among the sublines. Although the differences in expression appear to depend on the parental cell line from which the resistant sublines were derived, a strong correlation was observed between the expression of MRP and the levels of topo IIalpha. Cell lines with low levels of MRP had lower levels of topo IIalpha, while those with high levels of MRP maintained higher levels of topo IIalpha. While a reduced topo IIalpha level was common, there did not appear to be a compensating increase in the expression of topo IIbeta or topo I or casein kinase (CK) IIalpha in any of the cell lines. While the possibility that such compensation could occur has been discussed and even reported in some cell lines, such an adaptation was not observed in the present study, suggesting that it is not common.
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PMID:Expression of drug resistance genes in VP-16 and mAMSA-selected human carcinoma cells. 1147 29