ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients
Irinotecan is widely used in the treatment of metastatic colorectal cancer (mCRC) despite its severe toxicities. Toxicity is often associated with the UGT1A1*28/*28 genotype. An explanation for idiopathic toxicity beyond the UGT1A1 biomarker, however, remains a major concern for clinicians. One of t...
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Frontiers Media S.A.
2020-06-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2020.00973/full |
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| author | Pau Riera Pau Riera Pau Riera Alícia Artigas-Baleri Juliana Salazar Ana Sebio Anna C. Virgili María Jesús Arranz David Páez David Páez |
| author_facet | Pau Riera Pau Riera Pau Riera Alícia Artigas-Baleri Juliana Salazar Ana Sebio Anna C. Virgili María Jesús Arranz David Páez David Páez |
| author_sort | Pau Riera |
| collection | DOAJ |
| description | Irinotecan is widely used in the treatment of metastatic colorectal cancer (mCRC) despite its severe toxicities. Toxicity is often associated with the UGT1A1*28/*28 genotype. An explanation for idiopathic toxicity beyond the UGT1A1 biomarker, however, remains a major concern for clinicians. One of the main irinotecan transporters is P-glycoprotein (P-gp), which is a hepatic efflux pump encoded by ABCB1. P-gp is involved in the biliary excretion of irinotecan and its active metabolite SN-38. We aimed to assess whether functional variants in ABCB1 also contribute to identifying patients at risk of toxicity. A cohort of 308 mCRC patients treated with irinotecan-based regimens were genotyped for polymorphisms in ABCB1 (rs1128503, rs2032582, and rs1045642). The effect of these variants and their haplotypes on irinotecan-induced severe toxicity (diarrhea, neutropenia, asthenia, nausea, and mucositis) was assessed. After adjusting for the relevant clinical and pathological parameters in the multivariate analysis, we found rs1128503 was significantly associated with severe diarrhea and mucositis (P=0.014 and P=0.002, respectively). Additionally, rs2032582 was associated with severe mucositis (P<0.001). Our results show that rs1128503 genotyping could help to predict severe gastrointestinal toxicity induced by irinotecan. |
| first_indexed | 2024-04-14T00:48:26Z |
| format | Article |
| id | doaj.art-ef87d544c8fd470cadea439b80e3e587 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-14T00:48:26Z |
| publishDate | 2020-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-ef87d544c8fd470cadea439b80e3e5872022-12-22T02:21:54ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122020-06-011110.3389/fphar.2020.00973549961ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer PatientsPau Riera0Pau Riera1Pau Riera2Alícia Artigas-Baleri3Juliana Salazar4Ana Sebio5Anna C. Virgili6María Jesús Arranz7David Páez8David Páez9Genetics Department, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainFaculty of Pharmacy and Food Sciences, Universitat de Barcelona (UB), Barcelona, SpainPharmacy Department, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainGenetics Department, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainTranslational Medical Oncology Laboratory, Institut de Recerca Biomèdica Sant Pau, (IIB-Sant Pau), Barcelona, SpainMedical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainMedical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainResearch Laboratory, Fundació Docència i Investigació Mútua Terrassa, Terrassa, SpainMedical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainU705, ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, SpainIrinotecan is widely used in the treatment of metastatic colorectal cancer (mCRC) despite its severe toxicities. Toxicity is often associated with the UGT1A1*28/*28 genotype. An explanation for idiopathic toxicity beyond the UGT1A1 biomarker, however, remains a major concern for clinicians. One of the main irinotecan transporters is P-glycoprotein (P-gp), which is a hepatic efflux pump encoded by ABCB1. P-gp is involved in the biliary excretion of irinotecan and its active metabolite SN-38. We aimed to assess whether functional variants in ABCB1 also contribute to identifying patients at risk of toxicity. A cohort of 308 mCRC patients treated with irinotecan-based regimens were genotyped for polymorphisms in ABCB1 (rs1128503, rs2032582, and rs1045642). The effect of these variants and their haplotypes on irinotecan-induced severe toxicity (diarrhea, neutropenia, asthenia, nausea, and mucositis) was assessed. After adjusting for the relevant clinical and pathological parameters in the multivariate analysis, we found rs1128503 was significantly associated with severe diarrhea and mucositis (P=0.014 and P=0.002, respectively). Additionally, rs2032582 was associated with severe mucositis (P<0.001). Our results show that rs1128503 genotyping could help to predict severe gastrointestinal toxicity induced by irinotecan.https://www.frontiersin.org/article/10.3389/fphar.2020.00973/fullABCB1P-glycoproteinirinotecan (CPT-11)gastrointestinal toxicitydiarrheamucositis |
| spellingShingle | Pau Riera Pau Riera Pau Riera Alícia Artigas-Baleri Juliana Salazar Ana Sebio Anna C. Virgili María Jesús Arranz David Páez David Páez ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients Frontiers in Pharmacology ABCB1 P-glycoprotein irinotecan (CPT-11) gastrointestinal toxicity diarrhea mucositis |
| title | ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients |
| title_full | ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients |
| title_fullStr | ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients |
| title_full_unstemmed | ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients |
| title_short | ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients |
| title_sort | abcb1 genetic variants as predictors of irinotecan induced severe gastrointestinal toxicity in metastatic colorectal cancer patients |
| topic | ABCB1 P-glycoprotein irinotecan (CPT-11) gastrointestinal toxicity diarrhea mucositis |
| url | https://www.frontiersin.org/article/10.3389/fphar.2020.00973/full |
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