ABCMdb

PMID: 17323126

Huang Y
Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy.
Cancer Metastasis Rev. 2007 Mar;26(1):183-201., [PubMed]

Sentences

No. Mutations Sentence Comment

57 ABCC1 p.Ala893Ser ABCB1 p.Ala999Thr 2677G>T in exon 21 and 2995G>A/T in exon 24 were reported by Mickley et al. [22], leading to amino acid changes of A893S and A999T, respectively. Login to comment 89 ABCB1 p.Gly185Val Colchicine-selected cells exhibited Gly185Val substitution, resulting in increased resistance to colchicine but not to other drugs [35]. Login to comment 121 ABCC1 p.Gly671Val The 2012G>T mutation in exon 16 which leads to the substitution of a highly conserved Gly residue at position 671 with Val did not show functional differences with the wild type ABCC1 gene [58]. Login to comment 123 ABCC1 p.Cys43Ser An exon 2 mutation 128G>C, which results in a Cys43Ser substitution impaired the plasma membrane localization of ABCC1 protein and reduced the cellular resistance to vincristine and arsenite from that for wild-type ABCC1 [60]. Login to comment 124 ABCG2 p.Gln141Lys ABCG2 p.Gln126* ABCC1 p.Ala893Ser ABCC1 p.Cys43Ser ABCC1 p.Gly671Val ABCC1 p.Arg433Ser ABCC1 p.Ala989Thr ABCB1 p.Ala999Thr ABCG2 p.Gln126* Moreover, Letourneau et al. examined 10 non-synonymous ABCC1 SNPs to determine Table 2 Summary of genetic variants in ABC transporters ABCB1, ABCC1, ABCC2 and ABCG2 involved in cancer chemotherapy Variants (location, effect) Phenotype Drug Sample Reference ABCB1 +103T>C (5'flanking, non-coding) Increased transcription Doxorubicin vincristine osteosarcoma Stein et al., 1994 [19] +8T>C (5'flanking, non-coding) Unknown Leukemia Rund et al., 1999 [21] 1236C>T (exon12, synonymous) Higher expression AML blasts Illmer et al., 2002 [47] Lower clearance Irinotecan Cancer patients Sai et al., 2003 [44] Higher exposure Irinotecan, SN-38 Cancer patients Mathijssen et al., 2003 [45] 2677G>T/A (exon21, A893S/T) Lower expression placenta Tanabe et al., 2001 [42] Lower expression placenta Hitzl et al., 2004 [37] Higher expression AML blasts Illmer et al., 2002 [47] Allele specific expression Cell lines, lymphoma Mickley et al., 1998 [22] Lower clearance Irinotecan Cancer patients Sai et al., 2003 [44] Survival leukemia Illmer et al., 2002 [47] Survival leukemia van den Heuvel-Eibrink et al., 2001 [48] Worse survival AML blasts Kim et al., 2006 [10] Higher efficacy Paclitaxel Ovarian cancer Green et al., 2006 [50] 2995G>A (exon24, A999T) None Cell lines, lymphoma Mickley et al., 1998 [22] 3435C>T (exon26, synonymous) Lower expression Duodenal protein Hoffmeyer et al., 2000 [26] Lower expression placenta Hitzl et al., 2004 [37] Higher expression Intestine mRNA Nakamura et al., 2002 [32] Higher expression AML blasts Illmer et al., 2002 [47] Lower clearance Irinotecan Cancer patients Sai et al., 2003 [44] Lower efflux Digoxin CD56+ NK cells Hitzl et al., 2001 [27] Higher plasma level Digoxin Healthy volunteers Hoffmeyer et al., 2000 [26] Higher AUC Cyclosporin transplant patients Bonhomme-Faivre et al., 2004 [36] Lower CNS relapse Cancer patients Stanulla et al., 2005 [46] Better survival leukemia Illmer et al., 2002 [47] Higher efficacy Breast cancer Kafka et al., 2003 [49] Higher activity, worse survival AML Kim et al., 2006 [10] Better survival Platinums Esophageal cancer Wu et al., 2006 [43] No difference Docetaxel patients Puisset et al., 2004 [41] No difference Irinotecan Cancer patients Mathijssen et al., 2004 [39] No difference Vincristine patients Plasschaert et al., 2004 [40] No difference colon Taniguchi et al., 2003 [24] ABCC1 -260G>C (5'flanking, non-coding) Higher activity Transfected cell line Wang et al., 2005 [62] Table 2 (Continued) Variants (location, effect) Phenotype Drug Sample Reference 128G>C (exon2, C43S) Reduced resistance Vincristine, arsenite Transfected cell line Leslie et al., 2003 [60] 1299G>T (exon10, R433S) Reduced transport of LTC4, increased resistance to doxorubicin Leukotriene C4, doxorubicin Transfected cell line Conrad et al., 2002 [59] 2012G>T (exon16, G671V) No change in activityLeukotriene C4 Transfected cell line Conrad et al., 2001 [58] Heart toxicity Doxorubicin nLon-Hodgkin lymphoma Wojnowski et al., 2005 [63] 2965G>A (exon22, A989T) Reduced transport Estradiol 17β-glucuronide Transfected cell line Letourneau et al., 2005 [61] ABCC2 1271A>G (exon10, R421G) Reduced drug elimination, increased nephrotoxicity Methotrexate One lymphoma patient Hulot et al., 2005 [79] 3972C>T (exon28, nonsynonymous) Reduced drug clearance Irinotecan Cancer patients Innocenti et al., 2004 [80] ABCG2 376C>T (exon4, Q126stop) Reduced transport Porphyrin Trensfected cell Tamura et al., 2006 [104] 421C>A (exon5, Q141K) Lower expression Transfected cell lines Imai et al., 2002 [94] Lower expression Transfected cell lines Kondo et al., 2004 [95] Lower expression Placenta Kobayashi et al., 2005 [98] Reduced ATPase activity Trensfected cell lines Mizuarai et al., 2004 [97] Higher plasma levels Diflomotecan patients Sparreboom et al., 2004 [100] Increased bioavailability Topotecan patients Sparreboom et al., 2005 [101] Increased bioavailability 9-Aminocamptothecin patients Zamboni et al., 2006 [81] Increased drug accumulation Imatinib Transfected cell lines Gardner et al., 2006 [96] Increased drug accumulation Topotecan Trensfected cell lines Imai et al., 2002 [94] No difference Imatinib patients Gardner et al., 2006 [96] No difference intestine Zamber et al., 2003 [99] No difference MTX Trensfected cell lines Kondo et al., 2004 [95] the effects on expression and function of this transporter in transfected HEK293T cells [61]. Login to comment 125 ABCC1 p.Ala989Thr None of the SNPs resulted in changed protein expression and function, except that the 2965G>A (Ala989Thr) caused a significant decrease in transport of one of the ABCC1 substrate estradiol 17β-glucuronide. Login to comment 149 ABCC2 p.Val417Ile Among them, the 24C>T (promoter), 1249G>A (exon10) and 3972C>T (exon28) are frequently observed: 1249G>A is associated with amino acid alteration from Val to Ile at 417, whereas 3972C>T is a silent SNP at 1324. Login to comment 152 ABCC2 p.Arg412Gly This patient was heterozygous for a novel 1271A>G (R412G) mutation in the ABCC2. Login to comment 153 ABCC2 p.Arg412Gly Transfection of the R412G mutation showed a similar level of expression to the wild-type gene, whereas the mutant did not efflux methotrexate and other ABCC2 substrates. Login to comment 172 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys In vitro transfection experiments showed that 421C>A (substituting Lys for Gln-141, Q141K) resulted in decreased ABCG2 protein expression and a reduced level of drug resistance when compared with the wild type ABCG2 [94, 95]. Login to comment 175 ABCG2 p.Gln141Lys ATPase activity of the Q141K variant was reduced ~1.3-fold compared to the activity of the wild type ABCG2 [97]. Login to comment 187 ABCG2 p.Gln126* ABCG2 p.Gln126* Another polymorphism, 376C>T, substitutes a stop codon for Gln (Q126stop) and causes the absence of active ABCG2 protein from the T allele [95, 99]. Login to comment 189 ABCG2 p.Gln126* ABCG2 p.Gln126* It was recently demonstrated that in vitro the Q126stop protein was defective in porphyrin transport [104]. Login to comment 192 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly Furthermore, a mutational hot spot located in amino acid codon 482 of ABCG2 has been identified in drug selected cancer cell lines where a single amino acid change (R482G or R482T) occurs [105]. Login to comment