Association of High-Level <i>MRP1</i> Expression With Poor Clinical Outcome in a Large Prospective Study of Primary Neuroblastoma

Haber, Michelle; Smith, Janice; Bordow, Sharon B.; Flemming, Claudia L.; Cohn, Susan L.; London, Wendy B.; Marshall, Glenn M.; Norris, Murray D.

doi:10.1200/jco.2005.01.6196

Cited by 157 publications

(129 citation statements)

References 29 publications

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“…The expression by neuroblastoma cells of drug efflux transporters of the ABC transporter family such as MDR1 [44] and MRP1 [45] raises the possibility that drug efflux is a major determinant of the reduced sensitivity of neuroblastoma cells to imatinib. However, when evaluating this possibility the following points should be considered.…”

Section: Discussionmentioning

confidence: 99%

“…However, when evaluating this possibility the following points should be considered. First, imatinib is not a substrate for MRP1 [46] which in clinical settings [45] and in animal models [47] has been demonstrated to be a key factor for multidrug resistance in neuroblastoma. Second, although imatinib is a substrate of MDR1, the reported IC 50 of imatinib for MDR1 (3-8 mM) [48] is 1-2 log greater than the IC 50 of imatinib for its high affinity targets.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Exposure of neuroblastoma cell lines to imatinib results in the upregulation of the CDK inhibitor p27KIP1 as a consequence of c-Abl inhibition

Lupino

Ramondetti

Buccinnà

et al. 2014

Biochemical Pharmacology

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Exposure of neuroblastoma cell lines to imatinib results in the upregulation of the CDK inhibitor p27KIP1 as a consequence of c-Abl inhibition

Lupino

Ramondetti

Buccinnà

et al. 2014

Biochemical Pharmacology

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“…This was largely due to the fact that tumor samples contained a variable number of MRP1 expressing normal cells, cells, while other drug efflux transporters might contribute as well [44] . However, a prospective study demonstrated that MRP1 is an independent prognostic indicator of outcome in neuroblastoma patients [60] . In addition, a high expression of MRP1 was associated with shorter tumor-free survival (TFS) and overall survival (OS) in non-small cell lung cancer (NSCLC) [61] .…”

Section: Multi-drug Associated Proteinmentioning

confidence: 99%

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

Jaramillo¹,

Saig²,

Cloos³

et al. 2018

CDR

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P-glycoprotein (ABCB1), multidrug resistance protein-1 (ABCC1) and breast cancer resistance protein (ABCG2) belong to the ATP-binding cassette (ABC) superfamily of proteins that play an important physiological role in protection of the body from toxic xenobiotics and endogenous metabolites. Beyond this, these transporters determine the toxicity profile of many drugs, and confer multidrug resistance (MDR) in cancer cells associated with a poor treatment outcome of cancer patients.It has long been hypothesized that inhibition of ABC drug efflux transporters will increase drug accumulation and thereby overcome MDR, but until now no approved inhibitor of these transporters is available in the clinic. In this review we present molecular strategies to overcome this type of drug resistance and discuss for each of these strategies their promising value or indicate underlying reasons for their limited success.

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“…When compared to methods such as RT-PCR to detect mRNA expression (10,11,12,110) Norris and colleagues demonstrated MRP4 mRNA expression in 100% of 52 neuroblastomas from untreated patients (110). In this population of 52 patients, high MRP4 mRNA expression was a significant indicator of poor survival.…”

Section: Discussionmentioning

confidence: 99%

“…In solid tumor cells, drug efflux can be mediated by members of the ABC transport protein superfamily. P-glycoprotein (Pgp) and multi-drug resistance associated protein 1 (MRP1), both members of the ABC transporter superfamily, are expressed in tumor specimens from children with neuroblastoma (10,11,12). High Pgp and/ or MRP1 expression in neuroblastoma is associated with poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan

Turner¹

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Clinton Stewart for his guidance and support. I will always appreciate his patience, the numerous opportunities he has provided, and all of the time he has spent teaching me. iii Abstract High-risk neuroblastoma presents a significant therapeutic challenge because the 5-year survival rate remains less than 30% despite the use of surgery, multi-agent chemotherapy, radiation, and autologous bone marrow transplant. Novel therapeutic modalities are under development. The camptothecin analogs topotecan and irinotecan have been identified as successful cytotoxic agents. For topotecan, pharmacokinetically guided dosing to achieve a systemic exposure associated with preclinical anti-tumor activity in neuroblastoma xenograft models is feasible and has elicited favorable responses in children with high-risk neuroblastoma. However, some children with highrisk disease did not respond to the putatively effective topotecan systemic exposure.These children represent a subset of the disease intrinsically resistant to topotecan.Furthermore, mRNA expression of the adenosine triphosphate (ATP)-binding cassette (ABC) transporters P-glycoprotein (Pgp) and multidrug resistance associated protein 1 (MRP1), which efflux many drugs used in neuroblastoma therapy, has been implicated in poor outcome in neuroblastoma. Therefore, the purpose of our studies was to determine the role of ABC transport protein expression in neuroblastoma resistance to the camptothecin analogs topotecan and irinotecan. The results of the in vitro studies demonstrate that MRP4 and Pgp confer resistance to topotecan and SN-38. In the xenograft studies, MRP4 expression was associated with failure to respond to topotecan. However, this phenotype was not recapitulated in children treated with topotecan. These results may be confounded by small sample size and timing of sample acquisition. Further investigation of the role of ABC transporters in children with neuroblastoma who receive either topotecan or irinotecan may be warranted. In addition to the camptothecin analogs, patients will receive other drugs effluxed by the ABC transporters (e.g., doxorubicin, vincristine, etoposide, and cyclophosphamide). Therefore, analyzing ABC transporter expression by immunohistochemistry in diagnostic tumor specimens may help to select agents not subject to efflux by ABC transporters expressed in the tumor. However, eliminating drugs effluxed by ABC transporters from the treatment regimen creates a potential gap in therapy and may reduce drug intensity. Therefore, further rational design and development of drugs that evade ABC transporter-mediated efflux, and potentially other resistance mechanisms in neuroblastoma, is also warranted.

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Association of High-Level MRP1 Expression With Poor Clinical Outcome in a Large Prospective Study of Primary Neuroblastoma

Cited by 157 publications

References 29 publications

Exposure of neuroblastoma cell lines to imatinib results in the upregulation of the CDK inhibitor p27KIP1 as a consequence of c-Abl inhibition

Exposure of neuroblastoma cell lines to imatinib results in the upregulation of the CDK inhibitor p27KIP1 as a consequence of c-Abl inhibition

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan

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