Abstract
Irinotecan (CPT-11) is a semisynthetic derivative of the antineoplastic agent camptothecin used in a wide range as an anti-cancer agent in many solid tumors because of its cytotoxic effect through the interaction with the topoisomerase I enzyme. The major limiting factors for irinotecan treatment are its association with potentially life-threatening toxicities including neutropenia and acute or delayed-type diarrhea, results from distinct interindividual and interethnic variability due to gene polymorphism.
 This is a cross sectional pharmacogentics study was conducted on 25 cancer patients to estimate the prevalence of UGT1A1*93 and ABCC5 allele single nucleotide polymorphism (SNP) in Iraqi cancer patients treated with irinotecan-based therapy at Middle Euphrates Cancer Center. Four drops of venous blood was drawn for each patient and was applied onto the FTA classic card to perform a genotyping assay for the 2 SNPs. After DNA isolation and purification, real time PCR was performed to detect the SNPs of each gene.
 Results of this study showed the prevalence of one allele variant (heterozygous mutation) of UGT1A1*93 was 64% compared to 36% of patients were wild type to this SNP. No patient (0%) could be detected with homozygous polymorphism of the UGT1A1*93. For the ABCC5 polymorphism, results revealed that 32% of patients have one polymorphic allele (heterozygous), while 28% of them have two polymorphic alleles (homozygous mutation). Wild type ABCC5 gene constitutes 40% of patients. As a conclusion, high prevalence of UGT1A1*93 and ABCC5 polymorphic alleles were detected in patients at Middle Euphrates Cancer Center which may explain the high toxicity features associated with irinotecan therapy.
Highlights
Toxicity and efficacy as a result of the administered drugs is the field of interest for any health care providers (HCP) during the patientsThere is an evidence suggesting that the effectiveness and toxicity of any drug may be affected, at least in part, by a genetic polymorphism follow up.Iraqi Journal of Pharmaceutical Sciences responsible for drug metabolism or drug targets[1]
(7) Irinotecan is a pro-drug, and it activated through a hydrolysis reaction catalyzed by two isoforms of carboxylesterases enzyme (CES1 and 2) in vivo to active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) through cleavage of the ester-bond at C10(8,9)
This study is considered the first study that estimate the prevalence of the UGT1A1*93 and ABCC5 polymorphisms in Iraq
Summary
Toxicity and efficacy as a result of the administered drugs is the field of interest for any health care providers (HCP) during the patientsThere is an evidence suggesting that the effectiveness and toxicity of any drug may be affected, at least in part, by a genetic polymorphism follow up.Iraqi Journal of Pharmaceutical Sciences (changes in the genetic code that found in more than 1% of the human population) responsible for drug metabolism or drug targets[1]. Pharmacogenetics is the filed that interest in the study of how genetic variation affects individuals’ response to drugs[1,2]. This inter-individual variation can range from inadequate therapeutic efficacy to serious, potentially life-threatening adverse drug reactions.[2,3] The clinical use of this field aims to reduce the potential for adverse drug reactions and maximize drug response by matching the best available drug or dose to an individual’s genomic profile[4,5,6]. It is further conjugated and detoxified in the hepatic cells by UDP-glucuronosyltransferase (UGT) 1A1 and 1A9 enzyme and extrahepatic by UGT1A7 enzyme to yield its h-glucuronide, SN-38 G.(10) SN-38 and SN38G are substrates for protein pumps, responsible for a unidirectional compound efflux from hepatocytes into bile and urine [ATP binding cassette (ABC) transporters] to be eliminated. [11]
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