Article ; Online: ABC transporters: unvalidated therapeutic targets in cancer and the CNS.
Anti-cancer agents in medicinal chemistry
2010 Volume 10, Issue 8, Page(s) 625–633
Abstract: ... as therapeutic targets in the central nervous system (CNS). Both lines of investigation point to the need ... transporters including ABCG2 and members of the ABCC family have been linked with poor outcome, it remains ... for targeted therapies where an important dose-response relationship is likely to exist, and ...
| Abstract | The discovery of the multidrug transporter P-glycoprotein (Pgp) over 35 years ago in drug resistant cells prompted several decades of work attempting to overcome drug resistance by inhibition of drug efflux. Despite convincing laboratory data showing that drug transport can be inhibited in vitro, efforts to translate this discovery to the clinic have not succeeded. Since overexpression of Pgp and related transporters including ABCG2 and members of the ABCC family have been linked with poor outcome, it remains a reasonable hypothesis that this poor outcome is linked to reduction of drug exposure by efflux, and thus to drug resistance. In this review, we will discuss the question of whether ABC transporters mediate drug resistance in cancer through a reduction in drug accumulation in tumors, and whether the "Pgp inhibition hypothesis" might be wrong. The hypothesis, which holds that increased chemotherapy effectiveness can be achieved by inhibiting Pgp-mediated drug efflux has only been validated in model systems. Possible explanations for the failure to validate this clinically include the existence of other modulators of drug accumulation and uptake in tumors. Despite these difficulties, a potential role has emerged for drug transporters as therapeutic targets in the central nervous system (CNS). Both lines of investigation point to the need for imaging agents to facilitate the study of drug accumulation in human cancer. This is a critical need for targeted therapies where an important dose-response relationship is likely to exist, and where drug resistance renders many of the novel targeted agents ineffective in a subset of patients. |
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| MeSH term(s) | ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors ; ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; ATP-Binding Cassette Transporters/antagonists & inhibitors ; ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/metabolism ; Animals ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/therapeutic use ; Blood-Brain Barrier ; Central Nervous System/metabolism ; Clinical Trials as Topic ; Drug Resistance, Multiple/genetics ; Drug Resistance, Neoplasm/genetics ; Humans ; Molecular Targeted Therapy ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Polymorphism, Single Nucleotide ; Treatment Outcome | |||||
| Chemical Substances | ATP Binding Cassette Transporter, Subfamily B, Member 1 ; ATP-Binding Cassette Transporters ; Antineoplastic Agents | |||||
| Language | English | |||||
| Publishing date | 2010-12-07 | |||||
| Publishing country | Netherlands | |||||
| Document type | Journal Article ; Review | |||||
| ZDB-ID | 2217610-X | |||||
| ISSN | 1875-5992 ; 1871-5206 | |||||
| ISSN (online) | 1875-5992 | |||||
| ISSN | 1871-5206 | |||||
| DOI | 10.2174/187152010794473957 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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