Irinotecan eventually preventing DNA re-ligation leading to the

IrinotecanCamptothecin analogs were developed in the 1990s toprevent the solubility problems associated with camptothecin, a cytotoxic agentdeveloped as an anticancer agent in the early 1970s. Camptothecin and itsanalogs inhibit DNA topoisomerase I eventually preventing DNA re-ligationleading to the failure of the replication machinery 1. Irinotecan (also knownas CPT-11) is one of the analogs approved for first-line therapy of advancedcolorectal cancer in combination with 5-fluorouracil and/or leucovorin. In addition,irinotecan has also been used with cisplatin as a combination therapy for othercancers, such as lung and ovarian 2. The major limiting factors of irinotecan are diarrheaand neutropenia that can range from severe to potentially life-threatening. Thegastrointestinal and vascular effects have been associated with a highmortality rate in patients receiving the combination of irinotecan with bolusfluorouracil and leucovorin during the first 60 days of therapy. The severityof toxicities and effectiveness of irinotecan therapy vary greatly inpopulations due to genetic differences in different factors involved inpharmacokinetics and pharmacodynamics.

Pharmacogenomics can be applied toscreen patients for such genetic (DNA variations) prior to selecting irinotecantherapy so as to optimize its therapy and reduce health care costs 3.Irinotecan pharmacokineticsIrinotecan is a prodrug which is converted to SN-38 bycarboxylesterase 2, resulting in a greater than 1,000-fold enhancement ofcytotoxic activity. Irinotecan, before activation, is processed by cytochromeP450 (CYP450) enzymes and transported by ATP-Binding Cassette (ABC) effluxpumps.

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The active metabolite either binds to topoisomerase-I of the target(tumor) cell or is exported out of the cell via efflux pumps. SN-38 can also beinactivated by glucuronide conjugation.  Whileeach of these steps has the potential to substantially regulate irinotecanactivity, it is glucuronidation by the protein UGT1A1 that has the clearestpotential impact on patient care.Uridine-diphosphate glucoronosyl transferase (UGTs)are responsible for glucoronidation of lipophilic compounds that converts themto more polar form.

UDP-glucoronic acid is used as a co-substrate for thereaction that catalyzes a variety of substrates such as bilirubin, hormones,drugs, and other xenobiotics, leading to the formation of more hydrophilicconjugates facilitating their elimination through bile and urine.MetabolismIrinotecan is a prodrug, metabolized into the activeform, SN-38, via human carboxylesterases CES1 and CES2, primarily in the liver.Irinotecan is converted into APC, an inactive metabolite by CYP3A4. The activeSN-38 can be subsequently inactivated through glucoronidation via members ofthe UDP glucuronosyltransferase (UGT) family. A total of 13 UGT1A genes areencoded at the UGT1A locus located on chromosome 2q37t. Each UGT1A enzyme has aunique promoter and a unique exon 1, while the remaining four exons are sharedwith all members of the UGT1A family 4.

Metabolism pharmacogenomicsCES2—CPT-11 ishydrolyzed to the active form, SN-38, primarily by carboxylesterase-2 (CES2).CES2 expression is highly variable among individuals, and increased CES2expression leads to increased irinotecan metabolism 5. However, researchershave not been able to identify any functional polymorphisms associated with theCES2 gene expression. Some of the minor individual variations in CES2 expressioncan be attributed to the control of its three distinct promoters 6. CES1plays a minor role in irinotecan metabolism.

CYP3A4—CYP3A4inactivates irinotecan through conversion into the metabolite APC. While thereis no evidence of variants in the CYP3A4 gene providing a useful screen for APCconversion, the interindividual variability in CYP3A4 activity can be exploitedfor irinotecan dosing 7.UGT1A1—The mostcomprehensively studied genetic marker linked to toxicity from irinotecantherapy is found in the UDP-glucuronosyltransferase gene, UGT1A1.

The UGT1A1enzyme is responsible for hepatic bilirubin glucuronidation, and reduced UGT1A1expression leads to Gilbert’s syndrome, a condition characterized by rise inthe plasma levels of unconjugated bilirubin. In fact, three forms of heritableunconjugated hyperbilirubinemias exist in humans including Crigler-Najjarsyndrome type 1 and type 2 and Gilbert’s syndrome. These heritable syndromesare all the result of low activity UGT1A1 gene or promoter alleles.

Apolymorphic dinucleotide repeat within the UGT1A1 promoter TATA element consistingof between five and eight copies of a TA repeat (TAnTAA) control theexpression of UGT1A1 gene. The (TA)6TAA allele is the most common (consideredwild-type) and (TA)7TAA is the most frequently recorded variant allele (usuallydenoted UGT1A1*28) 8. The length of the repeat allele has been found to beinversely proportional to UGT1A1 expression, that is, the longer the repeatallele, the lower the corresponding UGT1A1 gene expression. The frequency ofthe UGT1A1*28 allele has been assessed worldwide and ranges from approximately15% in Asians to 45% in Africans.

It is also found in 26–38% of Caucasians,African–Americans and Hispanics. The decrease in expression of UGT1A1 geneleads to reduced glucoronidation leading to build up of SN-38 metabolite in theplasma, leading to increased toxicity 8. Many studies haveestablished the link between UGT1A1*28 and irinotecan toxicity, and a prospectivestudy of 66 patients with advanced disease treated with irinotecan found that patientshomozygous for UGT1A1*28 had a significantly greater risk of grade IV neutropeniacompared with patients with at least one wild-type allele.Other UGT1A1 polymorphisms—Thereare other significant polymorphisms in the UGT1A1 gene. Patients withhaplotypes containing both the ?3156G>A variant and UGT1A1*28 experiencedsignificantly higher incidence of severe neutropenia compared with patientswith haplotypes not containing ?3156G>A 9.

In Asian populations where the frequency of UGT1A1*28is low, other UGT1A1 variants can also play a role in irinotecan toxicity. Forexample, in Korean patients with non-small-cell lung cancer treated withirinotecan-containing therapy, there were associations between, irinotecan pharmacokinetics,and toxicity from irinotecan therapy. Other UGT1A genes—Variantsin UGT1A7 and UGT1A9 are also associated with SN-38 glucuronidation andirinotecan toxicities, although these studies require further exploration. UGT1A7*3has been associated with hematologic toxicity in metastatic colorectal cancerpatients treated with irinotecan 10. Furthermore, UGT1A7*2 and *3, as well asUGT1A9 -118(dT) alleles, were associated with response to irinotecan.