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The Effect of BCRP, MDR1 and OATP1B3 on the Antitumor Efficacy of the Lipophilic Camptothecin AR-67 In Vitro.

Drug Metab Dispos. 2013 Apr 25;

Authors: Tsakalozou E, Adane ED, Kuo KL, Daily A, Moscow JA, Leggas M


AR-67 is a lipophilic camptothecin analogue, currently under early stage clinical trials. Transporters are known to have an impact on the disposition of camptothecins and on the response to chemotherapeutics in general due to their expression in tumor tissues. Therefore, the interplay between the BCRP, MDR1 and OATP1B1/OATP1B3 transporters and AR-67 and their impact on the toxicity profile of AR-67 was investigated. Using cell lines expressing the aforementioned transporters, we showed that the lipophilic AR-67 lactone form is a substrate for efflux transporters BCRP and MDR1. Additionally, OATP1B1 and OATP1B3 facilitated the uptake of AR-67 carboxylate in SLCO1B1 and SLCO1B3-transfected cell systems compared to the mock-transfected ones. Notably, both BCRPand MDR1, conferred resistance to AR-67 lactone. Prompted by recent studies showing increased OATP1B3 expression in certain cancer types, we investigated the effect of OATP1B3 expression on cell viability after exposure to AR-67 carboxylate. OATP1B3 expressing cells had increased carboxylate uptake as compared to mock transfected cells, but were not sensitized because the intracellular amount of lactone was fifty-fold higher than that of carboxylate and comparable between OATP1B3 expressing and non-expressing cells. In conclusion, BCRP- and MDR1-mediated efflux of AR-67 lactone confers resistance to AR-67, but OATP1B3-mediated uptake of the AR-67 carboxylate does not sensitize OATP1B3 expressing tumor cells.

PMID: 23620484 [PubMed - as supplied by publisher]