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1.
Fei-fei Han Chang-long Guo Dan Yu Jin Zhu Li-li Gong Guang-run Li Ya-li Lv He Liu Guang-yu An Li-hong Liu 《Cancer chemotherapy and pharmacology》2014,73(4):779-788
Purpose
Neutropenia is a life-threatening side effect of irinotecan, and uridine diphosphate glucuronosyltransferases (UGTs) gene polymorphisms are considered to be one of the predictive markers of irinotecan-related toxicities. Many studies have demonstrated that patients bearing UGT1A1*28 have a higher risk of severe neutropenia on toxicity of irinotecan. However, UGT1A1 (TA7/TA7) was very rare in Asian populations. Some researches reported that UGT1A1*28 and/or UGT1A1*6 could predict irinotecan-induced toxicities in Asian populations, but controversial conclusions still remained. This study aims to investigate the association between UGT1A1 gene polymorphisms *6, *6/*28 and irinotecan-related neutropenia in Asian cancer patients receiving irinotecan regimen chemotherapy.Experimental design
Meta-analyses were done to assess the relationship between UGT1A1*6 or UGT1A1*6/*28 and irinotecan-induced neutropenia.Results
The risk of neutropenia was significantly higher among patients with a UGT1A1*6 genotype than among those carrying the UGT1A1*1 allele(s) [odds ratio (OR) 3.276; 95 % confidence interval (CI) 1.887–5.688; P = 0.000 (*6/*6 vs. *1/*6 or *1/*1)], [OR 1.542; 95 % CI 1.180–2.041; P = 0.001 (*6/*6 or *1/*6 vs. *1/*1)]. Also, the risk was significantly higher among patients with a UGT1A1*6/*28 than among those carrying the UGT1A1*1 allele(s) [OR 3.275; 95 % CI 2.152–4.983; P = 0.000 (*6/*6 or *28/*28 or *6/*28 vs. *1/*6 or *1/*28 or *1/*1)].Conclusions
In conclusion, the UGT1A1*6 and UGT1A1*6/*28 genotypes were associated with an increased risk of irinotecan-induced neutropenia in Asian cancer patients. 相似文献2.
Lamas MJ Duran G Balboa E Bernardez B Candamio S Vidal Y Mosquera A Giraldez JM Lopez R Carracedo A Barros F 《Cancer chemotherapy and pharmacology》2012,69(6):1591-1599
Purpose
We are trying to identify predictive factors of high risk of toxicity by analyzing candidate genes in the irinotecan pathways in order to identify useful tools to improve mCRC patient management under real practice conditions.Methods
Genomic DNA was genotyped for UGT1A1 (*28, *60 and *93) from all 101 patients, and irinotecan dose was 180 mg/m2 every second week. Clinical data were obtained by retrospective chart review. The primary endpoint is to find out whether the pharmacogenetic test in the clinical practice may predict toxicity.Results
Grade 3/4 diarrhea occurred in twelve patients and required dose reduction in six patients, and neutropenia reached grade 3/4 in 19 patients (only one patient with *28/*28 genotype). The UGT1A1*93 seemed to relate with grade 3/4 neutropenia but only in the heterozygote state (G/A), p = 0.071, and UGT1A*60 showed no association with neutropenia. Twenty-eight percentage of patients required the use of G-CSF; 64.3 % of them harbored *1/*28 or *28/*28 genotypes, p = 0.003. Thirty-seven (36.6 %) patients required dose reduction of irinotecan and/or 5-FU owing to toxicity, mainly neutropenia and diarrhea. No significant association was detected between *28, *60 and *93 UGT1A variants and severe irinotecan-associated hematologic or GI toxicity.Conclusion
The impact of increased risk of toxicity attributed to the UGT1A variants may be offset by irinotecan in clinical practice by dose reduction or the use of colony-stimulating factor. 相似文献3.
Kyu-pyo Kim Ho-Sook Kim Sun Jin Sym Kyun Seop Bae Yong Sang Hong Heung-Moon Chang Jae Lyun Lee Yoon-Koo Kang Jung Shin Lee Jae-Gook Shin Tae Won Kim 《Cancer chemotherapy and pharmacology》2013,71(6):1609-1617
Purpose
UGT1A1 genotypes are important when considering treatment with irinotecan-containing regimens. In this study, we determined the dose, efficacy, and tolerability of irinotecan according to UGT1A1 genotypes when combined with capecitabine in patients with metastatic colorectal cancer.Methods
Patients with histologically confirmed metastatic adenocarcinoma of the colon or rectum were enrolled into a UGT1A1 genotype-directed dose-escalation trial of irinotecan plus fixed-dose capecitabine (2,000 mg/m2/day). The starting dose of irinotecan was different for each genotype group and ranged from 200 to 280 mg/m2. Pharmacokinetic concentrations of irinotecan and metabolites were determined by LC/MS/MS.Results
Fifty patients were genotyped for UGT1A1 *28 and *6, and grouped according to the numbers of defective alleles (DA): 0, 1, and 2. Plasma concentrations of irinotecan, SN-38, and SN-38G were measured. The maximum tolerated dose of irinotecan was 350 mg/m2 for the 0 and 1 DA groups, and 200 mg/m2 for the 2 DA group. For the 0, 1, and 2 DA groups, mean AUClast ratios of SN-38G to SN-38 were 7.72, 5.71, and 2.72 (P = 0.0023) and relative dose intensities at recommended dose were 85, 83, and 97 %.Conclusion
Irinotecan dosing based on UGT1A1*28 and *6 is feasible, and higher doses of irinotecan can be safely administered in patients with 0 or 1 DA, compared to those with 2 DA. 相似文献4.
Crystal S. Denlinger Rebecca Blanchard Lu Xu Coen Bernaards Samuel Litwin Cynthia Spittle Daniel J. Berg Susan McLaughlin Maryann Redlinger Andrew Dorr Julie Hambleton Scott Holden Anne Kearns Sara Kenkare-Mitra Bert Lum Neal J. Meropol Peter J. O’Dwyer 《Cancer chemotherapy and pharmacology》2009,65(1):97-105
Purpose
The purpose of this study was to evaluate the effect of bevacizumab on the pharmacokinetics (PK) of irinotecan and its active metabolite. Exploratory analyses of the impact of variability in uridine diphosphate glucuronosyltransferase 1A (UGT1A) genes on irinotecan metabolism and toxicity were conducted.Methods
This was an open-labeled, fixed-sequence study of bevacizumab with FOLFIRI (irinotecan, leucovorin, and infusional 5-fluorouracil). Pharmacokinetic assessments were conducted in cycles 1 and 3.Results
Forty-five subjects were enrolled. No difference in dose-normalized AUC0–last for irinotecan and SN-38 between irinotecan administered alone or in combination with bevacizumab was identified. Leukopenia was associated with higher exposure to both irinotecan and SN-38. UGT1A1 polymorphisms were associated with variability in irinotecan PK. Gastrointestinal toxicity was associated with UGT1A6 genotype. No other associations between UGT1A genotypes and toxicity were detected.Conclusion
Bevacizumab does not affect irinotecan PK when administered concurrently. A variety of pharmacogenetic relationships may influence the pharmacokinetics of irinotecan and its toxicity. 相似文献5.
Genetic polymorphisms in human SULT1A1 and UGT1A1 genes associate with breast tumor characteristics: a case-series study 总被引:1,自引:0,他引:1
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Shatalova EG Walther SE Favorova OO Rebbeck TR Blanchard RL 《Breast cancer research : BCR》2005,7(6):R909-R921
Introduction
Estrogens are important in breast cancer development. SULT1A1 and UGT1A1 catalyze estrogen metabolism and are polymorphic. The SULT1A1*2 protein exhibits low activity, and a TA repeat within the UGT1A1 promoter alters the level of expression of the protein. We hypothesized that the SULT1A1*2 allozyme has decreased capacity to sulfate estrogens, that the SULT1A1*2 allele conferred increased capacity of cells to proliferate in response to estrogens, and that individuals with the variant SULT1A1 and UGT1A1 genotypes exhibited different breast tumor characteristics.Methods
The capacity for SULT1A1*2 to sulfate 17β-estradiol and the capacity for cells expressing SULT1A1*1 or SULT1A1*2 to proliferate in response to 17β-estradiol was evaluated. A case-series study was performed in a total of 210 women with incident breast cancer, including 177 Caucasians, 25 African-Americans and eight women of other ethnic background. The SULT1A1 and UGT1A1 genotypes were determined and a logistic regression model was used to analyze genotype–phenotype associations.Results
We determined that the SULT1A1*1/*1 high-activity genotype was associated with tumor size ≤2 cm (odds ratio = 2.63, 95% confidence interval = 1.25–5.56, P = 0.02). Individuals with low-activity UGT1A1 genotypes (UGT1A1*28/*28 or UGT1A1*28/*34) were more likely to have an age at diagnosis ≥60 years (odds ratio = 3.70, 95% confidence interval = 1.33–10.00, P = 0.01). Individuals with both SULT1A1 and UGT1A1 high-activity genotypes had low tumor grade (odds ratio = 2.56, 95% confidence interval = 1.04–6.25, P = 0.05). Upon stratification by estrogen receptor status, significant associations were observed predominantly in estrogen receptor-negative tumors.Conclusion
The data suggest that genetic variation in SULT1A1 and UGT1A1 may influence breast cancer characteristics and might be important for breast cancer prognosis. 相似文献6.
Lei Cheng Ming Li Jing Hu Wei Ren Li Xie Zhan-Peng Sun Bao-Rui Liu Gen-Xing Xu Xiao-Liang Dong Xiao-Ping Qian 《Cancer chemotherapy and pharmacology》2014,73(3):551-560
Purpose
Previous studies confirmed that genotyping uridine diphosphate glucuronosyltransferase (UGT) 1A1*28 polymorphisms could predict the side effects in cancer patients using irinotecan (IRI) and then reduce IRI-induced toxicity by preventative treatment or decrease in dose. However, the association between UGT1A1*6 polymorphisms and IRI-induced severe toxicity in Asian patients is still unclear. The aim of this study was to evaluate the association between UGT1A1*6 polymorphisms and IRI-induced severe neutropenia as well as diarrhea in Asian patients.Methods
We searched all papers on PubMed and Embase from February 1998 to August 2013. Then we assessed the methodologies quality, extracted data and made statistics analysis using STATA software. To uncover the sources of heterogeneity, subgroup meta-analysis was conducted according to the dosage of IRI.Results
Eleven papers were included according to the inclusion and exclusion criteria after searching Pubmed and Embase. Overall, an increased risk of severe toxicity in Asian patients with UGT1A1*6 polymorphisms was found. Patients with heterozygous variant of UGT1A1*6 showed an increased risk [odds ratio (OR) = 1.98, 95 % confidence intervals (CI) 1.45–2.71, P < 0.001], and homozygous mutation showed an even higher risk (OR = 4.44, 95 % CI 2.42–8.14, P < 0.001) for severe neutropenia. For severe diarrhea, heterozygous variant of UGT1A1*6 showed no significant risk, while the homozygous variant performed a notable risk (OR = 3.51, 95 % CI 1.41–8.73, P = 0.007). Subgroup meta-analysis indicated that for patients harboring either heterozygous or homozygous variant, low dose of IRI also presented comparably increased risk in suffering severe neutropenia.Conclusion
In this meta-analysis, UGT1A1*6 polymorphisms were revealed as potential biomarkers, predicting IRI-induced severe toxicity in patients from Asia, and increased incidences of severe neutropenia could occur in both high/medium and low doses of IRI. 相似文献7.
Eiji Oki Takeshi Kato Hideaki Bando Takayuki Yoshino Kei Muro Hiroya Taniguchi Yoshinori Kagawa Kentaro Yamazaki Tatsuro Yamaguchi Akihito Tsuji Shigeyoshi Iwamoto Goro Nakayama Yasunori Emi Tetsuo Touyama Masato Nakamura Masahito Kotaka Hideki Sakisaka Takeharu Yamanaka Akiyoshi Kanazawa 《Clinical colorectal cancer》2018,17(2):147-155
Background
FOLFOXIRI (Fluorouracil, folinate, oxaliplatin, and irinotecan) plus bevacizumab improved progression-free survival (PFS) and overall survival in patients with metastatic colorectal cancer (mCRC), compared with FOLFIRI (fluorouracil, folinate, and irinotecan) plus bevacizumab, but significantly increased the incidences of adverse events. The efficacy and safety profiles of FOLFOXIRI plus bevacizumab in ethnic Asian patients have not been established yet.Patients and Methods
This study was an open-label, single-arm, multi-centered phase II prospective clinical trial in patients with mCRC who received FOLFOXIRI plus bevacizumab. The primary endpoint was the PFS rate at 10 months. Secondary endpoints included overall survival, response rate, and safety.Results
A total of 69 patients received FOLFOXIRI plus bevacizumab as induction therapy and were assessed for efficacy and safety. The PFS rate at 10 months was 75.2% and the median PFS was 13.3 months. Complete response and partial response were achieved in 2 (2.9%) and 47 patients (69.1%), respectively. Grade 3 and 4 adverse events with incidence rates exceeding 20% were neutropenia (72.5%), hypertension (34.8%), leucopenia (33.3%), and febrile neutropenia (21.7%). Significantly more patients with grade 4 neutropenia had single-heterozygous UGT1A1*1/*6 or *1/*28 (46.2%) than UGT1A1 wild-type genotype (*1/*1) (13.3%) (P = .004).Conclusions
FOLFOXIRI plus bevacizumab is considered an effective first-line regimen that improves the outcome of patients with mCRC regardless of ethnicity. In Asian patients, utmost attention should be paid to the possible onset of severe neutropenia or febrile neutropenia attributed to different types of UGT1A1*6 and *28 polymorphism, when FOLFOXIRI plus bevacizumab is administered. 相似文献8.
Yoshitaka Nishikawa Masashi Kanai Maiko Narahara Akiko Tamon J. B. Brown Kei Taneishi Masahiko Nakatsui Kazuya Okamoto Yu Uneno Daisuke Yamaguchi Teruko Tomono Yukiko Mori Shigemi Matsumoto Yasushi Okuno Manabu Muto 《International journal of clinical oncology / Japan Society of Clinical Oncology》2017,22(2):269-273
Background
Lung cancer is the leading cause of cancer death and is closely linked to tobacco smoking. Genetic polymorphisms in genes that encode enzymes involved in metabolizing tobacco carcinogens could affect an individual’s risk for lung cancer. While polymorphism of UDP-glucuronosyltransferase1A1 (UGT1A1) is involved in detoxification of benzo(a)pyrene-7,8-dihydrodiol(–), a major tobacco carcinogen, the association between UGT1A1 genotype and lung cancer has not been examined.Methods
We retrieved the clinical data of 5,285 patients who underwent systemic chemotherapy at Kyoto University Hospital. A total of 765 patients (194 lung cancer patients and 671 patients with other malignancies) with UGT1A1 genotyping data were included in this analysis. We used logistic regression with recessive, dominant, and additive models to identify differences in genotype frequencies between lung cancer and other malignancies.Results
In the recessive model, UGT1A1*28*28 genotype was significantly associated with lung cancer compared to other malignancies (odds ratio 5.3, P = 0.0083). Among lung cancer patients with a smoking history, squamous cell carcinoma was significantly predominant in patients with UGT1A1*28*28 compared to those with other UGT1A1 genotypes (P = 0.024).Conclusion
This is the first study to demonstrate a significant association between the homozygous UGT1A1*28 genotype and lung cancer.9.
Kouichi Hirose Koushiro Yamashita Hirofumi Takada Noriko Kaneda Kohei Fukami Eiji Maruo Mizuho Kitamura Junichi Hasegawa Yorinobu Maeda 《International journal of clinical oncology / Japan Society of Clinical Oncology》2014,19(2):397-402
Background
It was recently reported that genetic polymorphisms of UDP glucuronyltransferase-1 polypeptide A1 (UGT1A1), a glucuronidation enzyme, were associated with irinotecan (CPT-11) metabolism. The active metabolite of CPT-11, 7-ethyl-10-hydroxycamptothecin (SN-38) was glucuronidated (SN-38G) by UGT1A1. Genetic polymorphisms of UGT1A1 were associated with potentially serious adverse events, including neutropenia. Several studies have suggested that the dose of CPT-11 should be decreased in patients homozygous for UGT1A1*6 or UGT1A1*28, or double heterozygotes (*6/*28). However, the reference dose for patients with these genetic polymorphisms is unclear.Methods
We investigated the relationship between the SN-38G/SN-38 concentration ratio and the dose of CPT-11 in 70 patients with colorectal cancer who received FOLFIRI-based regimens, by measuring the plasma concentrations of CPT-11, SN-38, and SN-38G.Results
The SN-38G/SN-38 concentration ratio was lower in patients who were homozygous for UGT1A1*6, heterozygous for UGT1A1*6 or UGT1A1*28, or were double heterozygotes compared with patients with wild-type genes. The relative decreases in the SN-38G/SN-38 concentration ratio in patients homozygous for UGT1A1*6 and in double heterozygotes were greater than in patients heterozygous for UGT1A1*6 or UGT1A1*28. Interestingly, decreases in the SN-38G/SN-38 concentration ratio were associated with decreases in the neutrophil count and the final infusion dose of CPT-11.Conclusion
Our results suggest that the SN-38G/SN-38 concentration ratio is an important factor for guiding dose adjustments, even in patients with wild-type genes. Therefore, the SN-38G/SN-38 concentration ratio, as an index of the patient’s metabolic capacity, is useful for assessing dose adjustments of CPT-11. 相似文献10.
Hoskins JM Goldberg RM Qu P Ibrahim JG McLeod HL 《Journal of the National Cancer Institute》2007,99(17):1290-1295
The Food and Drug Administration and Pfizer changed the package insert for irinotecan to include a patient's UGT1A1*28 genotype as a risk factor for severe neutropenia on the basis of the findings of four pharmacogenetic studies, which found that irinotecan-treated patients who were homozygous for the UGT1A1*28 allele had a greater risk of hematologic toxic effects than patients who had one or two copies of the wild-type allele (UGT1A1*1). Findings of subsequent irinotecan pharmacogenetic studies have been inconsistent. In a meta-analysis, we reviewed data presented in nine studies that included a total of 10 sets of patients (for a total of 821 patients) and assessed the association of irinotecan dose with the risk of irinotecan-related hematologic toxicities (grade III-IV) for patients with a UGT1A1*28/*28 genotype. The risk of toxicity was higher among patients with a UGT1A1*28/*28 genotype than among those with a UGT1A1*1/*1 or UGT1A1*1/*28 genotype at both medium (odds ratio [OR] = 3.22, 95% confidence interval [CI] = 1.52 to 6.81; P = .008) and high (OR = 27.8, 95% CI = 4.0 to 195; P = .005) doses of irinotecan. However, risk was similar at lower doses (OR = 1.80, 95% CI = 0.37 to 8.84; P = .41). Low doses of irinotecan (100-125 mg/m2) are in the commonly used therapeutic range. The risk of experiencing irinotecan-induced hematologic toxicity for patients with a UGT1A1*28/*28 genotype thus appears to be a function of the dose of irinotecan administered. 相似文献
11.
Jeffrey R. Infante Vicki L. Keedy Suzanne F. Jones William C. Zamboni Emily Chan Johanna C. Bendell Wooin Lee Huali Wu Satoshi Ikeda Hiroshi Kodaira Mace L. Rothenberg Howard A. Burris III 《Cancer chemotherapy and pharmacology》2012,70(5):699-705
Purpose
IHL-305 is a novel PEGylated liposome containing irinotecan. This study examined the safety profile and pharmacokinetics of IHL-305 and established the maximum tolerated dose and recommended phase II dose (RP2D).Patients and methods
In a standard 3?+?3 design, IHL-305 was administered IV on day 1 of a 28-day treatment schedule. Subsequently, a 14-day treatment schedule was also explored. Two patient populations were evaluated separately: Patients with at least one wild-type (wt) allele of UGT1A1 (UDP glucoronosyltransferase 1A1) wt/wt or wt/*28 as one group (referred to as UGT1A1 wt group) and patients with UGT1A1*28 homozygous variant (*28/*28) as another group.Results
Sixty patients were treated: 42 on the 28-day schedule and 18 on the 14-day schedule. Seven patients were homozygous variant (*28/*28). In the UGT1A1 wt group, the MTD and RP2D of IHL-305 was 160?mg/m2 every 28?days and 80?mg/m2 every 14?days. DLTs included nausea, vomiting, diarrhea, and neutropenia. The most common adverse events were nausea (75?%), vomiting (52?%), diarrhea (62?%), anorexia (57?%), and fatigue (57?%). At the MTD for both schedules, IHL-305 administration resulted in a high and prolonged exposure of sum total irinotecan, released irinotecan, and SN-38 in plasma. One partial response was observed in a patient with breast cancer and eight patients had stable disease for >6?months.Conclusions
IHL-305, a novel preparation of irinotecan encapsulated in liposomes, can be safely given to patients in a repeated fashion on a 4- or 2-week dosing schedule. 相似文献12.
Satoru Iwasa Kei Muro Satoshi Morita Young Suk Park Masato Nakamura Masahito Kotaka Tomohiro Nishina Hiroshi Matsuoka Joong Bae Ahn Keun-Wook Lee Yong Sang Hong Sae Won Han Sang-Hee Cho Dong-Sheng Zhang Wei-Jia Fang Li Bai Xiang-Lin Yuan Ying Yuan Yasuhide Yamada Junichi Sakamoto Tae Won Kim 《Cancer science》2021,112(11):4669-4678
The phase III AXEPT study showed the noninferiority of modified capecitabine plus irinotecan (mXELIRI) with or without bevacizumab relative to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab as a second-line treatment for metastatic colorectal cancer. We evaluated the associations between the UGT1A1 genotype linked to adverse events—caused by irinotecan—and the efficacy and safety of mXELIRI and FOLFIRI. The UGT1A1 genotype was prospectively determined and patients were categorized into three groups according to WT (*1/*1), single heterozygous (SH; *28/*1 or *6/*1), and double heterozygous or homozygous (DHH; *28/*28, *6/*6, or *28/*6). Overall survival (OS), progression-free survival, response rate, and safety were assessed. The UGT1A1 genotype was available in all 650 randomized patients (WT, 309 [47.5%]; SH, 291 [44.8%]; DHH, 50 [7.7%]). The median OS was 15.9, 17.7, and 10.6 months in the WT, SH, and DHH groups, respectively, with an adjusted hazard ratio (HR) of 1.53 (95% confidence interval [CI], 1.12-2.09; P = .008) for DHH vs WT or SH. The median OS in the mXELIRI and FOLFIRI arms was 18.1 vs 14.3 months (HR 0.80; 95% CI, 0.62-1.03) in the WT group, 16.3 vs 18.3 months (HR 1.04; 95% CI, 0.79-1.36) in the SH group, and 13.0 vs 9.1 months (HR 0.71; 95% CI, 0.39-1.31) in the DHH group, respectively. Modified capecitabine plus irinotecan with or without bevacizumab could be a standard second-line chemotherapy in terms of efficacy and safety regardless of the UGT1A1 genotype. 相似文献
13.
Yoshinori Miyata Tetsuo Touyama Takaya Kusumi Yoshitaka Morita Nobuyuki Mizunuma Fumihiro Taniguchi Mitsuaki Manabe 《International journal of clinical oncology / Japan Society of Clinical Oncology》2016,21(4):696-703
Background
Irinotecan (CPT-11)-induced neutropenia is associated with UDP-glucuronosyltransferase (UGT) 1A1*6 and *28 polymorphisms. This prospective study investigated whether using these polymorphisms to adjust the initial dose of CPT-11 as part of FOLFIRI treatment in colorectal cancer patients might improve safety.Methods
All data were collected by a physician. The relationship between UGT1A1 polymorphisms and first-cycle neutropenia, reasons for treatment discontinuation, and time-to-treatment failure were evaluated. Multivariate analysis was used to assess the risk of neutropenia.Results
A total of 795 patients were divided into wild-type (*1/*1) (50.1 %), heterozygous (*28/*1, *6/*1) (41.1 %), and homozygous (*28/*28, *6/*6, *28/*6) (8.which are associated with a decrease in the8 %) groups, in which the median starting dose of CPT-11 was 143.0, 143.0, and 115.0 mg/m2, respectively. First-cycle grade ≥3 neutropenia occurred in 17.3, 25.4, and 28.6 % of these patients, respectively. Multivariate analysis revealed that the incidence of grade ≥3 neutropenia was significantly greater in the heterozygous and homozygous groups than in the wild-type group [odds ratio (OR) 1.67; 95 % confidence interval (CI) 1.16–2.42; p = 0.0060, and OR 2.22; 95 % CI 1.22–4.02; p = 0.0088, respectively]. Age (OR 1.77; 95 % CI 1.24–2.53; p = 0.0017), coelomic fluid (OR 1.84; 95 % CI 1.05–3.25; p = 0.0343), and non-reduction in starting dose (OR 1.53; 95 % CI 1.08–2.18; p = 0.0176) were also identified as significant risk factors.Conclusion
The risk of neutropenia was higher in the heterozygous and homozygous groups at initiation of CPT-11 treatment. This suggests that when a reduction in dose is required in patients harboring two variant alleles, the decrease should be approximately 20 %.14.
Shoichi Hazama Hideyuki Mishima Ryouichi Tsunedomi Yusuke Okuyama Takeshi Kato Ken‐ichi Takahashi Hiroshi Nozawa Hideaki Ando Michiya Kobayashi Hiroyoshi Takemoto Naoki Nagata Shinsuke Kanekiyo Yuka Inoue Yoshihiko Hamamoto Yusuke Fujita Yuji Hinoda Naoko Okayama Koji Oba Jun‐ichi Sakamoto Masaaki Oka 《Cancer science》2013,104(12):1662-1669
Retrospective studies have suggested that UDP‐glucuronosyltransferase (UGT)1A1, UGT1A7, and UGT1A9 predict severe toxicity and efficacy of irinotecan‐containing regimens. We prospectively evaluated the impact of UGT1A genotypes and haplotypes on severe toxicity and efficacy in patients treated with fluorouracil, leucovorin, and irinotecan combination chemotherapy (FOLFIRI) for metastatic colorectal cancer (mCRC) from the two prospective multicenter phase II studies in Japan. The FLIGHT1 study was a first‐line FOLFIRI trial, and FLIGHT2 was a FOLFOX‐refractory, second‐line FOLFIRI trial. A total of 73 patients agreed to additional analysis, and were genotyped for UGT1A polymorphisms, UGT1A1*28 (TA6>TA7), UGT1A1*6 (211G>A), UGT1A1*27 (686C>A), UGT1A1*60 (?3279T>G), UGT1A1*93 (?3156G>A), UGT1A7 (?57T>G), UGT1A7*3 (387T>G, 622T>C), and UGT1A9*22 (T9>T10). Of 73 patients, 34 developed G3/4 severe hematological toxicities. The toxicities were significantly more frequent in patients with UGT1A1*6 (211A), UGT1A7 (387G), and UGT1A9*22 reference alleles (T9). Haplotype I, which consists of all favorable alleles, was associated with a significant reduction in hematologic toxicity (P = 0.031). In contrast, haplotype II, which contains four high‐risk alleles, showed significantly higher hematologic toxicity than the other haplotypes (P = 0.010). Six out of seven patients who were homozygous for UGT1A1*28 or *6 experienced severe hematological toxicity despite the fact that their response rate was not impaired (42.9%). We concluded that UGT1A polymorphisms, especially UGT1A1*6, are important for the prediction of severe toxicity of FOLFIRI in northeast Asian populations. In this regard, haplotype analyses should substantially impact the prediction of severe hematological toxicities of FOLFIRI. (Clinical Trial Registration: UMIN000002388 and UMIN000002476). 相似文献
15.
Kimie Sai Yoshiro Saito Keiko Maekawa Su-Ryang Kim Nahoko Kaniwa Tomoko Nishimaki-Mogami Jun-ichi Sawada Kuniaki Shirao Tetsuya Hamaguchi Noboru Yamamoto Hideo Kunitoh Yuichiro Ohe Yasuhide Yamada Tomohide Tamura Teruhiko Yoshida Yasuhiro Matsumura Atsushi Ohtsu Nagahiro Saijo Hironobu Minami 《Cancer chemotherapy and pharmacology》2010,66(1):95-105
Purpose
Effects of genetic polymorphisms/variations of ABCB1, ABCC2, ABCG2 and SLCO1B1 in addition to “UGT1A1*28 or *6” on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients were investigated.Methods
Associations between transporter haplotypes/variations along with UGT1A1*28 or *6 and SN-38 area under the time–concentration curve (AUC) or neutropenia were examined in irinotecan monotherapy (55 patients) and irinotecan–cisplatin-combination therapy (62 patients).Results
Higher SN-38 AUC values were observed in ABCB1 2677G>T (A893S) (*2 group) for both regimens. Associations of grade 3/4 neutropenia were observed with ABCC2 ?1774delG (*1A), ABCG2 421C>A (Q141K) and IVS12 + 49G>T ( # IIB) and SLCO1B1 521T>C (V174A) (*15 · 17) in the irinotecan monotherapy, while they were evident only in homozygotes of ABCB1*2, ABCG2 # IIB, SLCO1B1*15 · 17 in the cisplatin-combination therapy. With combinations of haplotypes/variations of two or more genes, neutropenia incidence increased, but their prediction power for grade 3/4 neutropenia is still unsatisfactory.Conclusions
Certain transporter genotypes additively increased irinotecan-induced neutropenia, but their clinical importance should be further elucidated. 相似文献16.
Satoh T Ura T Yamada Y Yamazaki K Tsujinaka T Munakata M Nishina T Okamura S Esaki T Sasaki Y Koizumi W Kakeji Y Ishizuka N Hyodo I Sakata Y 《Cancer science》2011,102(10):1868-1873
Irinotecan-induced severe neutropenia is associated with homozygosity for the UGT1A1*28 or UGT1A1*6 alleles. In this study, we determined the maximum-tolerated dose (MTD) of irinotecan in patients with UGT1A1 polymorphisms. Patients who had received chemotherapy other than irinotecan for metastatic gastrointestinal cancer were enrolled. Patients were divided into three groups according to UGT1A1 genotypes: wild-type (*1/*1); heterozygous (*28/*1, *6/*1); or homozygous (*28/*28, *6/*6, *28/*6). Irinotecan was given every 2 weeks for two cycles. The wild-type group received a fixed dose of irinotecan (150 mg/m(2)) to serve as a reference. The MTD was guided from 75 to 150 mg/m(2) by the continual reassessment method in the heterozygous and homozygous groups. Dose-limiting toxicity (DLT) and pharmacokinetics were evaluated during cycle 1. Of 82 patients enrolled, DLT was assessable in 79 patients (wild-type, 40; heterozygous, 20; and homozygous, 19). Dose-limiting toxicity occurred in one patient in the wild-type group, none in the heterozygous group, and six patients (grade 4 neutropenia) in the homozygous group. In the homozygous group, the MTD was 150 mg/m(2) and the probability of DLT was 37.4%. The second cycle was delayed because of neutropenia in 56.3% of the patients given the MTD. The AUC(0-24 h) of SN-38 was significantly greater (P < 0.001) and more widely distributed in the homozygous group. Patients homozygous for the UGT1A1*28 or UGT1A1*6 allele can receive irinotecan in a starting dose of 150 mg/m(2), but many required dose reductions or delayed treatment in subsequent cycles. UMIN Clinical Trial Registration number: UMIN000000618. 相似文献
17.
目的:比较尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)*28启动子为野生型的TA6/6患者在使用伊立替康(irinotecan,CPT-11)联合顺铂与CPT-11联合5-FU/亚叶酸钙治疗时不良反应方面的差异。方法根据采取的治疗方案将98例UGT1A1*28野生型TA6/6患者分为CPT-11联合顺铂组(IP组,n=47)和CPT-11联合5-FU/亚叶酸钙组(FOLFIRI组,n=51),对患者进行UGT1A1*28启动子多态性检测,比较不良反应差异。结果在总体3~4级不良反应方面,IP组的发生率(61.7%)明显高于FOLFIRI组(39.2%),且组间差异具有统计学意义(P=0.026)。在血液学不良反应方面,IP组3~4级白细胞减少、中性粒细胞减少、血小板减少和血红蛋白减少发生率分别为34.0%、51.1%、14.9%和8.5%,FOLFIRI组的发生率分别为11.8%、29.4%、2.0%、0,组间差异均有统计学意义(均P<0.05);在非血液学方面,FOLFIRI组3~4级迟发性腹泻发生率为9.8%,IP组未发生3~4级腹泻,两组间发生率的差异有统计学意义(P=0.028)。结论 UGT1A1*28野生型TA6/6患者在接受CPT-11联合顺铂和CPT-11联合5-FU/亚叶酸钙两种化疗方案治疗的不良反应谱存在差异;应用CPT-11时,不但要考虑到UGT1A1*28启动子多态性对不良反应的影响,而且还要考虑CPT-11联合不同药物出现不良反应情况。 相似文献
18.
Shulman K Cohen I Barnett-Griness O Kuten A Gruber SB Lejbkowicz F Rennert G 《Cancer》2011,117(14):3156-3162
BACKGROUND:
Metastatic colorectal cancer is frequently treated with irinotecan, a topoisomerase‐I inhibitor. The UGT1A1 gene encodes for an enzyme that metabolizes irinotecan, and its genetic variants were shown to be associated with increased drug toxicity. We evaluated clinical outcomes associated with the UGT1A1*28 variant.METHODS:
The study included 329 colorectal cancer patients from the Israeli population‐based Molecular Epidemiology of Colorectal Cancer study who were treated with a chemotherapy regimen that included irinotecan. Patients with metastases or disease recurrence were followed up for a median period of 2 years after occurrence of the event. Study end points were appearance of grade 3‐4 hematological and gastroenterological toxicity, hospitalization due to toxic events (mostly neutropenia, fever, diarrhea, or vomiting), length of hospitalization, and overall survival. UGT1A1*28 was genotyped from peripheral blood DNA by fragment analysis and reported as number of TATA sequence repeats in the promoter of the gene.RESULTS:
The 7/7 variant of UGT1A1*28 was detected in 11.9% of the 329 participants. Grade 3‐4 hematological toxicity was significantly higher in 7/7 carriers compared with 6/7 and 6/6 carriers (48.0%,10.2%, and 7.7% respectively; P < .001), as was the risk of toxicity‐related hospitalization (45.8%, 25.3%, and 14.4% respectively; P = .001). Both short‐term death within 2 months of treatment start (12.8%, 5.2%, and 2.9%, respectively) and median overall survival (1.6, 2.0, and 2.4 years, respectively; P = .01) were significantly worse in the 7/7 carriers. The age/stage‐adjusted hazard ratio for patients with the 7/7 genotype compared with 6/6 was 1.7 (95% confidence interval, 1.1‐2.3).CONCLUSIONS:
The UGT1A1*28 7/7 genotype is strongly associated with severe hematological toxicity and higher hospitalization rate and predicts lower survival of colorectal cancer in users of irinotecan. Cancer 2011. © 2011 American Cancer Society. 相似文献19.
Zeen Tong Usha Yerramilli Sekhar Surapaneni Gondi Kumar 《Cancer chemotherapy and pharmacology》2014,73(4):869-874
Purpose
Lenalidomide is an immunomodulatory agent used for the treatment of myelodysplastic syndromes and multiple myeloma. Renal clearance of lenalidomide is the predominant elimination route and is approximately twofold greater than the glomerular filtration rate (GFR), suggesting the potential contribution of an active secretory mechanism. In vitro studies were conducted to examine whether lenalidomide is a substrate of drug transporters, namely P-glycoprotein (P-gp), human breast cancer resistance protein (BCRP), multidrug resistance proteins (MRP1, MRP2, MRP3), organic anion transporters (OAT1, OAT3), organic cation transporters (OCT1 and OCT2), human organic cation transporter novel 1 and 2 (OCTN1 and OCTN2), multidrug and toxin extrusion (MATE1) and organic anion transporting polypeptide (OATP1B1). Lenalidomide was also evaluated as an inhibitor of P-gp, BCRP, MRP2, OCT2, OAT1, OAT3, OATP1B1, OATP1B3 and bile salt export pump (BSEP). In addition, inhibition of UDP-glucuronosyltransferase 1A1 (UGT1A1) variants by lenalidomide was also assessed.Method
Cells or vesicles expressing each of the human transporters were used for uptake and inhibition studies, with appropriate probe substrates and known inhibitors.Results
Results of these studies indicate that the lenalidomide is not a substrate for the transporters examined, except that it is weak substrate of P-gp. None of the transporters studied were inhibited by lenalidomide. Lenalidomide is not an inhibitor of UGT1A1*1/*1 or its polymorphic variants UGT1A1*1/*28 and UGT1A1*28/*28.Conclusions
Drug interactions are unlikely to occur when lenalidomide is co-administered with substrates or inhibitors of these transporters. In addition, lenalidomide is unlikely to cause interactions when co-administered with substrates of UGT1A1. 相似文献20.
Naminatsu Takahara Yousuke Nakai Hiroyuki Isayama Takashi Sasaki Yumiko Satoh Daiya Takai Tsuyoshi Hamada Rie Uchino Suguru Mizuno Koji Miyabayashi Dai Mohri Kazumichi Kawakubo Hirofumi Kogure Natsuyo Yamamoto Naoki Sasahira Kenji Hirano Hideaki Ijichi Minoru Tada Yutaka Yatomi Kazuhiko Koike 《Cancer chemotherapy and pharmacology》2013,71(1):85-92