ABCC2 p.Ala313Gly
Predicted by SNAP2: | C: N (78%), D: D (71%), E: D (71%), F: D (75%), G: D (53%), H: D (71%), I: D (53%), K: D (71%), L: D (66%), M: N (53%), N: D (63%), P: N (66%), Q: D (66%), R: D (63%), S: N (87%), T: N (87%), V: N (87%), W: D (80%), Y: D (71%), |
Predicted by PROVEAN: | C: N, D: D, E: D, F: D, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: N, Q: D, R: D, S: N, T: N, V: N, W: D, Y: D, |
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[hide] Sarcomas and pharmacogenetics. Pharmacogenomics. 2005 Sep;6(6):585-601. Biason P, Toffoli G
Sarcomas and pharmacogenetics.
Pharmacogenomics. 2005 Sep;6(6):585-601., [PMID:16142999]
Abstract [show]
Sarcomas are a heterogeneous group of tumors, requiring different chemotherapeutic approaches. Recently, several regimens for metastatic tumors were evaluated with respect to the different responses to conventional chemotherapy of the various histologic subtypes of sarcomas. The impact of pharmacogenetics in the progress of chemotherapy appears to be crucial in defining the clinical response to many drugs, such as anthracycline or alkylating agents, that are widely used in treatment regimens for soft tissue sarcomas (STS) or sarcomas of the bone. Polymorphisms of metabolizing enzymes (e.g., cytochrome P450 and glutathione-S-transferase), transporter proteins (reduced folate carrier and P-glycoprotein) or target proteins (thymidylate synthase, methylenetetrahydrofolate reductase, dihydrofolate reductase, and c-KIT) may be responsible for an altered clinical outcome, in terms of both response and toxicity. The administration of new chemotherapeutic agents, such as imatinib for gastrointestinal tumors (GIST), requires the study of genetic polymorphisms possibly affecting the integrity of the target (c-KIT), which may provide valid information regarding possible developments of therapy. For STS and sarcoma of the bone, the genetic markers, which could be unambiguously predictive of the phenotypic profile of patients, are as yet undetermined.
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No. Sentence Comment
56 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.
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ABCC2 p.Ala313Gly 16142999:56:1124
status: NEW124 The variant of GSTP widely studied for its impact on the pharmacodynamics of drugs such as DOX and CPA is A313G (Ile105Val).
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ABCC2 p.Ala313Gly 16142999:124:106
status: NEW