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. 2020 Aug 10;10(1):13486.
doi: 10.1038/s41598-020-70351-0.

Effect of drug metabolizing enzymes and transporters in Thai colorectal cancer patients treated with irinotecan-based chemotherapy

Chalirmporn Atasilp  1   2   3 , Phichai Chansriwong  4 , Ekaphop Sirachainan  4 , Thanyanan Reungwetwattana  4 , Suwannee Sirilerttrakul  4 , Monpat Chamnanphon  5 , Apichaya Puangpetch  2   3 , Chonlaphat Sukasem  6   7
Affiliations

Effect of drug metabolizing enzymes and transporters in Thai colorectal cancer patients treated with irinotecan-based chemotherapy

Chalirmporn Atasilp et al. Sci Rep. .

Abstract

Genetic polymorphisms in drug metabolizing enzymes and drug transporters may affect irinotecan toxicity. Although genetic polymorphisms have been shown to influence the irinotecan toxicity, data are limited in Thai population. Thus, the aim of this study was to assess the allele and genotype frequencies and the relationship between CYP3A4/5, DPYD, UGT1A1, ABCB1, and ABCC2 genetic variations and irinotecan-induced toxicity in Thai colorectal cancer patients. One hundred and thirty-two patients were genotyped, and the effect of genetic variations on irinotecan-induced toxicity was assessed in 66 patients who received irinotecan-based chemotherapy. Allele frequencies of ABCB1 c.1236C > T, ABCB1 c.3435C > T, ABCC2 c.3972C > T, ABCG2 c.421C > A, CYP3A4*1B, CYP3A4*18, CYP3A5*3, DPYD*5, UGT1A1*28, and UGT1A1*6 were 0.67, 0.43, 0.23, 0.27, 0.01, 0.02, 0.64, 0.19, 0.16, and 0.09, respectively. DPYD*2A and DPYD c.1774C > T variants were not detected in our study population. The ABCC2 c.3972C > T was significantly associated with grade 1-4 neutropenia (P < 0.012) at the first cycle. Patients carrying both UGT1A1*28 and *6 were significantly associated with severe neutropenia at the first (P < 0.001) and second (P = 0.017) cycles. In addition, patients carrying UG1A1*28 and *6 had significantly lower absolute neutrophil count (ANC) nadir at first (P < 0.001) and second (P = 0.001) cycles. This finding suggests that UGT1A1*28, *6, and ABCC2 c.3972C > T might be an important predictor for irinotecan-induced severe neutropenia.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Flow chart for patient screening. A total of 132 metastatic colorectal cancer patients were genotyped for genetic polymorphisms and 66 patients who did not treated with irinotecan-based chemotherapy were excluded. Of the 66 patients treated with irinotecan-based chemotherapy were included in this analysis.
Figure 2
Figure 2
Association of combined UGT1A1 genotype (*28 and *6) with absolute neutrophil count nadir (/mm3) at first cycle and second cycle. (A) At first cycle, (B) at second cycle.
Figure 3
Figure 3
Association of combined UGT1A1 genotype (*28 and *6) with absolute count neutrophil (ANC) nadir to the ANC baseline (pretreatment) at first cycle and second cycles. (A) At first cycle, (B) at second cycle.
See this image and copyright information in PMC

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