New ABC transporters in multi-drug resistance

TY - JOUR

T1 - New ABC transporters in multi-drug resistance

AU - Bates, Susan E.

AU - Robey, Robert

AU - Knutsen, Turid

AU - Honjo, Yasumasa

AU - Litman, Thomas

AU - Dean, Michael

PY - 2000/10/1

Y1 - 2000/10/1

N2 - ATP-binding cassette (ABC) transporters have been the subject of intense scrutiny as potential mediators of clinical drug resistance. Since the identification of MDR1/P-glycoprotein over 15 years ago, it has been recognised that reduced intracellular accumulation of anticancer agents can result in significant degrees of drug resistance. The multi-drug resistance associated protein (MRP1) was the second ABC transporter to be associated with drug resistance, and in the past three years, five additional MRP family members have been recognised. While studies to define the substrate specificity and normal physiology for the new transporters is underway, it appears that the principal function for P-glycoprotein and MRP is protection of the host from xenobiotics. The most recent addition to the list of ABC transporters mediating drug resistance is the half-transporter, MXR/BCRP/ABCP. Overexpression of this transporter is associated with mitoxantrone, anthracycline and camptothecin resistance. The discovery of multiple distinct ABC transporters capable of conferring multi-drug resistance offers the possibility that clinical reversal of drug resistance can be achieved. Studies with P-glycoprotein inhibitors alone have generated mixed results; one potential explanation is that other transporters may be co-expressed. These additional transporters offer new therapeutic targets, as both specific and multi-specific inhibitors should be identified for clinical trials in drug resistance reversal.

AB - ATP-binding cassette (ABC) transporters have been the subject of intense scrutiny as potential mediators of clinical drug resistance. Since the identification of MDR1/P-glycoprotein over 15 years ago, it has been recognised that reduced intracellular accumulation of anticancer agents can result in significant degrees of drug resistance. The multi-drug resistance associated protein (MRP1) was the second ABC transporter to be associated with drug resistance, and in the past three years, five additional MRP family members have been recognised. While studies to define the substrate specificity and normal physiology for the new transporters is underway, it appears that the principal function for P-glycoprotein and MRP is protection of the host from xenobiotics. The most recent addition to the list of ABC transporters mediating drug resistance is the half-transporter, MXR/BCRP/ABCP. Overexpression of this transporter is associated with mitoxantrone, anthracycline and camptothecin resistance. The discovery of multiple distinct ABC transporters capable of conferring multi-drug resistance offers the possibility that clinical reversal of drug resistance can be achieved. Studies with P-glycoprotein inhibitors alone have generated mixed results; one potential explanation is that other transporters may be co-expressed. These additional transporters offer new therapeutic targets, as both specific and multi-specific inhibitors should be identified for clinical trials in drug resistance reversal.

KW - ABC transporters

KW - drug resistance

KW - MDR

UR - http://www.scopus.com/inward/record.url?scp=33750430768&partnerID=8YFLogxK

U2 - 10.1517/14728222.4.5.561

DO - 10.1517/14728222.4.5.561

M3 - Review

AN - SCOPUS:33750430768

SN - 1472-8222

VL - 4

SP - 561

EP - 580

JO - Expert Opinion On Therapeutic Targets

JF - Expert Opinion On Therapeutic Targets

IS - 5

ER -