Improved Anti‐Emetic Efficacy of 5‐HT₃ Receptor Antagonists in Cancer Patients with Genetic Polymorphisms of ABCB1 (MDR1) Drug Transporter

Abstract

Chemotherapy-induced nausea and vomiting (CINV) remains a major adverse effect decreasing quality of life in patients with cancer. Genetic variations among patients may be responsible for part of the lack of efficacy of anti-emetic drugs. The aim of this study was to investigate how the genetic variants of the drug transporter ABCB1 (MDR1) gene affect anti-emetic treatment with 5-HT3 receptor antagonists. Patients (n = 239) receiving moderately or highly emetogenic chemotherapy and ondansetron or granisetron were included in the study. Anti-emetic responses were recorded daily. The primary end-point of the assessment was the total control rates of CINV in the acute and delayed phases after chemotherapy. Genotyping was performed by PCR-RFLP. In the acute phase, patients with ABCB13435TT, 1236TT or 2677TT genotypes had a higher control rate of CINV than other genotype groups: (64.7% in 3435TT versus 45.7% in 3435CC+CT, p = 0.016; 65.1% in 1236TT versus 46.4% in 1236CC+CT, p = 0.027; 66.7% in 2677TT versus 46.5% in other genotypes, p = 0.021). Subjects carrying homozygous variant alleles together (TT-TT-TT) showed a significantly higher protection from nausea and vomiting (67.7% in TT-TT-TT versus 47.1% in other genotypes, p = 0.032). After the logistic regression analysis with adjustment for other known covariates, the total control rate was significantly higher in the 3435TT genotype group during the acute phase (p = 0.021). No significant change was found between the total control rates among genotypes in the delayed phase. Each of three 3435TT, C1236TT, 2677TT genotypes of ABCB1 and their combination was associated with about 50% higher anti-emetic response to 5-HT3 receptor antagonists in the acute phase of chemotherapy in patients with cancer receiving moderately or highly emetogenic chemotherapy. ABCB1 (MDR1) genotypes may contribute to predict the anti-emetic efficacy of 5-HT3 antagonists.

Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine

“…In a previous study of patients with cancer using antiemetic drugs, Zoto et al 27 have reported that TT-TT-TT haplotype frequency was 13% in a Turkish sample of 239 patients. Hence, the nonexistence of the ABCB1 TT-TT-TT haplotype we found in the agranulocytosis group is unexpected and might be a distinguishing factor in the development of CAA.…”

“…The forward and reverse primers (Alpha DNA, Montreal, Quebec, Canada) and PCR conditions were used as presented in previous studies. 26,27 The PCR reactions were performed in a total volume of 50 μL containing 100-to 200-ng DNA, 100 μM of each deoxynucleotides, 0.2 μM of each primers for G2677T/A, C3435T polymorphisms, and 0.1 μM of each primers for C1236T polymorphism, 2.5 U of Taq polymerase (New England Biolabs GmbH, Frankfurt, Germany), and 0.75 μL of dimethyl sulfoxide for only C1236T detection. Amplification was performed by using a thermal cycler (Applied Biosystems 2720, Waltham, Mass); restriction enzymes (New England Biolabs GmbH), corresponding fragment sizes for each allele, and incubation conditions have been described previously.…”

“…Amplification was performed by using a thermal cycler (Applied Biosystems 2720, Waltham, Mass); restriction enzymes (New England Biolabs GmbH), corresponding fragment sizes for each allele, and incubation conditions have been described previously. 26,27 Statistical Analysis Statistical analyses were performed using Prism 6.02 (Graphpad Software Inc, La Jolla, Calif ) and SigmaPlot v11.0 softwares (Systat Software Inc, Chicago, Ill). Regarding the comparison of sociodemographic features, the differences between the groups were evaluated using t test for independent variables.…”

Influence of ABCB1 and ABCG2 polymorphisms on the antiemetic efficacy in patients with cancer receiving cisplatin-based chemotherapy: a TRIPLE pharmacogenomics study

“…14,15 Moreover, there are several reports showing that polymorphisms of the adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) transporter protein are also associated with CINV and postoperative nausea and vomiting. [16][17][18][19][20] However, these investigations were on the basis of first-generation 5-HT 3 receptor antagonists, such as ondansetron and granisetron, without neurokinin-1 receptor antagonist, and there are conflicting reports on the effects of ABCB1 polymorphisms. Furthermore, in these studies, the use of antiemetic medications, such as dexamethasone, was not in accordance with the antiemetic guidelines.…”

Polymorphisms inCYP1A1andCYP3A5Genes Contribute to the Variability in Granisetron Clearance and Exposure in Pregnant Women with Nausea and Vomiting

“…Previous publications have shown that the haplotype (TT/TT) at positions 3435 and 2677 of the ABCB1 gene was associated with poorer treatment outcomes in patients with epilepsy and a required higher methadone dose in patients with heroin dependence . On the contrary, other publications have found a higher antiemetic response in patients that carry the genotype TT at positions 3435 and/or 2677 of the ABCB1 gene . Finally, ABCB1 activity increases during pregnancy; therefore drugs that are substrates for ABCB1 may become even less effective during pregnancy in patients that carry ABCB1 SNPs associated with reduced control of emesis.…”