ABCMdb

PMID: 16142999

Biason P, Toffoli G
Sarcomas and pharmacogenetics.
Pharmacogenomics. 2005 Sep;6(6):585-601., [PubMed]

Sentences

No. Mutations Sentence Comment

56 ABCB1 p.Gly1249Ala ABCC2 p.Ala313Gly Gene Polymorphism Molecular effect of polymorphism Drug Effect on chemotherapy Ref. Phase I enzymes CYP2B6 CYP2B6*5 (C1459 T) Decreased enzyme expression Increased activity CPA Increased drug bioactivation [24] CYP2B6*6 (G516T, A785G) [28] CYP2B6*7 (G516T, A785G, C1459T) [24] CYP2C9 CYP2C9*2 (C430T) Decreased enzyme activity CPA Decreased drug bioactivation [31]CYP2C9*3 (A1075C) CYP2C19 CYP2C19*2 (G108620C) Lack of enzyme activity CPA No data available CYP3A4 CYP3A4*1B (A290G) Decreased mRNA expression CPA No data available [39,42] CYP3A5 CYP3A5*3 (A6986G) Lack of enzyme activity CPA No data available [42] CYP3A5*6 (G14690A) CYP2C8 CYP2C8*2 (A805T) Reduced protein activity Paclitaxel Reduced clearance of drug [44]CYP2C8*3 (G416A, A1196G) Reduced protein activity Paclitaxel Defective metabolism Phase II enzymes GST GSTA1*B (C-69T) Reduced enzyme activity CPA Increased survival [46] GSTM1 (null genotype) Complete absence of protein DOX CPA Poorer survival No impact in STS survival [47] [52] GSTT1 (null genotype) Complete absence of protein DOX CPA Increased response No impact in STS survival [49] [52] GSTP1 (A313G) Decreased enzyme activity DOX CPA Cisplatin Longer survival [53] Transporter MDR1 C3435T Decreased protein expression DOX MTX Better clinical response [59] MRP2 C24T Alteration in protein expression MTX Cisplatin No data available [63] G1249A RFC G80A Decreased affinity for MTX MTX Poorer response No correlation with toxicity [68,70] Intracellular target DHFR T91C Increased enzyme activity MTX Resistance to drug [72] MTHFR C677T Reduced enzyme activity MTX Higher toxicity [77] TYMS TSER (*3/*3 repeats) Increased mRNA expression MTX Necessity of higher dose of MTX [75] CPA: Cyclophosphamide; CYP: Cytochrome P450; DHFR: Dihydrofolate reductase; DOX: Doxorubicin; ERCC1: Excision repair cross-complementing rodent repair deficiency, complementation group 1; ET-743: Ecteinascidin-743; GST: Glutathione S-transferase; MDR: Multidrug resistance; MTHFR: Methylenetetrahydrofolate reductase; MTX: Methotrexate; RFC: Replication factor C; TYMS: Thymidylate synthetase; XPD: Xeroderma pigmentosum group D; XRCC1: X-ray repair complementing defective repair in Chinese hamster cells 1. Login to comment 124 ABCC2 p.Ala313Gly The variant of GSTP widely studied for its impact on the pharmacodynamics of drugs such as DOX and CPA is A313G (Ile105Val). Login to comment 143 ABCB1 p.Gly1249Ala Among these, two SNPs are mainly responsive to alterations in protein expression: C24T (promoter region) and G1249A (exon 10) [62]. Login to comment 235 ABCB1 p.Gly1249Ala Genetic analyses for MTX response are usually performed in transporter enzymes (RFC G80A, MRP C24T and G1249A) or in target enzymes (DHFR T91C, TSER and MTHFR C677T). Login to comment