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.