PII-20Irinotecan (CPT-11) related diarrhea: Functional significance of the polymorphic ABCC2 transporter protein

Uppsala University, Uppsala, Uppsala, Sweden
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 02/2007; 81(1):42-9. DOI: 10.1038/sj.clpt.6100019
Source: PubMed


BACKGROUNDPK variability of the anticancer agent CPT-11 is high. Life-threatening grade 3-4 diarrhea is seen in up to 25% of patients and has been related with CPT-11 PK and UGT1A1-status. Aim of this study was to evaluate the association of ABCC2 polymorphisms and haplotypes with CPT-11 disposition and diarrhea.METHODS105 European Caucasian cancer patients who were previously assessed for CPT-11 PK (90-min infusion; three-weekly), toxicity and UGT1A1*28, were genotyped for ABCC2 using Pyrosequencing (table 1).RESULTSFrequencies of wild type alleles and haplotypes (13 identified in 85 patients) are given in table 1. ABCC2*1 was associated with slower CPT-11 clearance (28.4 vs 33.9 L/h; P=.005). In 67 patients who received the recommended single agent dose (350 mg/m2 or 600 mg), ABCC2*1 was negatively correlated with grade 3-4 diarrhea (P=.040). A 3-fold reduced risk (30% vs 10%) was unrelated to UGT1A1*28 since severe diarrhea manifested itself in particular in patients homozygous for the UGT1A1*1 allele (P=.011).CONCLUSIONS
This study suggests that the ABCC2*1 haplotype is associated with CPT-11 related diarrhea, maybe as a consequence of altered CPT-11 excretion via the bile into the gut, and hence less local activation into the active metabolite, SN-38. As its protective effect on diarrhea is seen predominantly in patients not at risk for diarrhea due to UGT1A1*28, additional studies of the relationships of ABCC2 genotypes to CPT-11 PK and toxicity are warranted.Frequencies wild type alleles (p) of 6 ABCC2 polymorphisms, and constructed haplotypes (%; N=85).polymorphismphaplotype%−1549G>A0.60GGCGTC (ABCC2*1)35−1019A>G0.45GGCATC19−24C>T0.84AATGTT151249G>A0.79AACGTT12IVS26 −34T>C0.96AACGTC83972C>T0.67AACGCC5Clinical Pharmacology & Therapeutics (2005) 79, P41-P41; doi: 10.1016/j.clpt.2005.12.145

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Available from: Alex Sparreboom, May 11, 2015
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    • "Ainsi, dans une population de 85 patients atteints de CCR stade avancé et recevant de l'IRI en monothérapie (300 à 350 mg/m 2 toutes les trois semaines), 40 % de la variabilité des AUC de l'IRI était attribué principalement à des polymorphismes concernant les gènes ABCC2, notamment −24 T > C et 3972 C > T. Dans cette même étude, 30 % de la variabilité des AUC du SN- 38 était liée à des SNP affectant les gènes ABCC1 (1684 C > T) et ABCB1 (IVS9-44A > G) [84]. Dans une étude portant sur 167 patients caucasiens, et après exclusion des patients présentant le génotype UGT1A1*28, la mutation −1019 A > G du gène ABCC2 (ABCC2*2) a été associé à une clairance diminuée de l'IRI : 28,3 versus 31,6 L/heure (p = 0,020) et a une réduction très significative des diarrhées sévères : 10 % versus 44 %, (p = 0,005) [85]. Cette étude confirme ainsi que, chez les patients non prédisposés à une toxicité digestive du fait d'un phénotype UGT1A1 normal, d'autres polymorphismes impliquant les protéines de transport membranaire peuvent jouer un rôle important dans la pharmacocinétique de l'IRI. "
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    • "Differences in systemic exposure to irinotecan and SN-38 are to some extent explained by genetic variations in UGT1A1 (Paoluzzi et al, 2004) but not CYP3A (de Jong et al, 2006). Several membrane efflux pumps have a function in the bio-distribution of irinotecan and its metabolites, of which ABCB1 and ABCC2 are of particular interest (de Jong et al, 2007; Kweekel et al, 2008). Much effort has also been made to explore associations between polymorphisms in UGTs and either toxicity or antitumour response of irinotecan. "
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    ABSTRACT: A Valine residue at position 105 of the GSTP1 protein results in decreased enzyme activity. As nuclear GSTP1 activity decreases irinotecan cytotoxicity, Val-allele carriers may benefit more from irinotecan chemotherapy. Our aim was to investigate the association of GSTP1 genotype with treatment outcome of irinotecan. Progression-free survival (PFS) and toxicity were determined in 267 metastatic colorectal cancer (MCRC) patients who were treated with first-line capecitabine (CAP) plus irinotecan (CAPIRI), or CAP single agent in a prospective randomised phase III trial (CAIRO). GSTP1 genotype was determined by Pyrosequencing. Patients receiving CAP showed a PFS of 6.6 (Ile/Ile), 6.0 (Ile/Val) and 6.5 months (Val/Val); compared to 7.0 (Ile/Ile), 8.8 (Ile/Val) and 9.2 months (Val/Val) with CAPIRI. Median PFS was 2.7 months longer in Val-allele carriers treated with CAPIRI compared to CAP (P=0.005). Patients with the Ile/Ile genotype showed similar PFS with CAPIRI and CAP (7.0 compared to 6.6 months, P=0.972). Toxicity did not differ significantly among genotypes. GSTP1 codon 105 polymorphism may be predictive for the response to irinotecan-based chemotherapy in patients with MCRC, with the Val-allele being associated with a better outcome. Ile/Ile genotype patients do not appear to benefit from the addition of irinotecan to CAP.
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