ABCMdb

PMID: 19771428

Sai K, Saito Y, Maekawa K, Kim SR, Kaniwa N, Nishimaki-Mogami T, Sawada J, Shirao K, Hamaguchi T, Yamamoto N, Kunitoh H, Ohe Y, Yamada Y, Tamura T, Yoshida T, Matsumura Y, Ohtsu A, Saijo N, Minami H
Additive effects of drug transporter genetic polymorphisms on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients.
Cancer Chemother Pharmacol. 2010 May;66(1):95-105. Epub 2009 Sep 22., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCG2 p.Gln141Lys Associations of grade 3/4 neutropenia were observed with ABCC2 -1774delG (*1A), ABCG2 421C[A (Q141K) and IVS12 ? Login to comment 40 ABCG2 p.Gln141Lys Since the *9 haplotype with 1236C[T, 2677G[T (A893S) without 3435C[T [16] showed the same trend for PK/PD as *2 (data not shown), the current study classified the Table 1 List of major transporter haplotypes and their markers analyzed for Japanese cancer patients Gene Haplotype Tagging SNP Abbreviation used in this paper Haplotype frequency Monotherapy (N = 110)a With cisplatin (N = 124)a ABCB1 BJLb (block 1) -1789G[A 0.182 0.210 *2 groupc (block 2) 2677G[T(A893S) B 0.382 0.379 *10 groupd (block 2) 2677G[A(A893T) 0.182 0.169 *1b (block 3) IVS27-182G[T 0.200 0.169 ABCC2 *1A -1774delG C 0.373 0.371 *1C/G 3972C[T(I1324I) 0.218 0.266 ABCG2 # IIB [*1a-*2-*1b]e 421C[A(Q141K), IVS12 ? Login to comment 41 ABCG2 p.Val12Met 49G[T G 0.200 0.274 # IIIC [*1b-*3-*1c]e 34G[A(V12M), IVS9-30A[T 0.164 0.097 SLCO1B1 *1b 388A[G(N130D) 0.373 0.573 *15 Á 17 521T[C(V174A) S 0.191 0.153 a Number of chromosome b BJL consists of *1B (having -1789G[A), *1J (having -1789G[A and -371A[G) and *1L (having -1789G[A and -145C[G) previously defined [26] c *2 Group includes *2, *9, *12 and *14 haplotypes previously defined [26] d *10 Group includes *10 and *13 haplotypes previously defined [26] e Combination of ABCG2 haplotypes of three blocks [block (-1)-block 1-block 2] previously defined [28] haplotypes with 2677G[T (A893S), *2, *9, *12 and *14 [26], as the *2 group (*2 in this paper). Login to comment 46 ABCC2 p.Val417Ile ABCC2*2 [1246G[A (V417I)] and *1H [2934G[A (S978S)] [27] showed no statistically significant effects (data not shown). Login to comment 48 ABCG2 p.Gln141Lys Major combinations in 177 patients were the wild type # IA (frequency = 0.291), # IIB [containing 421C[A (Q141K) and IVS12 ? Login to comment 49 ABCG2 p.Val12Met 49G[T] (0.251) and # IIIC [containing 34G[A (V12M) and IVS9-30A[T] (0.107). Login to comment 50 ABCG2 p.Gln141Lys ABCG2 p.Val12Met Note that # IIB and # IIIC are subgroups of block 1 *2 [421C[A (Q141K)] and block 1*3 [34G[A (V12M)], respectively [28]. Login to comment 55 ABCB1 p.Glu448Lys Since the SN-38 AUC/dose level of one patient with haplotypes ABCB1*2 [2677G[T (A893S)] and *14 [2677G[T (A893S) and 1345G[A (E448K)] showed an outlying value (indicated as ''a`` in Fig. 1), this patient was excluded from the statistical analysis. Login to comment 86 ABCG2 p.Gln141Lys ABCB1 p.Val1251Ile ABCB1 p.Glu109Lys ABCB1 p.Gly102Arg = UGT1A1*6 or *28. a BJL contains -1789G[A, *2 (block 1) = 325G[A (E109K), *3 (block 1) = 304G[A (G102R); b *2 (block 2) contains 2677G[T (A893S); c *1b (block 3) = IVS27-182G[T, *2 (block 3) = 3751G[ A (V1251I); d *1A contains -1774delG; e IIB contains 421C[A (Q141K) and IVS12 ? Login to comment 107 ABCG2 p.Phe489Leu ABCG2 p.Gln126* ABCG2 p.Arg575* These variations include an amino acid substitution leading to reduced in vitro activity, ABCG2 1465T[C (F489L) [36], and the stop codons, ABCG2 376C[T (Q126X) and 1723C[T (R575X) [28]. Login to comment 118 ABCG2 p.Gln126* It was noted that the additive effect of g1 [ABCG2 376C[T (Q126X)] was not observed in the heterozygotes (g1/-), but was evident in the compound heterozygotes with another ABCG2 genetic polymorphism, # IIB, (G/g1) (Fig. 2a, b). Login to comment 124 ABCG2 p.Phe489Leu ABCG2 p.Gln126* ABCG2 p.Arg575* ABCB1 p.Val1251Ile ABCB1 p.Asp602Asn ABCB1 p.Thr1015Ala ABCB1 p.Gly102Arg ABCB1 p.Glu448Lys ABCC2 p.Arg393Trp patients who experienced grade 4 neutropenia ID Gene Genetic variation Nucleotide change (amino acid substitution) Haplotypea b1 ABCB1 304G[C (G102R) Block 1 *3 b2(B)b 1804G[A (D602N) Block 2 *12 b3(B)b 1342G[A (E448K) Block 2 *14 b4 3043A[G (T1015A) Block 2 *16 b5 3751G[A (V1251I) Block 3 *2 c1 ABCC2 1177C[T (R393W) *7 g1 ABCG2 376C[T (Q126X) Block 1 *4 g2 1465T[C (F489L) Block 2 *2 g3 1723C[T (R575X) Block 2 *5 s1(S)c SLCO1B1 1007C[G (P336R) s2 311T[A (M104K) u1 UGT1A1 -3279T[G, 1941C[G # 60-# IB (?/?) Login to comment 150 ABCG2 p.Gln141Lys ABCG2# IIB contains the non-synonymous SNP 421C[A (Q141K), which was detected at higher frequencies in Asians and was reported to cause reduced expression of BCRP in vitro [36, 39-41]. Login to comment 151 ABCG2 p.Gln141Lys In clinical studies, the association of 421C[A (Q141K) with higher plasma levels of diflomotecan was shown in Caucasians [42]. Login to comment 153 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys An association of 421C[A (Q141K) alone with irinotecan PK/PD was not significant in our hands (data not shown), but # IIB containing both 421C[A (Q141K) and IVS12 ? Login to comment 157 ABCG2 p.Val12Met ABCG2# IIIC contains a non-synonymous SNP 34G[A (V12M) which has no influence on BCRP expression or activity in vitro [36, 39-41]. Login to comment 159 ABCG2 p.Val12Met In contrast, a report on Korean patients suggested the association of ABCG2 34G[A (V12M) with a higher incidence of grade 3 diarrhea in a combination therapy of irinotecan and cisplatin [24]. Login to comment