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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    ABSTRACT: Colorectal cancer (CCR), which is one of the most common causes of cancer, has benefited from the major advances in the understanding of the intracellular signaling pathways implicated in the initiation, growing and local and metastasis dissemination of tumor, which have occurred during the 20 past years. The pharmacogenomics approach, especially the determination of the genetic polymorphisms, tries to find prognosis and predictive biomarkers permitting to identify patients who could benefit from a particular treatment or those exhibiting higher risks of toxicity. Among the numerous biomarkers, which have been studied, few are currently in use in clinical practice. The phenotyping of DPD and UGT1A1 activities, and to a lesser extent, its genotyping, appears as the most useful tool in terms of prediction of toxicities induced by two major drugs: 5-FU and irinotecan. For oxaliplatin, the determination of the polymorphisms of reparases and detoxification systems such as GSTpi seems interesting, but its exact place should be more defined. It is in the field of targeted therapies that the pharmacogenomics approach seems to be the more relevant. KRAS mutation is a dramatic example of single nucleotide polymorphism, which is able to identify a priori patients that could receive or not an anti-EGFR monoclonal antibody such as cetuximab or panitumumab. It is obvious that pre-clinical identification of molecular biomarkers predictive of the sensitivity of the drug targets, which subsequently implicate the selection of patients and the rational evaluation of responses, will be the cornerstone of any clinical trials concerning targeted therapies. Besides the determination of drug target polymorphisms, it is also important to consider those related to the distribution and metabolism. In this area, the determination of enzymatic activities should recover its place besides the genomic profiling.
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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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