ABCC2 p.Leu480Phe
| Predicted by SNAP2: | A: D (66%), C: N (53%), D: D (91%), E: D (91%), F: D (63%), G: D (85%), H: D (85%), I: N (82%), K: D (91%), M: N (72%), N: D (85%), P: D (91%), Q: D (85%), R: D (91%), S: D (80%), T: D (85%), V: N (78%), W: D (75%), Y: D (66%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D, |
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[hide] Irinotecan pathway genotype analysis to predict ph... Clin Cancer Res. 2003 Aug 15;9(9):3246-53. Mathijssen RH, Marsh S, Karlsson MO, Xie R, Baker SD, Verweij J, Sparreboom A, McLeod HL
Irinotecan pathway genotype analysis to predict pharmacokinetics.
Clin Cancer Res. 2003 Aug 15;9(9):3246-53., 2003-08-15 [PMID:12960109]
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PURPOSE: The purpose was to explore the relationships between irinotecan disposition and allelic variants of genes coding for adenosine triphosphate binding cassette transporters and enzymes of putative relevance for irinotecan. EXPERIMENTAL DESIGN: Irinotecan was administered to 65 cancer patients as a 90-min infusion (dose, 200-350 mg/m(2)), and pharmacokinetic data were obtained during the first cycle. All patients were genotyped for variants in genes encoding MDR1 P-glycoprotein (ABCB1), multidrug resistance-associated proteins MRP-1 (ABCC1) and MRP-2 (canalicular multispecific organic anion transporter; ABCC2), breast cancer resistance protein (ABCG2), carboxylesterases (CES1, CES2), cytochrome p450 isozymes (CYP3A4, CYP3A5), UDP glucuronosyltransferase (UGT1A1), and a DNA-repair enzyme (XRCC1), which was included as a nonmechanistic control. RESULTS: Eighteen genetic variants were found in nine genes of putative importance for irinotecan disposition. The homozygous T allele of the ABCB1 1236C>T polymorphism was associated with significantly increased exposure to irinotecan (P = 0.038) and its active metabolite SN-38 (P = 0.031). Pharmacokinetic parameters were not related to any of the other multiple variant genotypes, possibly because of the low allele frequency. The extent of SN-38 glucuronidation was slightly impaired in homozygous variants of UGT1A1*28, although differences were not statistically significant (P = 0.22). CONCLUSIONS: It is concluded that genotyping for ABCB1 1236C>T may be one of the factors assisting with dose optimization of irinotecan chemotherapy in cancer patients. Additional investigation is required to confirm these findings in a larger population and to assess relationships between irinotecan disposition and the rare variant genotypes, especially in other ethnic groups.
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136 Table 4 Genotype and Allele frequencies for the studied genes Polymorphisma Nomenclature Descriptionb Genotype frequenciesc Allele frequencies (95% CI)d Wt Het Var p q r ABCB1 1236 CϾT n/ae G411G 23 15 8 0.66 (0.52-0.78) 0.34 (0.22-0.48) ABCB1 3435 CϾT n/a E1143E 16 35 8 0.57 (0.44-0.69) 0.43 (0.31-0.56) ABCB1 2677 GϾT/A n/a A893S or T 12 23/4 13/1 0.48 (0.35-0.61) 0.47 (0.34-0.60) 0.05 (0.02-0.14) ABCC1 14008 GϾA n/a intron 27 32 27 5 0.71 (0.59-0.81) 0.29 (0.19-0.41) ABCC1 462 CϾT n/a P154P 65 0 0 1.00 0.00 ABCC1 34215 CϾG n/a intron 18 0 20 40 0.17 (0.1-0.28) 0.83 (0.72-0.90) ABCC2 156231 AϾG n/a intron 3 65 0 0 1.00 0.00 ABCG2 623TϾC n/a F208S 63 0 0 1.00 0.00 CES1 1440 AϾT n/a L480F 64 0 0 1.00 0.00 CES1 1525 AϾC n/a N509H 60 1 0 0.99 (0.92-1) 0.01 (0-0.08) CES2 1647 CϾT n/a L549L 56 1 0 0.99 (0.92-1) 0.01 (0-0.08) CYP3A4 -392 AϾG CYP3A4*1B Promoter 46 3 0 0.97 (0.88-0.99) 0.03 (0.01-0.12) CYP3A4 15713 TϾC CYP3A4*2 S222P 39 0 0 1.00 0.00 CYP3A4 23172 TϾC CYP3A4*3 M445T 62 2 0 0.98 (0.91-1) 0.02 (0-0.09) CYP3A5 22893 GϾA CYP3A5*3C Splice variant 56 8 0 0.94 (0.85-0.98) 0.06 (0.02-0.15) CYP3A5 30597 GϾA CYP3A5*6 Splice variant 63 0 0 1.00 0.00 UGT1A1 (TA)n f UGT1A1*28 Promoter 34 22 2 0.78 (0.66-0.87) 0.22 (0.13-0.34) UGT1A1 1456 TϾG UGT1A1*7 Y486D 62 0 0 1.00 0.00 XRCC1 26304 CϾT n/a R194W 35 8 0 0.91 (0.79-0.96) 0.09 (0.04-0.21) XRCC1 27466 GϾA n/a R280H 60 2 0 0.98 (0.91-1) 0.02 (0-0.09) XRCC1 28152 GϾA n/a R399Q 25 27 5 0.68 (0.55-0.79) 0.32 (0.21-0.45) a Number represents position in nucleotide sequence.
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ABCC2 p.Leu480Phe 12960109:136:745
status: NEW