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Clinical Investigations |
First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya 466-8550 [Y. A., M. A., Y. H.]; Department of Internal Medicine, Nagoya National Hospital, Nagoya 460-0001 [H. S.]; Division of Respiratory Medicine, Gifu Municipal Hospital, Gifu 500-8323 [T. S.]; Department of Medical Oncology, National Cancer Center Hospital, Tokyo 104-0045 [K. M.]; Second Department of Medicine, Okayama University Medical School, Okayama 700-8558 [H. U.]; Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata 951-8566 [A. Y.]; Department of Gastroenterology, Aomori Prefectural Central Hospital, Aomori 030-8553 [S.S.]; and Department of Preventive Clinical Medicine, Nagoya University, Nagoya, 461-0047 [K. S.], Japan
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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0.9 x 109/liter)
and/or grade 3 (watery for 5 days or more) or grade 4 (hemorrhagic or
dehydration) diarrhea. Of the 26 patients with the severe toxicity, the
genotypes of UGT1A1*28 were homozygous in 4 (15%) and
heterozygous in 8 (31%), whereas 3 (3%) homozygous and 10 (11%)
heterozygous were found among the 92 patients without the severe
toxicity. Multivariate analysis suggested that the genotype either
heterozygous or homozygous for UGT1A1*28 would be a
significant risk factor for severe toxicity by irinotecan
(P < 0.001; odds ratio, 7.23; 95%
confidence interval, 2.52–22.3). All 3 patients heterozygous for
UGT1A1*27 encountered severe toxicity. No statistical
association of UGT1A1*6 with the occurrence of severe
toxicity was observed. None had UGT1A1*29 or
UGT1A1*7. We suggest that determination of the
UGT1A1 genotypes might be clinically useful for
predicting severe toxicity by irinotecan in cancer patients. This
research warrants a prospective trial to corroborate the usefulness of
gene diagnosis of UGT1A1 polymorphisms prior to
irinotecan chemotherapy. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Irinotecan is metabolized by carboxylesterase to form an active SN-38, which is further conjugated and detoxified by UGT (EC 2.4.1.17) to yield its ß-glucuronide (7) . The glucuronide is excreted in the small intestine via bile, where bacterial glucuronidase resolves the glucuronide into the former SN-38 and glucuronic acid (8) . Interindividual differences in pharmacokinetics of SN-38 are suggested to cause the variation in drug effect (9 , 10) . On the other hand, there are two UGT enzymes in humans, UGT1 and UGT2, and the UGT1 family consists of one gene along with multiple promoters and the first exons which are spliced to the mutual exon 2 (11) . Thus, the substrate specificity of the enzyme depends on the first exon. The UGT1A1 gene is composed of a promoter and the first exon closest to exons 2–5 (11 , 12) . UGT1A1 enzyme, which is primarily responsible for conjugating bilirubin, can glucuronidate drugs (e.g., ethinylestradiol), xenobiotic compounds (e.g., phenols, anthraquinones, and flavones), and endogenous steroids (13) . At present, >30 genetic variations in a promoter region and exons have been known to decrease the enzyme activity, leading to constitutional unconjugated jaundice, Crigler-Najjar or Gilbert’s syndrome (12) . Recent in vitro analyses have revealed that the UGT1A1 isoform would be responsible for the glucuronidation of SN-38 and that the genetic variation would associate with the decreased activity of SN-38 glucuronidation as well as bilirubin (14 , 15) . Additionally, we have suggested an interindividual difference in the pharmacokinetics of SN-38 and SN-38 glucuronide, depending on the UGT1A1 genotype (16) . Thus, we speculated that the variant genotypes would increase the toxicity by irinotecan via excessive accumulation of its active metabolite SN-38.
Genotypes involved in Gilbert’s syndrome rather than Crigler-Najjar syndrome II would be clinically important for explanation of patient-patient variations in the reaction to a drug that is mainly conjugated by UGT1A1. Hyperbilirubinemia in a patient with Gilbert’s syndrome is usually milder than that in Crigler-Najjar syndrome II, and 3–10% of the general population are estimated to have Gilbert’s syndrome (17) . Moreover, genotypes found in Gilbert’s syndrome are also noted in seemingly healthy individuals and do not always cause hyperbilirubinemia (18, 19, 20, 21, 22) , probably because of nongenetic factors including diet and therapeutic drug use. Thus, cancer patients carrying the genotypes associated with Gilbert’s syndrome may be possible candidates for irinotecan chemotherapy.
This study retrospectively investigated the impact of the genetic
polymorphism of UGT1A1 on the likelihood of severe toxicity
in patients receiving irinotecan in cancer chemotherapy. The genotype
analyses were centered on those associated with Gilbert’s syndrome
(Table 1)
. Two types of variant genotypes
have been reported in this syndrome. One is a 2-bp insertion (TA) in
the TATA box in the promoter [normal (TA)6TAA],
resulting in the sequence (TA)7TAA,
UGT1A1*28 (12
, 18
, 19)
, and the other is a
heterozygous (sometimes homozygous) single nucleotide change in the
coding region (23)
, all of which have been reported to
reduce UGT1A1 activity (19
, 24 , 25)
. Our hypothesis is
that a patient with the variant genotypes would be at higher risk for
severe hematological toxicity and/or diarrhea because of a relatively
increased bioavailability of active unconjugated SN-38, and that some
of the unexpected severe toxicity might be explained by the genetic
factor. The goal of the present study is to explore a clinical
advantage of determining UGT1A1 polymorphisms prior to
irinotecan chemotherapy for predicting the toxicity.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We retrospectively reviewed the clinical records including patient
characteristics (age, gender, primary disease and previous treatments,
evidence of distant metastasis, Eastern Cooperative Oncology Group
performance status, and major complications), dosage, and schedule of
irinotecan administration, concurrent use of other drugs or
radiotherapy, and observed toxicity after irinotecan infusion. We
counted the number of days when patients received granulocyte-colony
stimulating factors or loperamide hydrochloride, which is commonly
prescribed for irinotecan-induced diarrhea in Japan. Prophylactic uses
of granulocyte-colony stimulating factor could not be clearly
distinguished from those for neutropenia. Because the dose-limiting
toxicity of irinotecan results in leukopenia and diarrhea
(4)
, we defined "severe toxicity" in this research as
leukopenia of grade 4 (0.9 x 109/liter) and/or diarrhea of grade 3 or worse
(grade 3, watery for 5 days or more; grade 4, hemorrhagic or
dehydration), classified in accordance with the Japan Society for
Cancer Therapy criteria (26)
. The other toxicity was not
included in the analysis because anemia would be influenced by
miscellaneous patients’ backgrounds including gastrointestinal lesions
or nutritious status, and because simultaneous uses of cisplatin or
carboplatin probably result in extremely exacerbated nausea/vomiting or
thrombocytopenia, respectively. Serum total bilirubin levels were
obtained just prior to irinotecan administration along with the highest
of those after initiation of the therapy. The study was approved by the
Ethical Committees of Nagoya University School of Medicine and the
participating institutes.
Genotyping.
Blood sampling and genetic analyses were performed after irinotecan
administration in each patient. Genomic DNA was prepared from whole
blood (100–200 µl) using the QIAamp Blood kit (Qiagen, Hilden,
Germany). We researched the following variant sequences (Table 1
; Ref.
12
): a two-extra-nucleotide insertion (TA) within the TATA
box resulting in the sequence (TA)7TAA (-39 to
-53, UGT1A1*28; Refs. 18
and 19
);
a transition (+211 from the initial site of the transcription, G to A)
at codon 71 in exon 1 that changes glycine to arginine (G71R,
UGT1A1*6; Refs. 23
and 27
); a
transversion (+686, C to A) at codon 229 in exon 1 that alters proline
to glutamine (P229Q, UGT1A1*27; Ref. 23
); a
transversion (+1099, C to G) at codon 367 in exon 4 that converts
arginine to glycine (R367G, UGT1A1*29; Ref.
23
); and a transversion (+1456, T to G) at codon 486 in
exon 5 that transforms tyrosine into aspartic acid (Y486D,
UGT1A1*7; Ref. 27
).
UGT1A1*28 was distinguished from the most common allele (UGT1A1*1) by direct sequencing (-147 to +106) of 253–255 bp produced by PCR using the method described previously (18 , 20) . Cycle sequencing was performed with a dye terminator sequence reaction (ABI Prism DNA Sequencing kit; Perkin-Elmer, Foster City, CA) using an ABI PRISM 310 Genetic Analyzer. The remaining variant sequences were distinguished from UGT1A1*1 by PCR-RFLP assay. For the analysis of exon 1, the first-step PCR amplification of a 923-bp fragment containing the exon 1 was performed in accordance with the reported method (21) . Subsequently, for the analysis of UGT1A1*6, the second set of PCR amplifications was carried out using nested primers designed to amplify a 235-bp segment. The mismatched forward and the reverse primer was 5'-CTAGCACCTGACGCCTCGTTGTACATCAGAGCC-3' (+178 to +210; underlining indicates mismatched site) and 5'-CCATGAGCTCCTTGTTGTGC-3' (+393 to +412), respectively. The forward primer was designed to introduce a MspI (Takara Shuzo Co., Ltd., Otsu, Japan) restriction site in UGT1A1*1 (+209 to +212), not in UGT1A1*6. The 1000-fold diluted product of the first PCR was subjected to nested PCR in a volume of 50 µl containing 0.2 mM of each deoxynucleoside triphosphate, 50 mM KCl, 10 mM Tris-HCl (pH 8.3), 1.5 mM MgCl2, 0.5 µM of each primer, and 1.3 unit of Taq polymerase (Takara Shuzo Co., Ltd.). PCR conditions were: 95°C for 5 min followed by 25 cycles of 94°C for 30 s, 60°C for 40 s, and 72°C for 40 s (PCR Thermal Cycler MP; Takara Shuzo Co., Ltd.). A 1-µl PCR product was digested with 4 units of MspI for 1 h at 37°C. DNA from UGT1A1*1 was digested into 203- and 32-bp fragments, DNA from UGT1A1*6 gave an undigested 235-bp fragment, and DNA from the heterozygous genotype gave all three fragments. For the sequence of UGT1A1*27, another set of the second PCR amplifications was performed using hemi-nested primers 5'-AGTACCTGTCTCTGCCCAC-3' (+485 to +503) and 5'-GTCCCACTCCAATACACAC-3' (+865 to +867 and intron 1), designed to amplify a 399-bp segment. Two BsrI (New England Biolabs, Inc., Beverly, MA) restriction sites exist in UGT1A1*27 (+552 to +556 and +684 to +688), but only one site (+552 to +556) exists in UGT1A1*1. The set of PCR amplifications was identical with that for MspI RFLP described above. Digestion of PCR products with 2.5 units of BsrI for 1 h at 65°C gave 199-, 132- and 68-bp fragments from UGT1A1*27 or 331- and 68-bp from UGT1A1*1. The heterozygous genotype gave all four fragments.
The sequence of UGT1A1*29 was also identified using a nested PCR-RFLP assay. The first-step PCR amplification encompassing exons 2, 3, and 4 was performed according to the reported method with minor modifications (21) . The mismatched forward and the reverse primers for the second PCR amplification designed to amplify a 285-bp segment was 5'-TCCTCCCTATTTTGCATCTCAGGTCACCCGATGGCC-3' (intron 3 and +1085 to +1098; underlining indicates mismatched site) and 5'-TGAATGCCATGACCAAA-3' (intron 4), respectively. The forward primer was designed to introduce a Cfr13I (Takara Shuzo Co., Ltd.) restriction site in UGT1A1*1 (+1095 to +1099) but not in UGT1A1*29. The PCR reaction mixture was the same as that used in the second PCR examination for UGT1A1*6. A PCR product was digested with Cfr13I enzyme. DNA from UGT1A1*1 was digested into 252- and 33-bp fragments, and DNA from UGT1A1*29 gave an undigested 285-bp fragment. For detection of UGT1A1*7, the PCR amplification for a 579-bp fragment of exon 5 was carried out using the primer described previously (21) . The reaction mixture was the same as that used in the second PCR assay for UGT1A1*6. There is a BsrI restriction site in the sequence of UGT1A1*1 (+1452 to +1456) but not in UGT1A1*7. After incubation with BsrI enzyme, DNA from UGT1A1*1 was digested into 365- and 214-bp fragments, and DNA from UGT1A1*7 gave an undigested 579-bp fragment.
Restriction fragments were analyzed by 4% agarose gel electrophoresis and ethidium bromide staining. The representative genotyping results of every variant genotype were confirmed by direct sequencing analyses.
Statistical Analysis.
Possible factors analyzed to assess associations with the severe
toxicity or the polymorphisms of UGT1A1 were as follows;
gender, age, performance status, primary disease, presence of distant
metastasis, previous treatments, complications of diabetes or liver
diseases, chemotherapy regimens, concurrent radiotherapy, and the
intended schedule and dosage for each infusion of irinotecan. The
chemotherapy regimens were categorized into three groups: irinotecan
alone, irinotecan plus platinum (cisplatin or carboplatin), and
irinotecan plus other agents (paclitaxel, docetaxel, etoposide,
mitomycin C, or 5-fluorouracil). The correlation or association between
potential variables was assessed using 
2
test
or Fisher’s exact test for categorical variables, or with Mann-Whitney
U test for continuous ones. Possible variables that seemed
to be associated with severe toxicity (P < 0.1) were considered for inclusion in an unconditional multiple
logistic regression analysis. We did not include the following factors
in the multivariate analysis because they were highly dependent on the
outcome of chemotherapy: total actual dosage and uses of granulocyte
colony-stimulating factor and loperamide hydrochloride. The variables
in the final models were chosen using forward and backward stepwise
procedures at the significance level of 0.25 and 0.1, respectively. The
importance of the genetic polymorphism for occurrence of severe
toxicity was verified when controlling for the other variables. We
performed these analyses using JMP version 3.0.2 software (SAS
Institute, Inc., Cary, NC). A difference was considered statistically
significant when the two-tailed P was <0.05.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and 3)
. Nine (8%) and 38 (32%) patients
experienced leukopenia of grade 4 (0.9 x 109/liter) and grade 3 (1.9–1.0 x 109/liter), respectively. Diarrhea was
reported in 3 patients (3%) with grade 4 (hemorrhagic or dehydration)
and 19 patients (16%) with grade 3 (watery for 5 days or more). Five
of the 9 patients with grade 4 leukopenia also had grade 3/4 diarrhea,
and 16 of the 22 patients with grade 3/4 diarrhea encountered grade 3/4
leukopenia. Then, we identified 26 patients who experienced severe
toxicity and 92 patients who did not (Tables 2
and 3)
. During the first
course, 19 of the 26 patients (73%) experienced severe toxicity.
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. Complete
or partial responses were observed more often in patients who
experienced severe toxicity, although the difference was not
significant (Table 3)
.
Distribution of Genotypes.
The genotypes were determined in the all 118 patients including 9
patients whose UGT1A1*28 genotyping results have been
reported elsewhere (16)
. The allele frequencies of
UGT1A1*28 were 0.308 (95% CI, 0.182–0.433) and 0.087 (95%
CI, 0.046–0.128), and those of UGT1A1*6 were 0.077 (95%
CI, 0.004–0.149) and 0.136 (95% CI, 0.086–0.185) among the patients
with and without severe toxicity, respectively (Table 4)
. The difference in allelic
distribution between the patients with and without severe toxicity was
significant for UGT1A1*28 (P < 0.001) but not significant for UGT1A1*6
(P > 0.2; GENEPOP version 3.1d software, the
Laboratoire de Génétique et Environment, Montpellier,
France). The co-occurrence of the polymorphisms was found in 5
patients: 2 patients were heterozygous for both UGT1A1*28
and UGT1A1*6, and 3 patients were heterozygous for
UGT1A1*27 and homozygous (2 patients) or heterozygous (1
patient) for UGT1A1*28. We did not examine the
cis or trans arrangement of the variant sequences
in these 5 patients. None of the patients had UGT1A1*29 or
UGT1A1*7.
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). There was no significant association
between the genotypes and objective responses (data not shown).
|
).
Conversely, no statistical association of UGT1A1*6 with the
occurrence of severe toxicity was observed (odds ratio, 0.55; 95% CI,
0.15–1.61; P > 0.2).
Besides the variant genotypes, the factors that seemed to affect severe
toxicity adversely (P < 0.1) were gender,
chemotherapy regimen, and intended schedule of irinotecan infusion
(Tables 2
and 3)
. These factors were assessed for correlation or
association. Significant association was found between chemotherapy
regimen and intended schedule (P < 0.001,
2
test); in other words, 12 of 19 patients
(63%) treated with irinotecan of 3- or 4-week cycle had received
additional anticancer drugs. Because the chemotherapy regimen was the
variable with stronger relationship with severe toxicity, we considered
the factor of chemotherapy regimen for inclusion in the model. The
other correlation or association among chemotherapy regimen, gender,
and UGT1A1*28 genotype was not significant. The stepwise
procedures identified female gender and use of other anticancer drugs
(apart from platinum) as important variables for the occurrence of
severe toxicity besides the UGT1A1*28 genotype (Table 6)
. After adjustment with these two
variables, the importance of the UGT1A1*28 genotype was
verified (Table 6)
.
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.
There was a significant increase in the bilirubin levels after
irinotecan infusion in both the patients who did
(P < 0.001, Wilcoxon signed-rank test) and
did not (P < 0.001; Table 4
) encounter the
severe toxicity. The increase in bilirubin levels after the initiation
of therapy tended to be worse in the patients who experienced severe
toxicity than in those who did not (P = 0.071, Mann-Whitney U test; Table 4
).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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.
Although the use of other anticancer drugs also significantly affected
severe toxicity, it was not beyond the UGT1A1*28 genotype
(Tables 2
and 6)
. The effects of female gender on severe toxicity did
not reach significant levels in the current analysis (Tables 2
and 6)
.
These findings clarify the clinical importance of UGT1A1*28
for UGT1A1 conjugation activity, especially in acute exposure to
irinotecan. We should mention that several biases might modify the distributions of the UGT1A1 polymorphisms in this study: (a) patients with high bilirubin levels would usually be precluded from irinotecan treatment because of a suspicion of liver dysfunction that may cause severe toxicity; (b) if our hypothesis is correct, potential patients who have the variant genotypes might die of fatal toxicity by irinotecan and inevitably be excluded from the analysis. This speculation is compatible with the fact that no patients had either UGT1A1*29 or UGT1A1*7, which occurs in common exons of UGT1A isoforms, resulting in a substantial reduction of their functional activities. Conversely, the patients who experienced severe toxicity from irinotecan would be more inclined to participate in this research than those who did not. Nevertheless, we consider that the patients analyzed here could approximate a population of Japanese cancer patients, because the incidence of severe toxicity in the patients of this research was comparable with those in the previous Phase II or III trials of irinotecan chemotherapy in Japan (2 , 3) . Thus, this retrospective research warrants a prospective trial to corroborate the usefulness of gene diagnosis of UGT1A1 polymorphisms prior to irinotecan chemotherapy.
We should be careful to understand the exact clinical importance of UGT1A1*6 for toxicity by irinotecan. According to in vitro expression studies, UGT1A1*6 in the homozygous and heterozygous genetic states decreases the enzyme activity to 32 and 60% of control, respectively (25) . In addition, UGT1A1*6 has been reported to be a significant risk factor for nonphysiological hyperbilirubinemia among Japanese neonates (21 , 22) . The genetic effect of UGT1A1*6 might be somehow masked in the current retrospective research; otherwise, the reduced enzyme activity might be compensated in adults by acquired factors. Particularly, UGT1A1*6 as well as UGT1A1*27 might considerably affect the susceptibility to irinotecan when they coexist with a variant sequence in the promoter UGT1A1*28.
The patients with variant UGT1A1 genotypes were not always
those who encountered the severe toxicity by irinotecan, and vice
versa. Generally, pharmacogenetic variations definitely alter the
relevant drug effects, as observed in a poor metabolizer of thiopurine
S-methyltransferase or dihydropyrimidine dehydrogenase
(28
, 29)
. In this research, the genetic effect of the
genotypes on toxicity by irinotecan would be relatively weak, because
they are originally responsible for Gilbert’s syndrome that shows mild
hyperbilirubinemia compared with Crigler-Najjar syndrome. Moreover, the
bioavailability of SN-38 depends on the capacity of not only UGT1A1 but
also carboxylesterase that metabolically transforms irinotecan to
SN-38. However, determining the UGT1A1 genotype would be
clinically important for Japanese patients because >20% of them have
the variant genotypes and possibly have an increased risk of severe
toxicity. Besides UGT1A1 polymorphisms, a recent report
suggested that the UGT1A7 isoform would glucuronidate SN-38 more than
UGT1A1 (30)
. However, because UGT1A7 is absent in human
liver (31)
, a primary organ for detoxifying i.v.
irinotecan, the evidence of SN-38 glucuronidation by UGT1A7 does not
deny the role of UGT1A1. In fact, the significant increase in bilirubin
levels after irinotecan infusion (Tables 4
and 5)
clearly supported
that the glucuronidation of SN-38 in the liver should competitively
inhibit that of bilirubin, which is a major substrate of UGT1A1.
Because UGT1A7 is expressed in gastrointestinal tissue, it might be
important especially for the efficacy against colon cancer and the
impact on diarrhea by irinotecan. Although genetic polymorphism of
UGT1A7 and their relationships with the phenotypic activity
have not yet been identified, more precise estimation of the clinical
effects by irinotecan might be possible by investigating the genetic
variations, if any.
The bilirubin level seems an inadequate parameter to predict severe
toxicity by irinotecan. At the suggestion of other investigators
(32)
, we also observed that the bilirubin levels were
increased more in the patients who experienced severe toxicity than in
those who did not, although the difference was not significant (Table 4)
. Indeed, the differences in bilirubin levels among the genotypes
were statistically significant but seemed clinically negligible as a
tool to predict toxicity (Table 5)
. Furthermore, UGT1A1*28
appeared to be important for Gilbert’s syndrome but not sufficient for
the complete manifestation of the syndrome (19)
. The
clinical usefulness of the bilirubin level might be improved if
patients abstain from drug and alcohol use and are strictly fasted, but
it does not seem to be practical.
Inter-ethnic differences can be easily predicted in metabolic profiles and clinical effects of irinotecan, although racial differences in tolerability and clinical outcomes of irinotecan treatment have not been investigated directly. Great differences in the distributions of the UGT1A1 polymorphisms between Caucasians and Japanese populations have been reported; the frequency of UGT1A1*28 in Caucasians is higher than among Japanese (20 , 24) . This implies that Caucasians might be more susceptible to the drug than the Japanese. On the contrary, UGT1A1*6 and UGT1A1*27, the variant sequences in exon 1, have been identified only in the Japanese (19 , 21 , 22) . Although the clinical significance for irinotecan chemotherapy of these genotypes in exon 1 remains uncertain, they might cause Japanese to be more sensitive to the drug than Caucasians. These findings suggest racial differences in the importance of UGT1A1 genotypes in irinotecan toxicity.
Individualization of drug dosage is critical for cancer chemotherapy to reduce unnecessary toxicity and to improve its therapeutic efficacy because the therapeutic index is often narrow. Oncologists traditionally used to predict toxicity by drugs and to optimize the dosage based on the patient’s physiological factors (e.g., body surface area, age), pathological conditions (e.g., performance status, organ functions), and clinical history (e.g., previous treatments). Recently, pharmacokinetic and pharmacodynamic analyses in chemotherapy provide more objective information for predicting the clinical effects of drugs. Furthermore, we believe that pharmacogenetic analyses would be an another clue for individualized chemotherapy. If there is the recognized difference in drug disposition and sensitivity caused by the polymorphic drug-metabolizing enzyme, the optimal dosage required for response with the least toxicity would be different in patients with the different genotypes. In the present study, the determination of the UGT1A1 genotypes for irinotecan treatment was suggested to be clinically useful. We are planning a dose escalation study of irinotecan in cancer patients who have been determined to have the variant genotypes.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by a Research Fellowship
of the Japan Society for the Promotion of Science for Young Scientists
(to Y. A.) and in part by a Grant-in-Aid for Cancer Research from the
Ministry of Health and Welfare of Japan. 
2 To whom requests for reprints should be
addressed, at First Department of Internal Medicine, Nagoya University
School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan.
Phone: 81-52-744-2143; Fax: 81-52-744-2157; E-mail: yhasega{at}tsuru.med.nagoya-u.ac.jp
3 The abbreviations used are: irinotecan,
7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin;
SN-38, 7-ethyl-10-hydroxycamptothecin; UGT,
UDP-glucuronosyltransferase; CI, confidence interval; RFLP, restriction
fragment length polymorphism.
Received 3/ 3/00. Accepted 10/17/00.
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L. R. Bomgaars, M. Bernstein, M. Krailo, R. Kadota, S. Das, Z. Chen, P. C. Adamson, and S. M. Blaney Phase II Trial of Irinotecan in Children With Refractory Solid Tumors: A Children's Oncology Group Study J. Clin. Oncol., October 10, 2007; 25(29): 4622 - 4627. [Abstract] [Full Text] [PDF]
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 J. M. Hoskins, R. M. Goldberg, P. Qu, J. G. Ibrahim, and H. L. McLeod UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Dose Matters J Natl Cancer Inst, September 5, 2007; 99(17): 1290 - 1295. [Abstract] [Full Text] [PDF]
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 M. H. Court A Pharmacogenomics Primer J. Clin. Pharmacol., September 1, 2007; 47(9): 1087 - 1103. [Abstract] [Full Text] [PDF]
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 R. H.J. Mathijssen, F. A. de Jong, W. J. Loos, J. M. van der Bol, J. Verweij, and A. Sparreboom Flat-Fixed Dosing Versus Body Surface Area Based Dosing of Anticancer Drugs in Adults: Does It Make a Difference? Oncologist, August 1, 2007; 12(8): 913 - 923. [Abstract] [Full Text] [PDF]
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N. L. Benowitz Cigarette Smoking and the Personalization of Irinotecan Therapy J. Clin. Oncol., July 1, 2007; 25(19): 2646 - 2647. [Full Text] [PDF]
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 D. J. Kroll, H. S. Shaw, and N. H. Oberlies Milk Thistle Nomenclature: Why It Matters in Cancer Research and Pharmacokinetic Studies Integr Cancer Ther, June 1, 2007; 6(2): 110 - 119. [Abstract] [PDF]
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J.-F. Cote, S. Kirzin, A. Kramar, J.-F. Mosnier, M.-D. Diebold, I. Soubeyran, A.-S. Thirouard, J. Selves, P. Laurent-Puig, and M. Ychou UGT1A1 Polymorphism Can Predict Hematologic Toxicity in Patients Treated with Irinotecan Clin. Cancer Res., June 1, 2007; 13(11): 3269 - 3275. [Abstract] [Full Text] [PDF]
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 Y. Fujiwara, I. Sekine, Y. Ohe, H. Kunitoh, N. Yamamoto, H. Nokihara, Y. Simmyo, T. Fukui, K. Yamada, and T. Tamura Serum Total Bilirubin as a Predictive Factor for Severe Neutropenia in Lung Cancer Patients Treated with Cisplatin and Irinotecan Jpn. J. Clin. Oncol., May 30, 2007; (2007) hym033v1. [Abstract] [Full Text] [PDF]
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 D. M. Roden, R. B. Altman, N. L. Benowitz, D. A. Flockhart, K. M. Giacomini, J. A. Johnson, R. M. Krauss, H. L. McLeod, M. J. Ratain, M. V. Relling, et al. Pharmacogenomics: Challenges and Opportunities. Ann Intern Med, November 21, 2006; 145(10): 749 - 757. [Abstract] [Full Text] [PDF]
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 K. K. Hahn, J. J. Wolff, and J. M. Kolesar Pharmacogenetics and irinotecan therapy Am. J. Health Syst. Pharm., November 15, 2006; 63(22): 2211 - 2217. [Abstract] [Full Text] [PDF]
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P. J. O'Dwyer and R. B. Catalano Uridine Diphosphate Glucuronosyltransferase (UGT) 1A1 and Irinotecan: Practical Pharmacogenomics Arrives in Cancer Therapy J. Clin. Oncol., October 1, 2006; 24(28): 4534 - 4538. [Full Text] [PDF]
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D. L. Kroetz Role for Drug Transporters Beyond Tumor Resistance: Hepatic Functional Imaging and Genotyping of Multidrug Resistance Transporters for the Prediction of Irinotecan Toxicity J. Clin. Oncol., September 10, 2006; 24(26): 4225 - 4227. [Full Text] [PDF]
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 S. J. Gardiner and E. J. Begg Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice Pharmacol. Rev., September 1, 2006; 58(3): 521 - 590. [Abstract] [Full Text] [PDF]
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F. A. de Jong, D. F. S. Kehrer, R. H. J. Mathijssen, G.-J. Creemers, P. de Bruijn, R. H. N. van Schaik, A. S. Th. Planting, A. van der Gaast, F. A. L. M. Eskens, J. Th. P. Janssen, et al. Prophylaxis of Irinotecan-Induced Diarrhea with Neomycin and Potential Role for UGT1A1*28 Genotype Screening: A Double-Blind, Randomized, Placebo-Controlled Study Oncologist, September 1, 2006; 11(8): 944 - 954. [Abstract] [Full Text] [PDF]
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H. Girard, L. Villeneuve, M. H. Court, L.-C. Fortier, P. Caron, Q. Hao, L. L. von Moltke, D. J. Greenblatt, and C. Guillemette THE NOVEL UGT1A9 INTRONIC I399 POLYMORPHISM APPEARS AS A PREDICTOR OF 7-ETHYL-10-HYDROXYCAMPTOTHECIN GLUCURONIDATION LEVELS IN THE LIVER Drug Metab. Dispos., July 1, 2006; 34(7): 1220 - 1228. [Abstract] [Full Text] [PDF]
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F. Innocenti, E. E. Vokes, and M. J. Ratain Irinogenetics: What Is the Right Star? J. Clin. Oncol., May 20, 2006; 24(15): 2221 - 2224. [Full Text] [PDF]
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M. L. Maitland, A. DiRienzo, and M. J. Ratain Interpreting Disparate Responses to Cancer Therapy: The Role of Human Population Genetics J. Clin. Oncol., May 10, 2006; 24(14): 2151 - 2157. [Abstract] [Full Text] [PDF]
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 S. Marsh and H. L. McLeod Pharmacogenomics: from bedside to clinical practice. Hum. Mol. Genet., April 15, 2006; 15(suppl_1): R89 - R93. [Abstract] [Full Text] [PDF]
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M. J. Ratain From bedside to bench to bedside to clinical practice: an odyssey with irinotecan. Clin. Cancer Res., March 15, 2006; 12(6): 1658 - 1660. [Full Text] [PDF]
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J.-F. Gagnon, O. Bernard, L. Villeneuve, B. Tetu, and C. Guillemette Irinotecan Inactivation Is Modulated by Epigenetic Silencing of UGT1A1 in Colon Cancer Clin. Cancer Res., March 15, 2006; 12(6): 1850 - 1858. [Abstract] [Full Text] [PDF]
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W. Sadee and Z. Dai Pharmacogenetics/genomics and personalized medicine Hum. Mol. Genet., October 15, 2005; 14(suppl_2): R207 - R214. [Abstract] [Full Text] [PDF]
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R. A. Walgren, M. A. Meucci, and H. L. McLeod Pharmacogenomic Discovery Approaches: Will the Real Genes Please Stand Up? J. Clin. Oncol., October 10, 2005; 23(29): 7342 - 7349. [Abstract] [Full Text] [PDF]
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W. P. Yong, J. Ramirez, F. Innocenti, and M. J. Ratain Effects of Ketoconazole on Glucuronidation by UDP-Glucuronosyltransferase Enzymes Clin. Cancer Res., September 15, 2005; 11(18): 6699 - 6704. [Abstract] [Full Text] [PDF]
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M. Katoh, T. Matsui, H. Okumura, M. Nakajima, M. Nishimura, S. Naito, C. Tateno, K. Yoshizato, and T. Yokoi EXPRESSION OF HUMAN PHASE II ENZYMES IN CHIMERIC MICE WITH HUMANIZED LIVER Drug Metab. Dispos., September 1, 2005; 33(9): 1333 - 1340. [Abstract] [Full Text] [PDF]
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 R. R Shah Pharmacogenetics in drug regulation: promise, potential and pitfalls Phil Trans R Soc B, August 29, 2005; 360(1460): 1617 - 1638. [Abstract] [Full Text] [PDF]
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M. A. Wright, G. Morrison, P. Lin, G. D. Leonard, D. Nguyen, X. Guo, E. Szabo, J. L. Hopkins, J. P. Leguizamo, N. Harold, et al. A Phase I Pharmacologic and Pharmacogenetic Trial of Sequential 24-Hour Infusion of Irinotecan Followed by Leucovorin and a 48-Hour Infusion of Fluorouracil in Adult Patients with Solid Tumors Clin. Cancer Res., June 1, 2005; 11(11): 4144 - 4150. [Abstract] [Full Text] [PDF]
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M. A. Shah, J. Kortmansky, M. Motwani, M. Drobnjak, M. Gonen, S. Yi, A. Weyerbacher, C. Cordon-Cardo, R. Lefkowitz, B. Brenner, et al. A Phase I Clinical Trial of the Sequential Combination of Irinotecan Followed by Flavopiridol Clin. Cancer Res., May 15, 2005; 11(10): 3836 - 3845. [Abstract] [Full Text] [PDF]
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 M Steiner, M Seule, B Steiner, I Bauer, M Freund, C H Kohne, and P Schuff-Werner 5-Fluorouracil/irinotecan induced lethal toxicity as a result of a combined pharmacogenetic syndrome: report of a case J. Clin. Pathol., May 1, 2005; 58(5): 553 - 555. [Abstract] [Full Text] [PDF]
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N. Kaniwa, K. Kurose, H. Jinno, T. Tanaka-Kagawa, Y. Saito, M. Saeki, J.-i. Sawada, M. Tohkin, and R. Hasegawa RACIAL VARIABILITY IN HAPLOTYPE FREQUENCIES OF UGT1A1 AND GLUCURONIDATION ACTIVITY OF A NOVEL SINGLE NUCLEOTIDE POLYMORPHISM 686C> T (P229L) FOUND IN AN AFRICAN-AMERICAN Drug Metab. Dispos., March 1, 2005; 33(3): 458 - 465. [Abstract] [Full Text] [PDF]
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O. Soepenberg, H. Dumez, J. Verweij, F. A. de Jong, M. J.A. de Jonge, J. Thomas, F. A.L.M. Eskens, R. H.N. van Schaik, J. Selleslach, J. ter Steeg, et al. Phase I Pharmacokinetic, Food Effect, and Pharmacogenetic Study of Oral Irinotecan Given as Semisolid Matrix Capsules in Patients with Solid Tumors Clin. Cancer Res., February 15, 2005; 11(4): 1504 - 1511. [Abstract] [Full Text] [PDF]
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L. E. Carlini, N. J. Meropol, J. Bever, M. L. Andria, T. Hill, P. Gold, A. Rogatko, H. Wang, and R. L. Blanchard UGT1A7 and UGT1A9 Polymorphisms Predict Response and Toxicity in Colorectal Cancer Patients Treated with Capecitabine/Irinotecan Clin. Cancer Res., February 1, 2005; 11(3): 1226 - 1236. [Abstract] [Full Text] [PDF]
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W. Lee, A. C. Lockhart, R. B. Kim, and M. L. Rothenberg Cancer Pharmacogenomics: Powerful Tools in Cancer Chemotherapy and Drug Development Oncologist, February 1, 2005; 10(2): 104 - 111. [Abstract] [Full Text] [PDF]
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M. Michael, M. Brittain, J. Nagai, R. Feld, D. Hedley, A. Oza, L. Siu, and M. J. Moore Phase II Study of Activated Charcoal to Prevent Irinotecan-Induced Diarrhea J. Clin. Oncol., November 1, 2004; 22(21): 4410 - 4417. [Abstract] [Full Text] [PDF]
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 Y. Hasegawa, T. Sarashina, M. Ando, C. Kitagawa, A. Mori, M. Yoneyama, Y. Ando, and K. Shimokata Rapid Detection of UGT1A1 Gene Polymorphisms by Newly Developed Invader Assay Clin. Chem., August 1, 2004; 50(8): 1479 - 1480. [Full Text] [PDF]
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L. Paoluzzi, A. S. Singh, D. K. Price, R. Danesi, R. H. J. Mathijssen, J. Verweij, W. D. Figg, and A. Sparreboom Influence of Genetic Variants in UGT1A1 and UGT1A9 on the In Vivo Glucuronidation of SN-38 J. Clin. Pharmacol., August 1, 2004; 44(8): 854 - 860. [Abstract] [Full Text] [PDF]
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E. Rouits, M. Boisdron-Celle, A. Dumont, O. Guerin, A. Morel, and E. Gamelin Relevance of Different UGT1A1 Polymorphisms in Irinotecan-Induced Toxicity: A Molecular and Clinical Study of 75 Patients Clin. Cancer Res., August 1, 2004; 10(15): 5151 - 5159. [Abstract] [Full Text] [PDF]
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H. L. McLeod and J. W. Watters Irinotecan Pharmacogenetics: Is It Time to Intervene? J. Clin. Oncol., April 15, 2004; 22(8): 1356 - 1359. [Full Text] [PDF]
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F. Innocenti, S. D. Undevia, L. Iyer, P. Xian Chen, S. Das, M. Kocherginsky, T. Karrison, L. Janisch, J. Ramirez, C. M. Rudin, et al. Genetic Variants in the UDP-glucuronosyltransferase 1A1 Gene Predict the Risk of Severe Neutropenia of Irinotecan J. Clin. Oncol., April 15, 2004; 22(8): 1382 - 1388. [Abstract] [Full Text] [PDF]
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 M. P. Goetz, M. M. Ames, and R. M. Weinshilboum Primer on Medical Genomics Part XII: Pharmacogenomics--General Principles With Cancer as a Model Mayo Clin. Proc., March 1, 2004; 79(3): 376 - 384. [Abstract] [PDF]
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J. Cummings, B. T. Ethell, L. Jardine, G. Boyd, J. S. Macpherson, B. Burchell, J. F. Smyth, and D. I. Jodrell Glucuronidation as a Mechanism of Intrinsic Drug Resistance in Human Colon Cancer: Reversal of Resistance by Food Additives Cancer Res., December 1, 2003; 63(23): 8443 - 8450. [Abstract] [Full Text] [PDF]
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C.-S. Ki, K.-A Lee, S.-Y. Lee, H.-J. Kim, S. S. Cho, J.-H. Park, S. Cho, K. M. Sohn, and J.-W. Kim Haplotype Structure of the UDP-Glucuronosyltransferase 1A1 (UGT1A1) Gene and Its Relationship to Serum Total Bilirubin Concentration in a Male Korean Population Clin. Chem., December 1, 2003; 49(12): 2078 - 2081. [Full Text] [PDF]
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M. P. Goetz, C. Erlichman, A. J. Windebank, J. M. Reid, J. A. Sloan, P. Atherton, A. A. Adjei, J. Rubin, H. Pitot, E. Galanis, et al. Phase I and Pharmacokinetic Study of Two Different Schedules of Oxaliplatin, Irinotecan, Fluorouracil, and Leucovorin in Patients With Solid Tumors J. Clin. Oncol., October 15, 2003; 21(20): 3761 - 3769. [Abstract] [Full Text] [PDF]
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 L. Villeneuve, H. Girard, L.-C. Fortier, J.-F. Gagne, and C. Guillemette Novel Functional Polymorphisms in the UGT1A7 and UGT1A9 Glucuronidating Enzymes in Caucasian and African-American Subjects and Their Impact on the Metabolism of 7-Ethyl-10-hydroxycamptothecin and Flavopiridol Anticancer Drugs J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 117 - 128. [Abstract] [Full Text] [PDF]
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R. Ahluwalia, R. Freimuth, H. L. McLeod, and S. Marsh Use of Pyrosequencing to Detect Clinically Relevant Polymorphisms in Dihydropyrimidine Dehydrogenase Clin. Chem., October 1, 2003; 49(10): 1661 - 1664. [Full Text] [PDF]
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H. Jinno, M. Saeki, Y. Saito, T. Tanaka-Kagawa, N. Hanioka, K. Sai, N. Kaniwa, M. Ando, K. Shirao, H. Minami, et al. Functional Characterization of Human UDP-Glucuronosyltransferase 1A9 Variant, D256N, Found in Japanese Cancer Patients J. Pharmacol. Exp. Ther., August 1, 2003; 306(2): 688 - 693. [Abstract] [Full Text] [PDF]
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R. H. J. Mathijssen, S. Marsh, M. O. Karlsson, R. Xie, S. D. Baker, J. Verweij, A. Sparreboom, and H. L. McLeod Irinotecan Pathway Genotype Analysis to Predict Pharmacokinetics Clin. Cancer Res., August 1, 2003; 9(9): 3246 - 3253. [Abstract] [Full Text] [PDF]
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T. D. Bjornsson, J. T. Callaghan, H. J. Einolf, V. Fischer, L. Gan, S. Grimm, J. Kao, S. P. King, G. Miwa, L. Ni, et al. THE CONDUCT OF IN VITRO AND IN VIVO DRUG-DRUG INTERACTION STUDIES: A PHARMACEUTICAL RESEARCH AND MANUFACTURERS OF AMERICA (PhRMA) PERSPECTIVE Drug Metab. Dispos., July 1, 2003; 31(7): 815 - 832. [Abstract] [Full Text] [PDF]
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T. D. Bjornsson, J. T. Callaghan, H. J. Einolf, V. Fischer, L. Gan, S. Grimm, J. Kao, S. P. King, G. Miwa, L. Ni, et al. The Conduct of In Vitro and In Vivo Drug-Drug Interaction Studies: A PhRMA Perspective J. Clin. Pharmacol., May 1, 2003; 43(5): 443 - 469. [Abstract] [Full Text] [PDF]
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H. Jinno, T. Tanaka-Kagawa, N. Hanioka, M. Saeki, S. Ishida, T. Nishimura, M. Ando, Y. Saito, S. Ozawa, and J.-i. Sawada Glucuronidation of 7-Ethyl-10-hydroxycamptothecin (SN-38), an Active Metabolite of Irinotecan (CPT-11), by Human UGT1A1 Variants, G71R, P229Q, and Y486D Drug Metab. Dispos., January 1, 2003; 31(1): 108 - 113. [Abstract] [Full Text] [PDF]
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 R. H. Tukey, C. P. Strassburg, and P. I. Mackenzie Pharmacogenomics of Human UDP-Glucuronosyltransferases and Irinotecan Toxicity Mol. Pharmacol., September 1, 2002; 62(3): 446 - 450. [Full Text] [PDF]
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J.-F. Gagne, V. Montminy, P. Belanger, K. Journault, G. Gaucher, and C. Guillemette Common Human UGT1A Polymorphisms and the Altered Metabolism of Irinotecan Active Metabolite 7-Ethyl-10-hydroxycamptothecin (SN-38) Mol. Pharmacol., September 1, 2002; 62(3): 608 - 617. [Abstract] [Full Text] [PDF]
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D. F.S. Kehrer, R. H.J. Mathijssen, J. Verweij, P. de Bruijn, and A. Sparreboom Modulation of Irinotecan Metabolism by Ketoconazole J. Clin. Oncol., July 15, 2002; 20(14): 3122 - 3129. [Abstract] [Full Text] [PDF]
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K. R. Crews, C. F. Stewart, D. Jones-Wallace, S. J. Thompson, P. J. Houghton, R. L. Heideman, M. Fouladi, D. C. Bowers, M. M. Chintagumpala, and A. Gajjar Altered Irinotecan Pharmacokinetics in Pediatric High-Grade Glioma Patients Receiving Enzyme-inducing Anticonvulsant Therapy Clin. Cancer Res., July 1, 2002; 8(7): 2202 - 2209. [Abstract] [Full Text] [PDF]
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H. L. McLeod Genetic Strategies to Individualize Supportive Care J. Clin. Oncol., June 15, 2002; 20(12): 2765 - 2767. [Full Text] [PDF]
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 Y. Ando, W. D. Figg, K. Noda, and N. Saijo Irinotecan in Small-Cell Lung Cancer N. Engl. J. Med., May 2, 2002; 346(18): 1414 - 1415. [Full Text] [PDF]
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M. Steiner, P. Schuff-Werner, M. Freund, C.-H. Kohne, J. P. Stevenson, A. S. Whitehead, and P. J. O'Dwyer Combined Chemotherapy Trials Require Combined Pharmacogenetic Approaches J. Clin. Oncol., March 1, 2002; 20(5): 1425 - 1426. [Full Text] [PDF]
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R. H.J. Mathijssen, J. Verweij, M. J.A. de Jonge, K. Nooter, G. Stoter, and A. Sparreboom Impact of Body-Size Measures on Irinotecan Clearance: Alternative Dosing Recommendations J. Clin. Oncol., January 1, 2002; 20(1): 81 - 87. [Abstract] [Full Text] [PDF]
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H. Minami, H. Fujii, T. Igarashi, K. Itoh, K. Tamanoi, T. Oguma, and Y. Sasaki Phase I and Pharmacological Study of a New Camptothecin Derivative, Exatecan Mesylate (DX-8951f), Infused Over 30 Minutes Every Three Weeks Clin. Cancer Res., October 1, 2001; 7(10): 3056 - 3064. [Abstract] [Full Text] [PDF]
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R. H. J. Mathijssen, R. J. van Alphen, J. Verweij, W. J. Loos, K. Nooter, G. Stoter, and A. Sparreboom Clinical Pharmacokinetics and Metabolism of Irinotecan (CPT-11) Clin. Cancer Res., August 1, 2001; 7(8): 2182 - 2194. [Abstract] [Full Text] [PDF]
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