Atypical Multidrug Resistance: Breast Cancer Resistance Protein Messenger RNA Expression in Mitoxantrone-Selected Cell Lines

Ross, Douglas D.; Yang, Weidong; Abruzzo, Lynne V.; Dalton, William S.; Schneider, Erasmus; Lage, Hermann; Dietel, Manfred; Greenberger, Lee M.; Cole, Susan P. C.; Doyle, L. Austin

doi:10.1093/jnci/91.5.429

Cited by 299 publications

(219 citation statements)

References 10 publications

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“…Though amplification of the ABCG2 gene has been observed during the selection of drug-resistant cell lines. [30][31][32] CGH analysis does not indicate a change in DNA copy number at the ABCG2 locus in MiaPaCa BCRP (Figure 2c). Upregulation of BCRP can occur independently of gene amplification.…”

Section: Discussionmentioning

confidence: 99%

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

et al. 2009

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Section: Discussionmentioning

confidence: 99%

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

et al. 2009

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“…24 Resistance to topoisomerase poisons has been mainly attributed to mutations in topoisomerase genes, to enhanced repair, and to overexpression of P-glycoprotein (Pgp), multidrug resistance protein (MRP), and breast cancer resistance protein (BCRP). 25,26 In addition, loss of MLH1 activity has also been reported to be associated with resistance to the topoisomerase II poisons doxorubicin and etoposide, 9,15 suggesting a role of mismatch repair in topoisomerase II poison-mediated cell killing. In the present study we extend this observation by demonstrating that loss of MSH2 or MLH1 results in resistance to epirubicin, doxorubicin and mitoxantrone.…”

Section: Discussionmentioning

confidence: 99%

Resistance to topoisomerase poisons due to loss of DNA mismatch repair

et al. 2001

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Sporadic breast carcinomas demonstrate microsatellite instability, reflecting the presence of DNA mismatch repairdeficient cells, in about one fourth of cases at the time of diagnosis. Loss of DNA mismatch repair has been reported to result in resistance not only to cisplatin and alkylating agents but also to the topoisomerase II poison doxorubicin, suggesting an association between DNA mismatch repair and topoisomerase II poison-induced cytotoxicity. Our study investigates the relationship between loss of MSH2 or MLH1 function and sensitivity to the topoisomerase I and II poisons, and to the taxanes, 2 classes of cytotoxic drugs commonly used in breast cancer. Two pairs of cell lines proficient and deficient in mismatch repair due to loss of either MSH2 or MLH1 function were used. Loss of either MSH2 or MLH1 function resulted in resistance to the topoisomerase II poisons doxorubicin, epirubicin and mitoxantrone, whereas only loss of MLH1 function was associated with low-level resistance to the topoisomerase I poisons camptothecin and topotecan. In contrast, there was no resistance to docetaxel and paclitaxel. Our data support the hypothesis that both MSH2 and MLH1 are involved in topoisomerase II poisonmediated cytotoxicity, whereas only MLH1 is involved in topoisomerase I poison-mediated cytotoxicity. Since our study shows that loss of DNA mismatch repair does not result in resistance to the taxanes, these drugs can be recommended for use in breast cancer deficient in mismatch repair.

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“…4 This cell line was transfected with a CMV promoter-driven eukaryotic expression vector carrying the anti-BCRP ribozyme RzB1 ( Fig 1). Recent studies revealed a high catalytic activity of the ribozyme RzB1 in a cell -free system.…”

Section: Expression Of the Anti -Bcrp Ribozyme Rzb1 In Atypical Mdr Cmentioning

confidence: 99%

“…The protein is overexpressed in a variety of atypical multidrugresistant human cancer cell lines, which were established by in vitro exposure to mitoxantrone, topotecan, doxorubicin, or bisantrene. 4 Transfection experiments demonstrated that the BCRP-encoding cDNA can confer an atypical MDR phenotype to formerly drug -sensitive cancer cells. 5 Several pharmacologically active products, designated as MDR modulators or chemosensitizers, may circumvent the classical MDR phenotype (overview in Ref.…”

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Modulation of the atypical multidrug-resistant phenotype by a hammerhead ribozyme directed against the ABC transporter BCRP/MXR/ABCG2

et al. 2002

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The phenomenon of multidrug resistance ( MDR ) in human cancers is one of the major causes of failure of chemotherapy. A recently identified new member of the superfamily of ATP -binding cassette transporters, breast cancer resistance protein ( BCRP ), was demonstrated to confer an atypical multidrug -resistant phenotype to tumor cells. To overcome the BCRP -mediated drug resistance, a specific anti -BCRP hammerhead ribozyme was introduced into the human gastric carcinoma cell line, EPG85 -257RNOV, exhibiting an atypical MDR phenotype. By this approach, the expression levels of the targeted BCRP -encoding mRNA and the BCRP transport protein were decreased to the low constitutive expression level that was observed in highly drug -sensitive parental gastric carcinoma cells. In addition, in the anti -BCRP ribozyme -treated cells, the cellular drug accumulation was dramatically increased to the level measured in drug -sensitive cells. These effects were accompanied by an extensive reversal of the drug -resistant phenotype of more than 80%. Because additional mechanisms contribute to the multimodal -mediated MDR phenotype exhibited by this gastric carcinoma cell line, the data suggest that the BCRP -mediated contingent to the drug resistance was overcome nearly completely. Moreover, the data indicate that ribozyme -based gene therapy may be clinically applicable in preventing and reversing BCRPmediated atypical MDR.

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Atypical Multidrug Resistance: Breast Cancer Resistance Protein Messenger RNA Expression in Mitoxantrone-Selected Cell Lines

Cited by 299 publications

References 10 publications

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

Resistance to topoisomerase poisons due to loss of DNA mismatch repair

Modulation of the atypical multidrug-resistant phenotype by a hammerhead ribozyme directed against the ABC transporter BCRP/MXR/ABCG2

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