ABCMdb

PMID: 15075385

Bates SE, Medina-Perez WY, Kohlhagen G, Antony S, Nadjem T, Robey RW, Pommier Y
ABCG2 mediates differential resistance to SN-38 (7-ethyl-10-hydroxycamptothecin) and homocamptothecins.
J Pharmacol Exp Ther. 2004 Aug;310(2):836-42. Epub 2004 Apr 9., [PubMed]

Sentences

No. Mutations Sentence Comment

31 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly To determine whether homocamptothecins are ABCG2 substrates, we compared the cytotoxicity of homocamptothecin and its clinical difluoro derivative, BN80915, to CPT and to SN-38 in three ABCG2-overexpressing selected cell lines expressing either wild type (R482) or mutant (R482T, R482G) ABCG2. Login to comment 79 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly In agreement with previous results (Brangi et al., 1999), we found that resistance to SN-38 was high in all three drug-selected cell lines overexpressing either wild-type 482R (MCF-7 MX100), mutant R482T (MCF-7 AdVp3000), or R482G (S1M1-80) ABCG2. Login to comment 98 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly Interestingly, cells transfected with a mutant R482G or R482T ABCG2 gene were 4-to 7-fold more resistant to homocamptothecin and 7-to 14-fold more resistant to BN80915 than cells transfected with wild-type R482 ABCG2, suggesting that amino acid 482 affects the ability of ABCG2 to confer resistance to these compounds. Login to comment 99 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly Previous studies had demonstrated that in addition to the absence of anthracycline resistance and rhodamine transport, the wild-type R482 protein was less effective in transporting mitoxantrone compared with mutant (R482G, R482T) ABCG2 (Robey et al., 2003). Login to comment 129 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly Three drug-selected cell lines overexpressing wild-type (R482) or mutant (R482G, R482T) ABCG2 as well as HEK-293 cells expressing wild-type or mutant ABCG2 were found to be resistant to homocamptothecin and BN80915. Login to comment 144 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly Resistance to homocamptothecin and BN80915 was highest in cells transfected with mutant (R482G, R482T) compared with wild-type Fig. 4. Login to comment 147 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly B, 4-day cytotoxicity assays were performed on HEK-293 cells transfected with empty vector (filled squares), wild-type (R482, triangles), or mutant (R482G, circles; R482T, hatched squares) ABCG2 with SN-38, camptothecin (CPT), homocamptothecin (hCPT), or BN80915. Login to comment