UGT1A1 gene polymorphism: Impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer

Schulz, Christoph; Heinemann, Volker; Schalhorn, Andreas; Moosmann, Nikolas; Zwingers, Thomas; Boeck, Stefan; Gießen, Clemens; Stemmler, Hans-Joachim

doi:10.3748/wjg.15.5058

Cited by 44 publications

(39 citation statements)

References 39 publications

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“…Despite previous studies [5, 9, 12], our results show that irinotecan, even in low doses, can cause serious toxicity in patients carrying UGT polymorphisms. However, some ten years after the first reports on the role of UGT s on irinotecan toxicity, many questions remain to be answered.…”

Section: Discussioncontrasting

confidence: 99%

“…Lankisch et al [5] did not correlate UGT1A1*28 polymorphism with toxicity in patients receiving low-dose irinotecan regimens (80 mg/m 2 /wk). Schulz et al [9] mentioned no significant effect of UGT1A1*28 polymorphism on irinotecan toxicity in patients treated with low-dose irinotecan (80 mg/m 2 /wk, modified FOLFIRI – modified IROX) as well. In a meta-analysis, Hoskins et al [12] concluded that the risk of toxicity was not statistically different between UGT1A1*28/*28 and UGT1A1*1/*1 at low irinotecan doses and patients receiving lower doses should not be genotyped.…”

Section: Discussionmentioning

confidence: 99%

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ecancermedicalscience

Τζιώτου

Kalotychou

Ntokou

et al.

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Uridine glucuronosyltransferase (UGT) gene polymorphisms have been linked to irinotecan toxicity. Our purpose was to study the association between UGT1A1*28, UGT1A7*2, and UGT1A7*3 polymorphisms and irinotecan toxicity in Greek patients receiving low-dose weekly irinotecan. Blood samples were collected for 46 patients. DNA was extracted and UGT1A1 promoter and UGT1A7 exon 1 genotyping was carried out. Laboratory tests and physical examination were performed on regular basis for the assessment of toxicity. UGT1A1*28 was significantly correlated with both haematologic and non-haematologic toxicity. Moreover, patients carrying UGT1A7 polymorphisms had significant incidence of toxicity. To conclude, UGT polymorphisms play a role in the toxicity of irinotecan, even if the drug is administered in low doses. The genotyping test may be a useful tool for the management of patients who are going to receive irinotecan.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ecancermedicalscience

Τζιώτου

Kalotychou

Ntokou

et al.

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“…For moderate-to-high doses (200–350 mg/m 2 ), the risk of severe hematological toxicity in patients homozygous for UGT1A1*28 is 27.8-times higher than for patients with at least one wild-type allele [38]. Furthermore, a European study confirmed that toxicity from low-dose irinotecan was not affected by the UGT1A1*28 variant [39]. Consequently, it appears necessary to further amend the irinotecan package insert to include dose/genotype guidelines.…”

Section: Irinotecan Pharmacokineticsmentioning

confidence: 99%

Irinotecan Pharmacogenomics

Marsh

Hoskins²

2010

Pharmacogenomics

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Irinotecan is a camptothecin analog used as an anticancer drug. Severe, potentially life-threatening toxicities can occur from irinotecan treatment. Although multiple genes may play a role in irinotecan activity, the majority of evidence to date suggests that variation in expression of UGT1A1 caused by a common promoter polymorphism (UGT1A1*28) is strongly associated with toxicity; however, this link is dose dependent. Variations in other pharmacokinetic genes, particularly the transporter ABCC2, also contribute to irinotecan toxicity. In addition, recent studies have shown that pharmacodynamic genes such as TDP1 and XRCC1 can also play a role in both toxicity and response. KeywordsABCC2; irinotecan; pharmacogenomics; TDP1; toxicity; UGT1A1; XRCC1 Camptothecin, a cytotoxic agent found in Camptotheca acuminata, was developed as an anticancer agent in the early 1970s [1][2][3]. Its mechanism of action is to bind to the DNA/ topoisomerase I complex during DNA replication, preventing the resealing of single-strand breaks. Ultimately, the replication machinery collides with the camptothecin/toposiomerase I complex, shattering the DNA [4]. However, camptothecin is insoluble and attempts to address this both reduced the efficacy and increased the toxicity of the drug.Camptothecin analogs were developed in the 1990s to circumvent the solubility problems. Irinotecan (also known as CPT-11, Camptosar®) is an analog approved for first-line therapy of advanced colorectal cancer in combination with 5-fluorouracil and/or leucovorin. In addition, irinotecan/cisplatin combination therapy is used for other cancers, for example lung and ovarian [5][6]. Recent studies have involved the combination of irinotecan with bevacizumab or cetuximab [1-2,7-8].Diarrhea and neutropenia are major limiting factors for irinotecan, with up to 36% of patients experiencing severe, potentially life-threatening toxicities [9]. Methods such as pharmacogenomics to prospectively screen patients for DNA variations (Table 1) Irinotecan pharmacokinetics MetabolismIrinotecan is a prodrug, metabolized into the active form, SN-38, via human carboxylesterases CES1 and CES2. CYP3A4 converts irinotecan into the inactive metabolite, APC. The active SN-38 can be subsequently inactivated through glucuronidation via members of the UDP-glucuronosyltransferase family [12]. UGT1A enzymes are a product of alternative splicing from the UGT1A locus located on chromosome 2q37. A total of 13 UGT1A genes are encoded at this locus (including four pseudogenes). Each UGT1A enzyme has a unique promoter and a unique exon 1, while the remaining four exons are shared with all members of the UGT1A family [13]. Metabolism pharmacogenomicsCarboxylesterases-Carboxylesterase 2 is the key enzyme responsible for hydrolyzing CPT-11 to the active SN-38 form [14]. CES2 expression is highly variable among individuals [15][16], and in vitro studies suggest that increased CES2 expression leads to increased irinotecan metabolism [17]. However, extensive assessment of the CES2 gene did n...

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“…[27,28] However, other reports suggested that UGT1A1 gene polymorphism did not affect patient survival times. [29][30][31] The results of a recent meta-analysis of studies on the correlation between UGT1A1*28 genotype and prognosis of patients with colorectal cancer suggested that there were significant differences in PFS and OS between the gene subtypes. In low-dose irinotecan treatment subgroup, there was a difference in the OS of homozygous mutant patients.…”

Section: Discussionmentioning

confidence: 97%