Irinotecan Pharmacogenomics

Abstract

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...

Preclinical Activity of Nanoliposomal Irinotecan Is Governed by Tumor Deposition and Intratumor Prodrug Conversion

“…Pharmacogenetic and pharmacodynamic markers such as TOP1 have shown limited correlations with free irinotecan response (6,(32)(33)(34). In addition to the intrinsic sensitivity of tumor cells to SN-38, our data indicate that the duration for which tumor cells are exposed to SN-38 (tumor SN-38 duration) also plays a critical role in driving treatment response to irinotecan.…”

“…SN-38 is used when referring to the active metabolite of CPT-11.) The active SN-38 can be subsequently inactivated through glucuronidation by members of the UDP glucuronosyltransferase family (6). The principal mechanism of action leading to cell death is through DNA damage after replication-fork collisions with transient drug-TOP1 cleavage complexes, thus emphasizing the time of drug exposure as important driver for cytotoxicity of camptothecins (7,8).…”

Genetic polymorphisms in cytochrome P450 and clinical outcomes of FOLFIRI chemotherapy in patients with metastatic colorectal cancer

“…The metabolic pathways of irinotecan are complex, which include a number of enzymes and transporter proteins. Variability in genes coding for carboxylesterases (CES) involved i n i r i n o t e c a n a c t i v a t i o n , C Y P 4 5 0 a n d U D Pglucuronosyltransferase (UGT) participated in inactivation process, and ATP-binding cassette transporter family, specifically ABCB1, ABCC2, and ABCG2, which transported irinotecan and its metabolites out of the cell, may modulate irinotecan-induced toxicity and response [17,18]. Over the last decades, a variety of SNPs in the CES and UGT family have been comprehensively investigated in FOLFIRI regimen for mCRC, but only UGT1A1*28 and several SNPs in ABC family showed a correlation with good response and/or survival outcomes [19][20][21][22][23][24][25].…”

Correlation between plasma concentration ratios of SN-38 glucuronide and SN-38 and neutropenia induction in patients with colorectal cancer and wild-type UGT1A1 gene

“…These patients received CPT-11 chemotherapy for the first time (3 out of 5 patients) or the second time (1 patient), suggesting that, in certain cases, neutropenia induction cannot be predicted by UGT activity alone. In the clearances of CPT-11 and SN-38, multiple enzymes and transporters are involved, including carboxyesterases, UGT1A1, CYP3A4, P-glycoprotein, MRP2, BCRP and/or OATP1B1, although the contribution of OATP1B1 remains under discussion (12,(17)(18)(19)(20)(21)(22). To predict CPT-11-induced neutropenia in all patients systemically (Fig.…”