1. Introduction
Irinotecan, an anticancer prodrug is widely used for the treatment of solid cancer including colorectal, lung, and gastric cancer. It has been used either as monotherapy or in combination with 5-fluorouracil (5-FU)/leucovorin and is considered as first-line therapy in treating these cancers [1]. Severe neutropenia and diarrhea are the main toxicities associated with irinotecan treatment, resulting in treatment failure or even death [2].
As an inhibitor of topoisomerase I, irinotecan is converted by carboxylesterase into 7-ethyl-10-hydroxycamptothecin (SN-38), which is 100-1000 fold more active than the parent drug [3]. The active SN-38 causes cell death by preventing the DNA strand reannealing and interruption of DNA replication [4]. The active form of irinotecan, SN-38 is glucuronidated by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) to inactive SN-38 glucuronide (SN-38G) as part of detoxification process and is eliminated further through biliary/urinary excretion [5]. Therefore, the conjugating agent UGT1A1 encoded by the UGT1A1 gene is an important enzyme that plays a pivotal role in the glucuronidation of SN-38 [6].
Since life-threatening diarrhea or neutropenia may observed in ~25% of cancer patients taking irinotecan, these toxicities may have been related to interindividual UGT1A1genetic variability [7]. Being highly polymorphic of UGT1A1 , the most well-known polymorphism is UGT1A1*28 with seven TA repeats (A(TA)7TAA) in promoter region leading to ~70% reduced expression and ~48% reduced function of UGT1A1 conjugating enzyme [8]. Although several clinical studies have established the strong associations of UGT1A1*28 genetic polymorphisms with irinotecan induced severe toxicity such as diarrhea and neutropenia especially in Caucasian cancer patients, however, the results for this association are still inconclusive and controversial especially in Asian cancer patients [9-18].
In addition to UGT1A1*28 genetic polymorphism, other very important mutation of this gene is UGT1A1*6 causing ~30-60% reduced activity of UGT1A1 enzyme and is leading to irinotecan-induced toxicity, especially diarrhea and neutropenia in considerable proportion of Asian cancer patients as evidenced in multiple studies [19-25]. However, some studies did not find any significant association of UGT1A1*6 genetic polymorphism and irinotecan driven toxicities [18, 26].
When patients inheriting both of these polymorphisms (UGT1A1*6and UGT1A1*28), the toxicities of irinotecan may be exacerbated profoundly due to combined genetic effects as evidenced in some studies [14, 26-28] although the results are again inconclusive and inconsistent as found in other studies [18, 29-31]. In these controversial clinical situations, it is also important to noted that in addition to the UGT1A1 enzyme, irinotecan, SN-38 and SN-38G are transported out of the cell into bile by members of the ATP-binding cassette (ABC) transporter family especially ABCC2 encoded by theABCC2 gene [32, 33]. Therefore, genetic variations of theABCC2 especially c.3972C>T single nucleotide polymorphism is also suspected to influence inter-individual variability of irinotecan which may lead to toxicity as well [7, 32-35].
Although there are some meta-analyses that have assessed aggregated risk of neutropenia and diarrhea in cancer patients treating with irinotecan and inherited either UGT1A1*6 or UGT1A1*28 but the results were highly conflicting and inconsistent even combined effects (UGT1A1*6+*28 ) were not assessed in majority of these analyses especially in Asian patients [16, 18, 20, 36-40]. Also, there was no meta-analysis appeared in the literature assessing the association ofABCC2 c.3972C>T genetic polymorphism with irinotecan-induced toxicity. Therefore, this study was aimed to establish a robust evidence by assessing the aggregated risk of neutropenia or diarrhea in Asian cancer patients inherited eitherUGT1A1*6, UGT1A1*28 , combination of these variants (UGT1A1*6+UGT1A1*28 ) or ABCC2 c.3972C>T genetic polymorphisms.