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Liu JH, Tsai TH, Chen YJ, Wang LY, Liu HY, Hsieh CH. Local Irradiation Modulates the Pharmacokinetics of Metabolites in 5-Fluorouracil-Radiotherapy-Pharmacokinetics Phenomenon. Front Pharmacol 2020; 11:141. [PMID: 32174836 PMCID: PMC7056828 DOI: 10.3389/fphar.2020.00141] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 02/03/2020] [Indexed: 12/30/2022] Open
Abstract
Background The effects of radiotherapy (RT) on the pharmacokinetics (PK) of 5-FU and 5-fluoro-5,6-dihydro-uracil (5-FDHU) were investigated by animal experiments. Methods Whole-pelvis RT with 0.5 and 2 Gy was delivered to Sprague–Dawley rats. 5-FU at 100 mg/kg was intravenously infused 24 h after radiation. The pharmacokinetics of 5-FU and 5-FDHU in the plasma and bile system were calculated. Results The areas under the concentration versus time curve (AUC) of 5-FU in the plasma were reduced by local irradiation by 23.7% at 0.5 Gy (P < 0.001) and 35.3% at 2 Gy (P < 0.001). The AUCs of 5-FDHU were also reduced by 21.4% at 0.5 Gy (P < 0.001) and 51.5% at 2 Gy (P < 0.001). Irradiation significantly increased the clearance values (CLs) of 5-FU by 30.6% at 0.5 Gy and 50.1% at 2 Gy, respectively. The CLs of 5-FDHU were increased by 27.2% at 0.5 Gy and 106% at 2 Gy. The AUCs of 5-FU in the bile were increased by 36.7% at 0.5 Gy (P < 0.001) and 68.6% at 2 Gy (P = 0.005). The AUCs of 5-FDHU in the bile were increased by 40.3% at 0.5 Gy (P < 0.001) and 248.1% at 2 Gy (P < 0.001). The CLs of 5-FU in the bile were increased by 31.8% at 0.5 Gy and 11.2% at 2 Gy. However, the CLs of 5-FDHU in the bile were decreased by 29.1% at 0.5 Gy and 71.0% at 2 Gy. Conclusion Both conventional and low-dose irradiation can affect the pharmacokinetics of 5-FU and its metabolite, 5-FDHU. RT plus 5-FU could cause more adverse events than 5-FU alone by increasing the AUC ratio of 5-FU/5-FDHU. Irradiation decreases the AUC of 5-FU in the plasma, which may cause poor clinical outcomes.
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Affiliation(s)
- Ju-Han Liu
- School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan.,Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan.,Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan
| | - Tung-Hu Tsai
- Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan.,Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan.,School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Chemical Engineering, National United University, Miaoli, Taiwan
| | - Yu-Jen Chen
- Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan.,Departments of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan.,Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Li-Ying Wang
- School and Graduate Institute of Physical Therapy, College of Medicine, National Taiwan University, Taipei, Taiwan.,Physical Therapy Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsin-Yu Liu
- Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chen-Hsi Hsieh
- Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
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Yusof HM, Ab-Rahim S, Suddin LS, Saman MSA, Mazlan M. Metabolomics Profiling on Different Stages of Colorectal Cancer: A Systematic Review. Malays J Med Sci 2018; 25:16-34. [PMID: 30914860 PMCID: PMC6419892 DOI: 10.21315/mjms2018.25.5.3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 05/16/2018] [Indexed: 12/18/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Early diagnosis and accurate staging of the disease is vital to improve the prognosis. Metabolomics has been used to identify changes in metabolite profiles in the different stages of cancer in order to introduce new non-invasive molecular tools for staging. In this systematic review, we aim to identify the common metabolite changes in human biological samples and the dominant metabolic pathways associated with CRC progression. A broad systematic search was carried out from selected databases. Four reviewers screened and reviewed the titles, abstracts, and full-text articles according to the inclusion and exclusion criteria. Quality assessment was conducted on the eight articles which met the criteria. Data showed that the metabolites involved with redox status, energy metabolism and intermediates of amino acids, choline and nucleotides metabolism were the most affected during CRC progression. However, there were differences in the levels of individual metabolites detected between the studies, and this might be due to the study population, sample preparation, analytical platforms used and statistical tools. In conclusion, this systematic review highlights the changes in metabolites from early to late stages of CRC. Moreover, biomarkers for prognosis are important to reduce CRC-related mortality.
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Affiliation(s)
- Hazwani Mohd Yusof
- Faculty of Medicine, Universiti Teknologi MARA, Jalan Hospital, 47000 Sg Buloh, Selangor, Malaysia
| | - Sharaniza Ab-Rahim
- Faculty of Medicine, Universiti Teknologi MARA, Jalan Hospital, 47000 Sg Buloh, Selangor, Malaysia
| | - Leny Suzana Suddin
- Faculty of Medicine, Universiti Teknologi MARA, Jalan Hospital, 47000 Sg Buloh, Selangor, Malaysia
| | - Mohd Shahril Ahmad Saman
- Faculty of Medicine, Universiti Teknologi MARA, Jalan Hospital, 47000 Sg Buloh, Selangor, Malaysia
| | - Musalmah Mazlan
- Faculty of Medicine, Universiti Teknologi MARA, Jalan Hospital, 47000 Sg Buloh, Selangor, Malaysia
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Tian Y, Xu T, Huang J, Zhang L, Xu S, Xiong B, Wang Y, Tang H. Tissue Metabonomic Phenotyping for Diagnosis and Prognosis of Human Colorectal Cancer. Sci Rep 2016; 6:20790. [PMID: 26876567 PMCID: PMC4753490 DOI: 10.1038/srep20790] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 01/12/2016] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide and prognosis based on the conventional histological grading method for CRC remains poor. To better the situation, we analyzed the metabonomic signatures of 50 human CRC tissues and their adjacent non-involved tissues (ANIT) using high-resolution magic-angle spinning (HRMAS) (1)H NMR spectroscopy together with the fatty acid compositions of these tissues using GC-FID/MS. We showed that tissue metabolic phenotypes not only discriminated CRC tissues from ANIT, but also distinguished low-grade tumor tissues (stages I-II) from the high-grade ones (stages III-IV) with high sensitivity and specificity in both cases. Metabonomic phenotypes of CRC tissues differed significantly from that of ANIT in energy metabolism, membrane biosynthesis and degradations, osmotic regulations together with the metabolism of proteins and nucleotides. Amongst all CRC tissues, the stage I tumors exhibited largest differentiations from ANIT. The combination of the differentiating metabolites showed outstanding collective power for differentiating cancer from ANIT and for distinguishing CRC tissues at different stages. These findings revealed details in the typical metabonomic phenotypes associated with CRC tissues nondestructively and demonstrated tissue metabonomic phenotyping as an important molecular pathology tool for diagnosis and prognosis of cancerous solid tumors.
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Affiliation(s)
- Yuan Tian
- CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Tangpeng Xu
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, 430071, China
| | - Jia Huang
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Limin Zhang
- CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Shan Xu
- CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Bin Xiong
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yulan Wang
- CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, 430071, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, 310058, China
| | - Huiru Tang
- CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, 430071, China
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Ministry of Education Key Laboratory of Contemporary Anthropology, Metabonomics and Systems Biology Laboratory, School of Life Sciences, Fudan University, Shanghai, 200438, China
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Prospective DPYD genotyping to reduce the risk of fluoropyrimidine-induced severe toxicity: Ready for prime time. Eur J Cancer 2016; 54:40-48. [DOI: 10.1016/j.ejca.2015.11.008] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 11/05/2015] [Accepted: 11/07/2015] [Indexed: 01/29/2023]
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Integrative metabonomics as potential method for diagnosis of thyroid malignancy. Sci Rep 2015; 5:14869. [PMID: 26486570 PMCID: PMC4613561 DOI: 10.1038/srep14869] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 09/10/2015] [Indexed: 12/22/2022] Open
Abstract
Thyroid nodules can be classified into benign and malignant tumors. However, distinguishing between these two types of tumors can be challenging in clinics. Since malignant nodules require surgical intervention whereas asymptomatic benign tumors do not, there is an urgent need for new techniques that enable accurate diagnosis of malignant thyroid nodules. Here, we used 1H NMR spectroscopy coupled with pattern recognition techniques to analyze the metabonomes of thyroid tissues and their extracts from thyroid lesion patients (n = 53) and their adjacent healthy thyroid tissues (n = 46). We also measured fatty acid compositions using GC−FID/MS techniques as complementary information. We demonstrate that thyroid lesion tissues can be clearly distinguishable from healthy tissues, and malignant tumors can also be distinguished from the benign tumors based on the metabolic profiles, both with high sensitivity and specificity. In addition, we show that thyroid lesions are accompanied with disturbances of multiple metabolic pathways, including alterations in energy metabolism (glycolysis, lipid and TCA cycle), promotions in protein turnover, nucleotide biosynthesis as well as phosphatidylcholine biosynthesis. These findings provide essential information on the metabolic features of thyroid lesions and demonstrate that metabonomics technology can be potentially useful in the rapid and accurate preoperative diagnosis of malignant thyroid nodules.
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Hino-Shishikura A, Suzuki A, Minamimoto R, Shizukuishi K, Oka T, Tateishi U, Sugae S, Ichikawa Y, Horiuchi C, Inoue T. Biodistribution and radiation dosimetry of [¹⁸F]-5-fluorouracil. Appl Radiat Isot 2013; 75:11-7. [PMID: 23416442 DOI: 10.1016/j.apradiso.2013.01.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Revised: 10/31/2012] [Accepted: 01/07/2013] [Indexed: 12/20/2022]
Abstract
PURPOSE To estimate the radiation dose and biodistribution of (18)F-5-fluorouracil ([(18)F]-5-FU) from positron emission tomography/computed tomography (PET/CT) data, and to extrapolate mouse data to human data in order to evaluate cross-species consistency. METHODS Fifteen cancer patients (head and neck cancer (n=11), colon cancer (n=4)) were enrolled. Sequential PET/CT images were acquired for 2h after intravenous administration of [(18)F]-5-FU, and the percent of the injected dose delivered to each organ was derived. For comparison, [(18)F]-5-FU was administered to female BALB/cAJcl-nu/nu nude mice (n=19), and the percent of the injected dose delivered to mouse organs was extrapolated to the human model. Absorbed radiation dose was calculated using OLINDA/EXM 1.0 software. RESULTS In human subjects, high [(18)F]-5-FU uptake was seen in the liver, gallbladder and kidneys. The absorbed dose was highest in the gallbladder wall. In mice, the biodistribution of [(18)F]-5-FU corresponded to that of humans. Estimated absorbed radiation doses for all organs were moderately correlated, and doses to organs (except the gallbladder and urinary bladder) were significantly correlated between mice and humans. The mean effective [(18)F]-5-FU dose was higher in humans (0.0124mSv/MBq) than in mice (0.0058mSv/MBq). CONCLUSION Biodistribution and radiation dosimetry of [(18)F]-5-FU were compared between humans and mice: biodistribution in mice and humans was similar. Data from mice underestimated the effective dose in humans, suggesting that clinical measurements are needed for more detailed dose estimation in order to ensure radiation safety. The observed effective doses suggest the feasibility of [(18)F]-5-FU PET/CT for human studies.
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Affiliation(s)
- Ayako Hino-Shishikura
- Department of Radiology, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
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Loupakis F, Schirripa M, Zhang W, Falcone A, Lenz HJ. Pharmacogenetic Concerns in Metastatic Colorectal Cancer Therapy. CURRENT COLORECTAL CANCER REPORTS 2012. [DOI: 10.1007/s11888-012-0137-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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Hirota T, Date Y, Nishibatake Y, Takane H, Fukuoka Y, Taniguchi Y, Burioka N, Shimizu E, Nakamura H, Otsubo K, Ieiri I. Dihydropyrimidine dehydrogenase (DPD) expression is negatively regulated by certain microRNAs in human lung tissues. Lung Cancer 2012; 77:16-23. [PMID: 22306127 DOI: 10.1016/j.lungcan.2011.12.018] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Revised: 12/13/2011] [Accepted: 12/18/2011] [Indexed: 11/17/2022]
Abstract
Dihydropyrimidine dehydrogenase (DPD) is important to the antitumor effect of 5-fluorouracil (5-FU). DPD gene (DPYD) expression in tumors is correlated with sensitivity to 5-FU. Because the 5-FU accumulated in cancer cells is also rapidly converted into inactivated metabolites through catabolic pathways mediated by DPD, high DPD activity in cancer cells is an important determinant of the response to 5-FU. DPD activity is highly variable and reduced activity causes a high risk of 5-FU toxicity. Genetic variation in DPYD has been proposed as the main factor responsible for the variation in DPD activity. However, only a small proportion of the activity of DPD can be explained by DPYD mutations. In this study, we found that DPYD is a target of the following microRNAs (miRNA): miR-27a, miR-27b, miR-134, and miR-582-5p. In luciferase assays with HepG2 cells, the overexpression of these miRNAs was associated with significantly decreased reporter activity in a plasmid containing the 3'-UTR of DYPD mRNA. The level of DPD protein in MIAPaca-2 cells was also significantly decreased by the overexpression of these four miRNAs. The results suggest that miR-27a, miR-27b, miR-134, and miR-582-5p post-transcriptionally regulate DPD protein expression. The levels of miRNAs in normal lung tissue and lung tumors were compared; miR-27b and miR-134 levels were significantly lower in the tumors than normal tissue (3.64 ± 4.02 versus 9.75 ± 6.58 and 0.64 ± 0.75 versus 1.48 ± 1.39). DPD protein levels were significantly higher in the tumors. Thus, the decreased expression of miR-27b would be responsible for the high levels of DPD protein. This study is the first to show that miRNAs regulate the DPD protein, and provides new insight into 5-FU-based chemotherapy.
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Affiliation(s)
- Takeshi Hirota
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Iwahashi S, Shimada M, Utsunomiya T, Morine Y, Imura S, Ikemoto T, Mori H, Hanaoka J. Role of thymidylate synthase and dihydropyrimidine dehydrogenase mRNA expressions in gallbladder carcinoma. Surg Today 2012; 42:565-9. [PMID: 22270332 DOI: 10.1007/s00595-012-0118-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Accepted: 05/06/2011] [Indexed: 12/16/2022]
Abstract
PURPOSE Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are important enzymes in the metabolism of 5-fluorouracil, which have been examined as possible predictive markers. We conducted this study to clarify the role of TS and DPD expressions in gallbladder carcinoma (GBC). METHODS The subjects were 28 patients who underwent surgical resection of GBC. We examined intratumoral TS and DPD mRNA expressions, using the Danenberg tumor profile method. The expression levels were classified into two groups, based on median values. Clinicopathological variables, including prognosis, were then compared between the high and low expression groups. RESULTS There was a significant difference in the incidence of lymph node metastasis between the high and low TS expression groups. The incidence of advanced clinical stage was higher in the low TS expression group than in the high TS expression group. However, no clear correlation was observed between the DPD mRNA expression and any clinicopathological variable. There was no significant difference in the postoperative survival rates between the groups, in accordance with the expression of TS or DPD genes. CONCLUSION Low TS mRNA was correlated with a high incidence of lymph node metastasis and advanced clinical stage. Therefore, TS gene expression may help identify patients at increased risk of the progression of GBC.
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Affiliation(s)
- Shuichi Iwahashi
- Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Japan
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Morine Y, Shimada M, Utsunomiya T, Imura S, Ikemoto T, Hanaka J, Kanamoto M, Kurita N, Miyake H. Role of thymidylate synthase and dihydropyrimidine dehydrogenase mRNA in intrahepatic cholangiocarcinoma. Surg Today 2011; 42:135-40. [PMID: 22143355 DOI: 10.1007/s00595-011-0054-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2010] [Accepted: 02/06/2011] [Indexed: 12/17/2022]
Abstract
PURPOSE Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are important enzymes in the metabolism of 5-fluorouracil and possible predictive markers. We conducted this study to clarify if TS and DPD gene expressions are a prognostic indicator for intrahepatic cholangiocarcinoma (IHCC). METHODS The subjects of this study were 21 patients with IHCC who had undergone surgical resection. Intratumoral TS and DPD mRNA expressions were examined using the Danenberg tumor profile method and classified into two groups according to the median value of each. We then compared the clinicopathological variables, including prognosis, between the high and low expression groups. RESULTS Low DPD expression was correlated with macroscopic type, namely, mass-forming + infiltrative (P = 0.08). Postoperative survival rates in the low DPD expression group were significantly lower than those in the high DPD expression group. Multivariate analysis revealed macroscopic type to be an independent prognostic factor, whereas TS mRNA expression did not correlate with any clinicopathological variables, including prognosis. CONCLUSIONS Low DPD mRNA expression was related to macroscopic type and associated with poor prognosis. DPD mRNA expression in tumor cells is suggested to be an important regulator of malignant behavior in IHCC.
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Affiliation(s)
- Yuji Morine
- Department of Surgery, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
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Hagiwara S, Kudo M, Ueshima K, Chung H, Yamaguchi M, Takita M, Haji S, Kimura M, Arao T, Nishio K, Park AM, Munakata H. The cancer stem cell marker CD133 is a predictor of the effectiveness of S1+ pegylated interferon α-2b therapy against advanced hepatocellular carcinoma. J Gastroenterol 2011; 46:212-21. [PMID: 20683621 DOI: 10.1007/s00535-010-0294-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2009] [Accepted: 07/08/2010] [Indexed: 02/04/2023]
Abstract
BACKGROUND Combination therapy with the oral fluoropyrimidine anticancer drug S1 and interferon is reportedly effective for the treatment of advanced hepatocellular carcinoma (HCC), but selection criteria for this therapy have not been clarified. In this study, we attempted to identify factors predicting the effectiveness of this combination therapy. METHODS Pathological specimens of HCC were collected before treatment from 31 patients with advanced HCC who underwent S1+ pegylated-interferon (PEG-IFN) α-2b therapy between January 2007 and January 2009. In these pathological specimens, the expression levels of CD133, thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and interferon-receptor 2 (IFNR2) proteins were determined by Western blot assay. The presence or absence of p53 gene mutations was determined by direct sequencing. The relationships between these protein expression levels and the response rate (RR), progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS The CD133 protein expression level was significantly lower in the responder group than in the nonresponder group. Comparing the PFS and OS between high- and low-level CD133 expression groups (n = 13 and 18, respectively) revealed that both parameters were significantly prolonged in the latter group. The expression levels of TS, DPD, and IFNR2 protein and the presence of p53 gene mutations did not correlate with the RR. CONCLUSIONS CD133 was identified as a predictor of the therapeutic effect of S1+ PEG-IFN α-2b therapy against advanced HCC.
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Affiliation(s)
- Satoru Hagiwara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kinki University School of Medicine, 377-2 Ohno-Higashi, Ōsakasayama, Osaka 589-8511, Japan
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Li L, Davie JR. The role of Sp1 and Sp3 in normal and cancer cell biology. Ann Anat 2010; 192:275-83. [PMID: 20810260 DOI: 10.1016/j.aanat.2010.07.010] [Citation(s) in RCA: 452] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Accepted: 07/22/2010] [Indexed: 10/19/2022]
Abstract
Sp1 and Sp3 are transcription factors expressed in all mammalian cells. These factors are involved in regulating the transcriptional activity of genes implicated in most cellular processes. Dysregulation of Sp1 and Sp3 is observed in many cancers and diseases. Due to the amino acid sequence similarity of the DNA binding domains, Sp1 and Sp3 recognize and associate with the same DNA element with similar affinity. However, others and our laboratory demonstrated that these two factors possess different properties and exert different functional roles. Both Sp1 and Sp3 can interact with and recruit a large number of proteins including the transcription initiation complex, histone modifying enzymes and chromatin remodeling complexes, which strongly suggest that Sp1 and Sp3 are important transcription factors in the remodeling chromatin and the regulation of gene expression. In this review, the role of Sp1 and Sp3 in normal and cancer cell biology and the multiple mechanisms deciding the functional roles of Sp1 and Sp3 will be presented.
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Affiliation(s)
- Lin Li
- Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba R3E 0V9, Canada
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Nguyen H, Tran A, Lipkin S, Fruehauf JP. Pharmacogenomics of Colorectal Cancer Prevention and Treatment. Cancer Invest 2009; 24:630-9. [PMID: 16982469 DOI: 10.1080/07357900600896281] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Pharmacogenomic tools are beginning to emerge that will provide guidance in the treatment and prevention of colorectal cancer. Significant individual genetic variation exists in drug metabolism of 5FU, capecitabine, irinotecan, and oxaliplatin that influences both the toxicity and efficacy of these agents. Recent FDA approval of genetic testing for mutations in the UGT1A1 gene that predict adverse reactions to irinotecan is ushering in a new era that will increasingly rely on genotyping to individualize treatment decisions for patients with cancer as well as for patients at high risk who may be candidates for chemoprevention agents. This review focuses on current knowledge regarding key mutations and polymorphisms which affect outcomes for colorectal cancer patients, as well as the pharmacogenetics of chemoprevention trials.
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Affiliation(s)
- Hoa Nguyen
- University of California Irvine Chao Family Comprehensive Cancer Center, Orange, California, USA
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Hoffmann AC, Brabender J, Metzger R, Ling F, Warnecke-Eberz U, Lurje G, Hoelscher AH, Schneider PM, Vallböhmer D. Dihydropyrimidine dehydrogenase mRNA expression in peripheral blood of rectal cancer patients is significantly associated with residual tumor and distant metastases following resection. J Surg Oncol 2009; 99:296-301. [PMID: 19180589 DOI: 10.1002/jso.21233] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND DPD and TS expression have been shown to correlate with response of 5-FU based chemotherapy in colorectal cancer tissue. Little is known about mRNA expression levels of TS and DPD in peripheral blood. The goals of this study were to test the feasibility of DPD and TS detection in blood and their associations to TNM staging and complete surgical resection. METHODS Whole blood was drawn 1 day pre- and 10 days post-operatively from 23 patients with rectal cancer. Either adjuvant (n = 15) or neoadjuvant (n = 8) treatment was performed. Tumor cells were enriched from whole blood by density gradient centrifugation prior to extraction of total cellular RNA and subsequent direct quantitative reverse transcriptase-PCR assays. RESULTS DPD was detectable in 21/23 patients (91.3%) and TS in 14/23 (61.7%). Stepwise multiple linear regression models showed a significant association of DPD expression with distant metastases (P = 0.004) and residual tumor categories (P = 0.03). CONCLUSIONS Quantitative analysis of TS and DPD mRNA expression in peripheral blood of rectal cancer patients is technically feasible. DPD expression levels appear to be associated with residual tumor categories and might serve as a molecular marker for complete tumor resection. Larger studies seem to be warranted to scrutinize our hypothesis.
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Bandrés E, Zárate R, Ramirez N, Abajo A, Bitarte N, García-Foncillas J. Pharmacogenomics in colorectal cancer: The first step for individualized-therapy. World J Gastroenterol 2007; 13:5888-901. [PMID: 17990354 PMCID: PMC4205435 DOI: 10.3748/wjg.v13.i44.5888] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Interindividual differences in the toxicity and response to anticancer therapies are currently observed in practically all available treatment regimens. A goal of cancer therapy is to predict patient response and toxicity to drugs in order to facilitate the individualization of patient treatment. Identification of subgroups of patients that differ in their prognosis and response to treatment could help to identify the best available drug therapy according the genetic profile. Several mechanisms have been suggested to contribute to chemo-therapeutic drug resistance: amplification or overexpression of membrane transporters, changes in cellular proteins involved in detoxification or in DNA repair, apoptosis and activation of oncogenes or tumor suppressor genes. Colorectal cancer (CRC) is regarded as intrinsically resistant to chemotherapy. Several molecular markers predictive of CRC therapy have been included during the last decade but their results in different studies complicate their application in practical clinical. The simultaneous testing of multiple markers predictive of response could help to identify more accurately the true role of these polymorphisms in CRC therapy. This review analyzes the role of genetic variants in genes involved in the action mechanisms of the drugs used at present in colorectal cancer.
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Zhang X, Soong R, Wang K, Li L, Davie JR, Guarcello V, Diasio RB. Suppression of DPYD expression in RKO cells via DNA methylation in the regulatory region of the DPYD promoter: a potentially important epigenetic mechanism regulating DPYD expression. Biochem Cell Biol 2007; 85:337-46. [PMID: 17612628 DOI: 10.1139/o07-009] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Dihydropyrimidine dehydrogenase (DPD) is one of the factors that determine the efficacy and toxicity of 5-fluorouracil. Variations in DPD activity may result from alterations at the transcriptional level of the DPYD gene. Heterogeneity in DPYD expression has been reported, but the molecular mechanisms responsible for this remain unclear. We investigated methylation of the DPYD promoter as a mechanism for transcriptional regulation of DPYD in the RKO colorectal cancer cell line. We demonstrate that the active transcription machinery for DPYD is present in RKO cells, but promoter binding of Sp1, a transactivator of DPYD, was inhibited, which on subsequent examination was shown to be associated with dense promoter methylation. Treatment with 5-aza-2'-deoxycytidine alone or the combination of 5-aza-2'-deoxycytidine and trichostatin A induced demethylation of the promoter and markedly increased the DPYD mRNA level in RKO cells but not in unmethylated WiDr cells. Furthermore, in vitro methylation of the DPYD promoter decreased promoter activity. These data suggest an important role for methylation in DPYD suppression. The transcriptional suppression of DPYD by methylation may be responsible for the increased 5-fluorouracil sensitivity observed in some patients. This may also provide insight into the mechanism underlying the downregulation of DPYD in some colorectal cancers.
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MESH Headings
- Azacitidine/analogs & derivatives
- Azacitidine/pharmacology
- Base Sequence
- Cell Line, Tumor
- Colorectal Neoplasms/drug therapy
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/metabolism
- DNA Methylation
- DNA Primers/genetics
- DNA, Neoplasm/genetics
- DNA, Neoplasm/metabolism
- Decitabine
- Dihydrouracil Dehydrogenase (NADP)/genetics
- Epigenesis, Genetic
- Gene Expression Regulation, Enzymologic
- Humans
- Hydroxamic Acids/pharmacology
- Promoter Regions, Genetic
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- Sp1 Transcription Factor/metabolism
- Suppression, Genetic
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Affiliation(s)
- Xue Zhang
- Mayo Clinic Cancer Center, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA
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17
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Zhang X, Diasio RB. Regulation of human dihydropyrimidine dehydrogenase: implications in the pharmacogenetics of 5-FU-based chemotherapy. Pharmacogenomics 2007; 8:257-65. [PMID: 17324113 DOI: 10.2217/14622416.8.3.257] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Dihydropyrimidine dehydrogenase is the enzyme that is critical for the efficacy and toxicity of the anticancer reagent 5-fluorouracil. It has been demonstrated that the regulation of the dihydropyrimidine dehydrogenase gene has an important role in the determination of the enzyme activity of dihydropyrimidine dehydrogenase. The regulation of the gene expression is thus discussed from two aspects: normal regulation by specificity proteins, and the epigenetic regulation by promoter methylation. The influence of the polymorphism on dihydropyrimidine dehydrogenase enzyme activity and other factors that have been suggested to be involved in dihydropyrimidine dehydrogenase regulation are also discussed.
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Affiliation(s)
- Xue Zhang
- University of Alabama, Department of Pharmacology and Toxicology, Birmingham, AL 35294, USA
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18
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Li Y, Mizutani Y, Shiraishi T, Nakamura T, Mikami K, Takaha N, Okihara K, Kawauchi A, Sakai T, Miki T. The significance of the expression of dihydropyrimidine dehydrogenase in prostate cancer. BJU Int 2007; 99:663-8. [PMID: 17092280 DOI: 10.1111/j.1464-410x.2006.06606.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To measure dihydropyrimidine dehydrogenase (DPD), an enzyme involved in the metabolism of 5-fluorouracil (5-FU), expression in prostate cancer and determine whether 5-chloro-2,4-dihydroxypyridine (CDHP), a potent inhibitor of DPD, enhances the antitumoral activity of 5-FU against prostate cancer. PATIENTS, MATERIALS AND METHODS In all, 44 prostate tissue specimens were obtained from men who had a radical prostatectomy alone for prostate cancer, and 38 specimens from men who had had neoadjuvant hormonal therapy. We analysed the cancerous tissue and normal prostate tissue for DPD expression using immunohistochemistry, and determined its prognostic significance. In cultured human prostate cancer lines (DU145 and LNCaP), we compared the cytotoxicity of 5-FU/CDHP with that of 5-FU alone. Finally, in experiments on immunodeficient mice, we studied the effect of oral administration of tegafur, a pro-drug for 5-FU, with or without CDHP on the growth of tumours introduced by injection of DU145 cells. RESULTS The expression of DPD was significantly higher in cancerous than normal prostate tissue; 36 of 44 (82%) specimens of prostate cancer expressed DPD, whereas only 25 of 44 (57%) specimens of normal prostate tissue expressed DPD. For men with prostate cancer who had radical prostatectomy alone, men with negative DPD expression tended to have a longer recurrence-free survival than those with positive expression; there were no recurrences in men with prostate cancer and negative DPD expression in the 5-year follow-up. DPD expression was significantly lower in men with prostate cancer who received neoadjuvant hormonal therapy. In vitro treatment of human prostate cancer cell lines with 5-FU/CDHP showed more cytotoxicity than with 5-FU treatment alone. Finally, DU145 tumours in mice treated with tegafur and CDHP were significantly smaller than in mice given tegafur alone. CONCLUSION The present study showed that DPD expression is elevated in prostate cancer, and indicate that DPD inhibitors might enhance the antitumour activity of 5-FU against prostate cancer.
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Affiliation(s)
- Yongnan Li
- Department of Urology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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19
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Taomoto J, Yoshida K, Wada Y, Tanabe K, Konishi K, Tahara H, Fukushima M. Overexpression of the Orotate Phosphoribosyl-Transferase Gene Enhances the Effect of 5-Fluorouracil on Gastric Cancer Cell Lines. Oncology 2007; 70:458-64. [PMID: 17237621 DOI: 10.1159/000098873] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2006] [Accepted: 09/14/2006] [Indexed: 01/13/2023]
Abstract
OBJECTIVE Orotate phosphoribosyl-transferase (OPRT) is the initial enzyme of the 5-fluorouracil (5-FU) metabolic pathway, converting 5-FU into 5-fluorouridinemonophosphate, which is the most important mechanism of 5-FU activation. We therefore investigated whether overexpression of the OPRT gene enhances sensitivity to 5-FU. METHODS An expression vector of the OPRT gene (pTARGET-OPRT) was transfected into two gastric cancer cell lines, TMK-1 and MKN-45, with low baseline expression levels of OPRT. The sensitivity to and anti-tumor activity of 5-FU were then investigated in vitro and in vivo in these two transfected clones (TMK-OPRT and MKN-OPRT). RESULTS Although cell growth was unaltered compared to parent cells, overexpression of the OPRT gene was confirmed by Western blotting in both the TMK-OPRT and MKN-OPRT cells. OPRT enzyme activity increased 38-fold in TMK-OPRT cells and 8.0 fold in MKN-OPRT cells compared to their parent cells. Interestingly, although the sensitivity to Adriamycin, cis-platinum, mitomycin C and paclitaxel was unaltered in the transfected clones, the sensitivity to 5-FU was increased 14.2- and 6.0-fold in TMK-OPRT and MKN-OPRT cells, respectively, compared to their parent cells. Moreover, enhanced sensitivity was also confirmed in the in vivo study. CONCLUSION The results indicate that overexpression of the OPRT gene plays an important role in the antiproliferative effect of 5-FU and might therefore be a predictive factor of response to 5-FU in gastric cancer patients.
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Affiliation(s)
- Jyunnya Taomoto
- Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Graduate School of Medical Science, Hiroshima University, Hiroshima, Japan
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20
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Mercier C, Ciccolini J. Profiling dihydropyrimidine dehydrogenase deficiency in patients with cancer undergoing 5-fluorouracil/capecitabine therapy. Clin Colorectal Cancer 2007; 6:288-96. [PMID: 17241513 DOI: 10.3816/ccc.2006.n.047] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Fluoropyrimidine drugs such as 5-fluorouracil (5-FU) and capecitabine are a mainstay in the treatment of numerous solid tumors, including colorectal cancers, alone or as part of combination therapies. Cytotoxic drugs such as 5-FU and oral capecitabine display narrow therapeutic indexes combined with high interpatient pharmacokinetic variability. As a result, severe toxicities often limit or delay the administration of successive, optimal chemotherapeutic courses, leading to unfavorable clinical outcome in patients with cancer. Catabolism and deactivation of fluoropyrimidine drugs depend on a single and exclusive enzymatic step driven by dihydropyrimidine dehydrogenase (DPD). Dihydropyrimidine dehydrogenase is prone to marked circadian rhythms, drug-drug interactions, and genetic polymorphisms; influence of its erratic activity on 5-FU pharmacokinetics and toxicity profile has been extensively investigated, and it is now well known that DPD deficiency leads to severe toxicities with 5-FU or possibly capecitabine exposure. With the ever-increasing number of patients with cancer likely to be treated with fluoropyrimidines, predicting and preventing the occurrence of such toxicities is now a major issue in clinical oncology. Early determination of DPD status in patients with cancer would allow identification of those at risk and help in subsequent dose adjustment or selection of other treatment modalities. Numerous methods, either genotypic or phenotypic, have been proposed to achieve this goal. This review covers a wide range of techniques available to establish DPD status in patients with cancer.
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Affiliation(s)
- Cédric Mercier
- EA3286, Medical Oncology Unit, La Timone University Hospital, Marseille, France.
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21
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Zhou ZW, Wang GQ, Wan DS, Lu ZH, Chen YB, Li S, Chen G, Pan ZZ. The Dihydrouracil/Uracil Ratios in Plasma and Toxicities of 5-Fluorouracil-Based Adjuvant Chemotherapy in Colorectal Cancer Patients. Chemotherapy 2007; 53:127-31. [PMID: 17308379 DOI: 10.1159/000099984] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2005] [Accepted: 01/10/2006] [Indexed: 11/19/2022]
Abstract
BACKGROUND This study was designed to measure the dihydrouracil (UH(2))/uracil (U) ratio in plasma as a surrogate marker for dihydropyrimidine dehydrogenase (DPD) activity and to investigate the relationships of the UH(2)/U ratios in plasma with the toxicities of 5-fluorouracil (5-FU)-based adjuvant chemotherapy and 5-FU plasma concentrations in colorectal cancer patients. METHODS Thirty colorectal cancer patients received adjuvant chemotherapy of leucovorin plus 5-FU after operations. The concentrations of UH(2), U and 5-FU were assayed by the high-performance liquid chromatography method. The relationships of the UH(2)/U ratios with the 5-FU toxicities and 5-FU plasma concentrations were analyzed. RESULTS There was a negative relationship between the UH(2)/U ratios and 5-FU plasma concentrations (p <0.001). 5-FU toxicities had a negative correlation with the UH(2)/U ratios and a positive correlation with 5-FU plasma concentrations (p < 0.05). CONCLUSION The UH(2)/U ratio in plasma has close correlations with the 5-FU plasma concentration and 5-FU toxicity during chemotherapy, which may highlight the theoretical base of individual therapy for patients with colorectal cancer.
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Affiliation(s)
- Zhi Wei Zhou
- Department of Abdominal Surgery, State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, China
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22
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N/A, 徐 光. N/A. Shijie Huaren Xiaohua Zazhi 2006; 14:3290-3293. [DOI: 10.11569/wcjd.v14.i34.3290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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23
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Okita A, Tsukuda K, Murakami M, Ota T, Doihara H, Suda M, Nakano T, Matsuoka K, Suzuki E, Naito M, Andou A, Shimizu N. Thymidine phosphorylase and dihydropyrimidine dehydrogenase expression levels in tumor and normal tissue specimens of T3 human colorectal carcinoma. Surg Today 2006; 36:348-53. [PMID: 16554992 DOI: 10.1007/s00595-005-3145-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2005] [Accepted: 07/12/2005] [Indexed: 10/24/2022]
Abstract
PURPOSE Thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) are important enzymes related to the metabolism of 5-fluorouracil and its derivatives. We evaluated the association between the clinicopathological factors and these enzymes in patients with T3 colorectal carcinoma. METHODS The TP and DPD expression levels in 15 patients with T3 colorectal carcinomas were measured in tumor and adjacent normal tissue specimens by enzyme-linked immunosorbent assay. Correlations between each enzyme and clinicopathological factors were also statistically evaluated. RESULTS The TP levels in tumor and normal tissue specimens were 77.9 +/- 33.6 and 24.7 +/- 10.3, respectively (P < 0.001). The DPD levels in tumor and normal tissue specimens were 44.1 +/- 18.2 and 53.1 +/- 24.1, respectively (P = 0.46). The TP/DPD ratios in tumor and normal tissue specimens were 1.84 +/- 0.52 and 0.53 +/- 0.26, respectively (P < 0.001). The tumor/normal ratios of TP level in patients with and without liver metastasis were 1.79 +/- 0.91 and 4.67 +/- 2.51, respectively (P = 0.024). CONCLUSION The measurement of the enzyme expression levels of TP and DPD is considered to be useful for better understanding the conditions of tumor progression. The mechanisms of regulation of these enzymes thus require further evaluation.
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Affiliation(s)
- Atsushi Okita
- Department of Surgery, National Hospital Organization, Shikoku Cancer Center, Matsuyama, Japan
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24
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O'Neil BH, McLeod HL. Thymidine Phosphorylase and Capecitabine: A Predictive Marker for Therapy Selection? J Clin Oncol 2006; 24:4051-3. [PMID: 16943521 DOI: 10.1200/jco.2006.07.1803] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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25
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Gardiner SJ, Begg EJ. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev 2006; 58:521-90. [PMID: 16968950 DOI: 10.1124/pr.58.3.6] [Citation(s) in RCA: 235] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The application of pharmacogenetics holds great promise for individualized therapy. However, it has little clinical reality at present, despite many claims. The main problem is that the evidence base supporting genetic testing before therapy is weak. The pharmacology of the drugs subject to inherited variability in metabolism is often complex. Few have simple or single pathways of elimination. Some have active metabolites or enantiomers with different activities and pathways of elimination. Drug dosing is likely to be influenced only if the aggregate molar activity of all active moieties at the site of action is predictably affected by genotype or phenotype. Variation in drug concentration must be significant enough to provide "signal" over and above normal variation, and there must be a genuine concentration-effect relationship. The therapeutic index of the drug will also influence test utility. After considering all of these factors, the benefits of prospective testing need to be weighed against the costs and against other endpoints of effect. It is not surprising that few drugs satisfy these requirements. Drugs (and enzymes) for which there is a reasonable evidence base supporting genotyping or phenotyping include suxamethonium/mivacurium (butyrylcholinesterase), and azathioprine/6-mercaptopurine (thiopurine methyltransferase). Drugs for which there is a potential case for prospective testing include warfarin (CYP2C9), perhexiline (CYP2D6), and perhaps the proton pump inhibitors (CYP2C19). No other drugs have an evidence base that is sufficient to justify prospective testing at present, although some warrant further evaluation. In this review we summarize the current evidence base for pharmacogenetics in relation to drug-metabolizing enzymes.
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Affiliation(s)
- Sharon J Gardiner
- Department of Medicine, Christchurch School of Medicine, Private Bag 4345, Christchurch, New Zealand.
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26
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Wada Y, Yoshida K, Suzuki T, Mizuiri H, Konishi K, Ukon K, Tanabe K, Sakata Y, Fukushima M. Synergistic effects of docetaxel and S-1 by modulating the expression of metabolic enzymes of 5-fluorouracil in human gastric cancer cell lines. Int J Cancer 2006; 119:783-91. [PMID: 16557585 DOI: 10.1002/ijc.21879] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
We have recently demonstrated in a Phase I/II study that combination chemotherapy with docetaxel (TXT) and S-1 is active against metastatic gastric carcinomas. To elucidate the mechanisms underlying the synergistic effects of these drugs, both the growth inhibitory effects and the expression profiles of enzymes involved in fluorouracil (5-FU) metabolism were examined in vitro and in vivo. TXT alone and in combination with 5-FU inhibited the growth of each of the 5 gastric cancer cell lines that we examined (TMK-1, and MKN-1, -28, -45 and -74), in a time- and dose-dependent manner. Moreover, striking synergistic effects were observed in TMK-1 cells in vitro with IC50 values of between 4.73 and 0.61 nM 5-FU. Furthermore, in TMK-1 xenografts, 5-FU/TXT cotreatments exhibited synergistic antitumor effects. The combination of S-1 and TXT, however, exhibited greater growth-inhibitory effects than the 5-FU/TXT cotreatments. The mechanisms underlying these synergistic effects of S-1 and TXT were examined by expression and activity analyses of the 5-FU metabolic enzymes. The expression of thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) were decreased 50 and 73% of control levels, respectively, and that of orotate phosphorybosyl transferase (OPRT) was increased by 3.9-fold at the protein level. These findings suggested that biochemical modulation of the 2 drugs had occurred, which was further confirmed by the results of the activity assays. These data strongly indicate that a combination chemotherapy of TXT and S-1 is effective against gastric carcinomas and is therefore a good candidate as a standard chemotherapeutic strategy in treating these tumors.
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Affiliation(s)
- Yoshiyuki Wada
- Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
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Abstract
Metastatic growth is a selective, non-random process, which in the case of colorectal cancer, frequently occurs in the liver and is the major cause of cancer related death in these patients. This review summarises attempts to find biological and molecular markers of metastasis and their role in establishment of secondary tumours. Recent evidence suggests that liver metastases are phenotypically different to the primary from which they were derived and thus represent a separate disease entity.
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Affiliation(s)
- Nigel C Bird
- Liver Research Group, Clinical Sciences (South), Royal Hallamshire Hospital, Sheffield, United Kingdom.
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Zhang X, Li L, Fourie J, Davie JR, Guarcello V, Diasio RB. The role of Sp1 and Sp3 in the constitutive DPYD gene expression. ACTA ACUST UNITED AC 2006; 1759:247-56. [PMID: 16806531 DOI: 10.1016/j.bbaexp.2006.05.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2005] [Revised: 04/29/2006] [Accepted: 05/03/2006] [Indexed: 11/16/2022]
Abstract
Dihydropyrimidine dehydrogenase (DPD), the initial and rate-limiting enzyme in the 5-fluorouracil (5-FU) catabolic pathway, has been implicated as one of the factors determining the efficacy and toxicity of the anticancer agent 5-FU. Studies have attributed variation in DPD activity partially to alterations at the transcriptional level of DPYD gene. We investigated the transcription factors implicated in the constitutive expression of DPYD by utilizing a 174-bp fragment of the DPYD promoter region in which three consensus Sp protein binding sites (SpA, SpB and SpC) were predicted. The binding of Sp1 and Sp3 transcription factors to this region was detected by electrophoretic mobility shift and chromatin immunoprecipitation assays. By ectopically expressing human Sp1 and Sp3 in Sp-deficient Drosophila S2 cells, we demonstrated that Sp1 is a strong activator, while Sp3 by its own is a weak activator of the DPYD promoter. Moreover, Sp3 may serve as a competitor of Sp1, thus decreasing the Sp1 induced promoter activity. SpA, SpB and SpC sites are all Sp1 inducible. In the full activation of the DPYD promoter in human cell lines, the SpB site is essential; the SpC site works cooperatively with SpB, while SpA has minor promoter activity. These studies provide further insight into the molecular mechanisms underlying the heterogeneity of DPD activity, and may facilitate the efficacy and safety of 5-FU-based chemotherapy.
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Affiliation(s)
- Xue Zhang
- Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Barbado M, Preisser L, Boisdron-Celle M, Verriele V, Lorimier G, Gamelin E, Morel A. Tumor quantification of several fluoropyrimidines resistance gene expression with a unique quantitative RT-PCR method. Implications for pretherapeutic determination of tumor resistance phenotype. Cancer Lett 2006; 242:168-79. [PMID: 16387426 DOI: 10.1016/j.canlet.2005.11.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2005] [Revised: 10/27/2005] [Accepted: 11/02/2005] [Indexed: 11/19/2022]
Abstract
Pretherapeutic determination of tumor resistance to chemotherapy is a main challenge, hindered by the low number of mechanisms characterized at the same time, the small size of the clinical specimens and the heterogeneity of the techniques or the lack of true quantification. The aim of the present study was to determine in real time quantitative RT-PCR, tumor cell expression of several transcripts involved in cancer cell resistance with a unique cDNA sample from a tumor biopsy. The technique had to be suitable in clinical practice for determination of several factors involved in resistance to a given drug family, for example, fluoropyrimidines resistance factors: thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine kinase (TK), dihydrofolate reductase (DHFR), folylpolyglutamate synthetase (FPGS). A frame-shifted artificial construct was designed specifically to work within the same conditions. We validated our technique by quantifying expressions of these 5 genes starting from tissue samples of colorectal carcinoma and the surrounding normal mucosa of 33 different patients. That real time quantitative RT-PCR technique using the frame-shifted artificial construct as a standard provided a real comparison and quantification of different resistance factors. Tumor resistance phenotype determination based on that approach will be investigated in a control study.
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Affiliation(s)
- Maud Barbado
- Laboratoire d'Oncopharmacologie, INSERM U564, Centre Paul Papin, 2 Rue Moll, 49 033 Angers Cedex, France
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Hasegawa T, Kim HS, Fukushima M, Wataya Y. Sequence analysis of the 5'-flanking regions of human dihydropyrimidine dehydrogenase gene: identification of a new polymorphism related with effects of 5-fluorouracil. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2005; 24:233-42. [PMID: 16021908 DOI: 10.1081/ncn-59679] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Dihydropyrimidine dehydrogenase (DPD), known as a rate-limiting metabolic enzyme in the catabolism of 5-fluorouracil (5-FU), degrades more than about 80% of the administered 5-FU in human liver. Since it was reported that the anticancer effects of 5-FU were observed in cancer patients with lower DPD activities, many attempts have been conducted to anticipate the expected anticancer effects of 5-FU based on expression of intracanceral DPD. It have been reported that 39 different mutations and polymorphisms in the coding regions of DPD genes have been identified; however, there is no report on polymorphisms in the 5'-flanking region of DPD genes. We investigated polymorphisms in the 5'-flanking regions (3,058 bp), which are considered to control expression of DPD genes, in genomic DNA extracted from 37 kinds of human cancer cells. As the results, out of 37 cancer cells subjected to analysis, DLD- 7 cells had C insertion and 7 strains G deletion, which were hetelozygote. No significant relationship was identified between the DPD activity and the expression levels of DPD mRNA in examined 10 kinds of human cancer cells. However, in DLD-1 cells, which have C-insertion polymorphism in 5'-flanking region of DPD gene, the DPD activity was below detection limit (< or = 0.5 pmol/min/mg protein). Furthermore, 50% of cytosine residue on the CpG site generated by the C insertion was methylated at the 5 position. In this study, we have identified novel polymorphism possibly related the cytotoxicity of 5-FU in the 5'-flanking region of DPD gene. It is suggested that newly identified polymorphism of DPD gene might affect transcription of DPD, thereby providing influence on the clinical outcome of cancer patients treated with 5-FU.
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Affiliation(s)
- Takako Hasegawa
- Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama-shi, Okayama 700-8530, Japan.
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Megyeri A, Bacsó Z, Shields A, Eliason JF. Development of a stereological method to measure levels of fluoropyrimidine metabolizing enzymes in tumor sections using laser scanning cytometry. Cytometry A 2005; 64:62-71. [PMID: 15729713 DOI: 10.1002/cyto.a.20121] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND The enzymes thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) influence the activities of fluoropyrimidine anticancer drugs. The sensitivity of cancer cells to capecitabine, which is an oral, tumor-selective pre-prodrug of 5-fluorouracil may correlate better to the TP/DPD ratio than to levels of either enzyme alone. Our goal was to develop a quantitative immunofluorescent method for estimating the levels of TP, DPD, and their ratio in archival tumor sections. METHODS Mouse anti-TP and rat anti-DPD monoclonal antibodies were used for parallel indirect immunofluorescent staining. The fluorescence was measured using a laser scanning cytometer (LSC; CompuCyte, Cambridge, MA) in single cells and in sections prepared from cell lines and a human tumor. The phantom contouring feature of the LSC provided a stereologic approach for collecting the fluorescence intensity data from sections. RESULTS The relative fluorescence intensities measured in single cells or in sections of the cell lines, using single or double labeling, were similar, supporting the suitability of phantom contouring and two-color staining. Sections of the T-24 and ZR-75-1 cell lines placed on the same slide as the tumor section were used as internal standards for fluorescence measurements. The TP/DPD ratios measured in three cell lines correlated well with the cytotoxicity of 5'-deoxy-5-fluorouridine measured in vitro, indicating that the measurements are related to the biological activity of the drug. CONCLUSIONS Plotting the data as contour maps of the topologic distribution of fluorescence intensities in tumor sections allows subsequent histopathologic examination, which may reveal features of the tumors leading to high or low ratios of these enzymes. In addition, this method can be used for any drug target/metabolic system where the key components are known and suitable antibodies are available.
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Affiliation(s)
- Attila Megyeri
- Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48202, USA
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Lentz F, Tran A, Rey E, Pons G, Tréluyer JM. Pharmacogenomics of fluorouracil, irinotecan, and oxaliplatin in hepatic metastases of colorectal cancer: clinical implications. ACTA ACUST UNITED AC 2005; 5:21-33. [PMID: 15727486 DOI: 10.2165/00129785-200505010-00002] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Hepatic metastases occur in about half of patients with colorectal cancer. Since hepatic metastases are often not accessible for surgery, chemotherapy of metastases is important. The most commonly used chemotherapy drugs for hepatic metastases are fluorouracil, irinotecan, and oxaliplatin. Several enzymes are known to be involved in the catabolism and anabolism of these drugs, and the activity of these enzymes varies greatly between individuals. The causes of this variation include genetic polymorphisms, different regulation between normal and cancer tissue, and the influence of chemotherapy on enzyme expression. The varying enzyme activity may have an important effect on the outcome of chemotherapy. Several studies confirm the influence of the activity of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase on the outcome of fluorouracil therapy for colorectal cancer, with higher enzyme activities predicting lower treatment efficacy. Although fewer studies are available regarding therapy of hepatic metastases, the same relationship between thymidylate synthase activity and outcome of fluorouracil therapy observed for primary colorectal cancer was found. For the other two enzymes, only a few studies are available, but the results indicate similarly that higher enzyme activity seems to be disadvantageous. The enzymes responsible for the activation, metabolism and mechanism of action of irinotecan, namely carboxylesterase 2, cytochrome P450 (CYP) 3A4, uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1), and topoisomerase-I, also exhibit variable interindividual activity. Thus, there may be an association between enzyme activity and response to therapy. For instance, in patients with colorectal cancer, higher enzyme activity of topoisomerase-I seems to be predictive of a better response to irinotecan. CYP3A4 and UGT1A1 activity levels might be predictive of irinotecan toxicity rather than efficacy. The degradation of oxaliplatin is independent of potentially varying enzyme activity, but for this drug, the DNA repair enzyme ERCC1 may influence the survival time after chemotherapy. Taken together, the available data indicate the importance of the different enzyme activities on the outcome of chemotherapy of hepatic metastases in colorectal cancer. More information is needed, especially for the newer drugs irinotecan and oxaliplatin. However, the existing data are very promising in respect to the potential to guide dose and drug selection for more efficient and less toxic chemotherapy of hepatic metastases.
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Affiliation(s)
- Frederike Lentz
- Service de Pharmacologie, Hôpital Saint Vincent de Paul, avenue Denfert-Rochereau, Paris, 75014, France
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Abstract
Current use of chemotherapeutic and targeted agents for advanced colorectal cancer (CRC) results in high tumor response rates and relatively long overall patient survival. Fluoropyrimidines, irinotecan, and oxaliplatin are highly active in first-line and salvage therapy of colorectal cancer. Targeted therapies, including anti-angiogenesis agents and anti-epidermal growth factor receptor antibodies, have been incorporated with traditional chemotherapy and offer additional options for patients with CRC. However, there is marked variability in response to therapy, as well as frequency and severity of toxicities. Molecular markers and pharmacogenomic profiling may improve prediction of patients who will experience significant benefit or toxicity from currently available agents. Validation of these predictive factors in prospective clinical trials is now necessary to allow for a rational and systematic individualization of cancer therapy.
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Affiliation(s)
- Benjamin R Tan
- Department of Medicine and The Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA
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Russo A, Corsale S, Cammareri P, Agnese V, Cascio S, Di Fede G, Macaluso M, Bazan V. Pharmacogenomics in colorectal carcinomas: Future perspectives in personalized therapy. J Cell Physiol 2005; 204:742-9. [PMID: 15828025 DOI: 10.1002/jcp.20357] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The recent introduction of new drugs such as capecitabine, irinotecan, and oxaliplatinum has greatly improved the clinical outcome of patients with advanced/metastatic colorectal cancer. Nevertheless, some patients may suffer from the adverse drug reactions which will probably be the main cause of chemotherapy failure. The goal of pharmacogenomics is to find correlations between therapeutic responses to drugs and the genetic profiles of patients; the different responses to a particular drug are due, in fact, not only to the specific clinico-pathological features of the patient or to environmental factors, but also to the ethnic origins and the particular individual's genetic profile. Genes which codify for the metabolism enzymes, receptor proteins, or protein targets of chemotherapy agents often present various genetic polymorphisms. The main aim of this review is to provide an overview of the known polymorphisms present in the genes which codify for factors (thymidylate synthase dihydropyrimidine dehydrogenase, uridine diphosphate (UDP)-glucuronosyl-transferase 1A1, enzymes implicated in DNA repair) involved in the action mechanisms of the drugs now utilized in chemotherapeutic treatment of colorectal carcinoma, such as fluoropyrimidines, irinotecan, and platinum agents.
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Affiliation(s)
- Antonio Russo
- Department of Oncology, University of Palermo, Italy.
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Tsuji T, Sawai T, Takeshita H, Nakagoe T, Hidaka S, Yamaguchi H, Yasutake T, Nagayasu T, Tagawa Y. Tumor dihydropyrimidine dehydrogenase expression is a useful marker in adjuvant therapy with oral fluoropyrimidines after curative resection of colorectal cancer. Cancer Chemother Pharmacol 2004; 54:531-6. [PMID: 15309506 DOI: 10.1007/s00280-004-0802-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2003] [Accepted: 02/04/2004] [Indexed: 10/26/2022]
Abstract
PURPOSE Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of 5-fluoropyrimidine (5-FU) catabolism. We examined whether tumor DPD expression is an effective marker in adjuvant therapy with oral fluoropyrimidines after curative resection of colorectal cancer. METHODS We studied 89 patients with stage II-III colorectal cancers who had undergone curative resections and received oral 5-FU-based adjuvant chemotherapy. The levels of DPD expression in tumor and normal colonic mucosa were measured by an enzyme-linked immunosorbent assay. In 53 tumor samples, DPD enzymatic activity was also analyzed in order to evaluate the relationship between DPD expression and enzymatic activity. RESULTS DPD expression significantly correlated with DPD enzymatic activity in these 53 tumors ( r=0.56; P<0.001). DPD expression in the tumors was significantly lower than in normal mucosa (47.1+/-30.8 and 56.4+/-18.5 U/mg protein, respectively; P<0.05). We designated the cut-off value of tumor DPD as its median value (46.0 U/mg protein). Patients with low DPD expression had longer disease-free intervals than those with high DPD expression according to univariate analysis ( P=0.026). In a multivariate analysis, low DPD expression was significantly and independently associated with better survival. CONCLUSIONS Tumor DPD expression is a useful marker for use with adjuvant chemotherapy with oral fluoropyrimidines after curative resection of colorectal cancer.
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Affiliation(s)
- Takashi Tsuji
- Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
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van Kuilenburg ABP. Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur J Cancer 2004; 40:939-50. [PMID: 15093568 DOI: 10.1016/j.ejca.2003.12.004] [Citation(s) in RCA: 349] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2003] [Revised: 11/18/2003] [Accepted: 12/09/2003] [Indexed: 12/15/2022]
Abstract
The identification of genetic factors associated with either responsiveness or resistance to 5-fluorouracil (5-FU) chemotherapy, as well as genetic factors predisposing patients to the development of severe 5-FU-associated toxicity, is increasingly being recognised as an important field of study. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). Although the role of tumoral levels as a prognostic factor for clinical responsiviness has not been firmly established, there is ample evidence that a deficiency of DPD is associated with severe toxicity after the administration of 5-FU. Patients with a partial DPD deficiency have an increased risk of developing grade IV neutropenia. In addition, the onset of toxicity occurred twice as fast compared with patients with a normal DPD activity. To date, 39 different mutations and polymorphisms have been identified in DPYD. The IVS14+1G>A mutation proved to be the most common one and was detected in 24-28% of all patients suffering from severe 5-FU toxicity. Thus, a deficiency of DPD appears to be an important pharmacogenetic syndrome.
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Affiliation(s)
- André B P van Kuilenburg
- Academic Medical Center, University of Amsterdam, Emma Children's Hospital and Department of Clinical Chemistry, PO Box 22700, 1100 DE Amsterdam, The Netherlands.
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Tsuji T, Sawai T, Takeshita H, Nakagoe T, Hidaka S, Yamaguchi H, Yasutake T, Nagayasu T, Tagawa Y. Tumor dihydropyrimidine dehydrogenase in stage II and III colorectal cancer: low level expression is a beneficial marker in oral-adjuvant chemotherapy, but is also a predictor for poor prognosis in patients treated with curative surgery alone. Cancer Lett 2004; 204:97-104. [PMID: 14744539 DOI: 10.1016/j.canlet.2003.09.030] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The aim of this study was to evaluate the prognostic significance of tumor dihydropyrimidine dehydroganase (DPD) in curatively resected colorectal cancer patients who received or did not receive oral 5-FU based-adjuvant chemotherapy. Among 182 patients with stage II-III colorectal cancers, 89 patients (adjuvant chemotherapy group) received oral 5-FU based-adjuvant chemotherapy, and 93 patients (surgery alone group) did not receive 5-FU. DPD expressions in the tumors and in the normal colonic mucosa were measured by enzyme-linked immunosorbent assays. The mean DPD expression of the tumors was significantly lower than that of the normal mucosa (54.4 +/- 40.4 versus 72.3 +/- 23.3 Unit/mg protein, P < 0.01). For survival analyses, we designated the cut-off value of tumor DPD as its median value (46.3). In the adjuvant chemotherapy group, high tumor DPD levels were associated with poor survival (HR, 5.24; P = 0.03). In the surgery alone group, high tumor DPD levels were associated with better survival (HR, 0.32; P = 0.02). In conclusion, tumor DPD level is an efficacious marker in oral 5-FU based-adjuvant chemotherapy for colorectal cancer; however, low tumor DPD predicts reduced survival in patients treated with curative surgery alone.
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Affiliation(s)
- Takashi Tsuji
- Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto 1-7-1, Nagasaki, 852-8501, Japan.
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Fujiwaki R, Iida K, Nakayama K, Kanasaki H, Ozaki T, Hata K, Sakai E, Miyazaki K. Dihydropyrimidine dehydrogenase in normal and malignant endometrium: relationship with cell proliferation and thymidine phosphorylase. Virchows Arch 2003; 443:672-7. [PMID: 12910418 DOI: 10.1007/s00428-003-0866-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2003] [Accepted: 06/19/2003] [Indexed: 11/30/2022]
Abstract
Dihydropyrimidine dehydrogenase (DPD) is a pyrimidine salvage enzyme responsible for degradation of thymine, which is produced from thymidine by thymidine phosphorylase (TP). Our purpose was to determine the relationship between DPD, cell proliferation and TP expression in human endometrium. We examined DPD gene expression using reverse transcription-polymerase chain reaction, DPD protein levels using enzyme-linked immunosorbent assay, and DPD protein localization using immunohistochemistry in 58 normal endometria and 28 endometrial cancers. DPD gene expression was then related to the proliferating cell nuclear antigen index and to TP gene expression. DPD gene expression, which was correlated with DPD protein level, was relatively stable throughout various menstrual phases but was significantly elevated in postmenopausal status. It was significantly lower in endometrial cancer than in normal endometrium. Localization analysis revealed that DPD protein was located primarily in epithelial cells, but was also present in stromal cells. DPD gene expression correlated inversely with the PCNA index. TP gene expression pattern contrasted with that of DPD in postmenopausal and malignant endometrium. A high ratio of TP to DPD gene expression was significantly more frequent in endometrial cancer than in normal endometrium in any menstrual phase. DPD may act cooperatively with TP to affect cell function by maintaining the pyrimidine nucleotide pool balance in normal and malignant endometrium.
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Affiliation(s)
- Ritsuto Fujiwaki
- Department of Obstetrics and Gynecology, Shimane Medical University, 693-8501, Izumo, Japan.
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Yoshinare K, Kubota T, Watanabe M, Wada N, Nishibori H, Hasegawa H, Kitajima M, Takechi T, Fukushima M. Gene expression in colorectal cancer and in vitro chemosensitivity to 5-fluorouracil: a study of 88 surgical specimens. Cancer Sci 2003; 94:633-8. [PMID: 12841874 PMCID: PMC11160140 DOI: 10.1111/j.1349-7006.2003.tb01495.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2003] [Revised: 04/14/2003] [Accepted: 04/25/2003] [Indexed: 11/30/2022] Open
Abstract
To predict the sensitivity of colorectal cancer to 5-fluorouracil (5-FU), we compared the gene expression of surgically obtained colorectal cancer specimens with chemosensitivity to 5-FU as detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay. Eighty-eight patients with advanced and/or metastatic colorectal cancer provided written informed consent and entered the trial from September 2000 to October 2001. Fresh surgical specimens were used for the MTT assay, and sensitivity to 5-FU was evaluated at a cutoff concentration of 50 microg/ml and 48-h incubation time. Frozen samples were stored at - 80 degrees C until mRNA analysis of thymidylate synthetase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), es-nucleoside transporter (NT), and E2F1 by real-time RT-PCR. The correlations between the variables were analyzed, and the predictive value of these mRNAs was assessed statistically using a receiver operating characteristic (ROC) curve. NT and DPD, TP and DPD, and TP and NT mRNA expression levels correlated significantly, while TS and E2F1 showed no correlations. High NT expression was associated with low sensitivity to 5-FU (P < 0.013), as were high DPD and E2F1 expression (P < 0.022 for both). High TP mRNA expression correlated with low sensitivity to 5-FU (P < 0.034), although high TS mRNA expression did not. ROC curves indicated that DPD and NT mRNAs were possible predictors of sensitivity to 5-FU, with cutoff values of 0.6 and 0.4, respectively. The sensitivity of colorectal cancer to 5-FU may be regulated by DPD, the rate-limiting enzyme of catabolism, and NT, an important transmembrane transporter of nucleosides.
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Affiliation(s)
- Kentaro Yoshinare
- Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan
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Mizutani Y, Wada H, Yoshida O, Fukushima M, Nakanishi H, Nakao M, Miki T. Significance of dihydropyrimidine dehydrogenase activity in renal cell carcinoma. Eur J Cancer 2003; 39:541-7. [PMID: 12751387 DOI: 10.1016/s0959-8049(02)00730-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the pathway of uracil and thymine catabolism. DPD is also the principal enzyme involved in the degradation of 5-fluorouracil (5-FU), an anticancer chemotherapeutic agent that is used clinically to treat renal cell carcinoma (RCC). Little is known about the significance of DPD activity in human cancers. We investigated the activity of DPD in 68 RCC and the relationship between DPD activity and the sensitivity to 5-FU. The levels of DPD activity in RCC and normal kidney samples were determined by the 5-FU degradation assay. The sensitivity to 5-FU was assessed by the microculture tetrazolium dye assay. The activity of DPD was approximately 2-fold higher in normal kidney compared with RCC. DPD activity in Stage I/II RCC was approximately 2-fold higher than that in Stage III/IV RCC. The levels of DPD activity in Grade 1 and Grade 2 RCC were 3 and 2-fold higher, respectively, than that in the Grade 3 cancers. There was an inverse correlation between DPD activity in RCC cells and their sensitivity to 5-FU. Furthermore, 5-chloro-2,4-dihydroxypyridine (CDHP), a potent DPD inhibitor, enhanced the sensitivity to 5-FU. The current study is the first to demonstrate that the level of DPD activity was inversel correlated with both the progression of the disease and increased grade of RCC, and that DPD activity was inversely associated with the sensitivity of RCC to 5-FU, which was enhanced by a DPD inhibitor. These results suggest that a low DPD activity may be associated with the malignant potential of RCC. In addition, it may be possible to overcome 5-FU resistance by using DPD inhibitors in the treatment protocols of 5-FU-based chemotherapy for RCC.
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Affiliation(s)
- Y Mizutani
- Department of Urology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
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Hirano Y, Takayama T, Kageyama S, Ushiyama T, Suzuki K, Fujita K. Thymidine phosphorylase and dihydropyrimidine dehydrogenase in renal cell carcinoma: relationship between histological parameters and chemosensitivity to 5-fluorouracil. Eur Urol 2003; 43:45-51; discussion 51-2. [PMID: 12507543 DOI: 10.1016/s0302-2838(02)00498-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVES Thymidine phosphorylase (TdR-Pase) and dihydropyrimidine dehydrogenase (DPD) are thought to be key enzymes in the metabolic pathway of 5-fluorouracil (5-FU). Theoretically, cancer cells which have high TdR-Pase activity and/or low DPD activity should be sensitive to 5-FU. TdR-Pase is also known to have angiogenic activity which helps tumor progression and metastasis. On the other hand, little is known concerning the relationship of DPD activity with clinical malignant potential in renal cell carcinoma (RCC). In this study, we measured both TdR-Pase and DPD activities in surgically obtained RCC tissues and examined the relationship between these enzymatic activities and histological parameters. In addition, the results of in vitro chemosensitivity testing were also analyzed to determine whether TdR-Pase and/or DPD activity in carcinoma cells can predict the efficacy of 5-FU. METHODS RCC tissues from 53 patients were obtained. TdR-Pase and DPD activities were measured by ELISA and radioenzyme assay, respectively. Sensitivity to 5-FU was assessed by histoculture drug response assay (HDRA), an in vitro chemosensitivity test, for 20 of the 53 specimens. RESULTS Both TdR-Pase and DPD activities of RCC increased with histological grade. There was a significant positive correlation between the TdR-Pase activity and 5-FU sensitivity. In addition, a stronger positive correlation was found between TdR-Pase / DPD ratio and 5-FU sensitivity. DPD exhibited no correlation with 5-FU sensitivity. CONCLUSIONS The activity of both enzymes increased with malignant potential of RCC. TdR-Pase appeared to be the enzyme regulating activation of 5-FU in RCC.
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Affiliation(s)
- Yasuhiro Hirano
- Department of Urology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan.
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Gardiner SJ, Begg EJ, Robinson BA. The effect of dihydropyrimidine dehydrogenase deficiency on outcomes with fluorouracil. ADVERSE DRUG REACTIONS AND TOXICOLOGICAL REVIEWS 2002; 21:1-16. [PMID: 12140902 DOI: 10.1007/bf03256180] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The use of fluorouracil has been complicated by unpredictable pharmacokinetics, low response rates and seemingly random toxicity. The variable pharmacology is largely due to inherited differences in expression of the metabolising enzyme dihydropyrimidine dehydrogenase (DPD). This converts fluorouracil to inactive metabolites (catabolic pathway) and ultimately dictates the amount of fluorouracil that is available to be metabolised to cytotoxic nucleotides (anabolic pathway). Absolute and partial DPD deficiency affect around 0.1 and 3% of the Caucasian population, respectively. Administration of conventional doses of fluorouracil to these individuals has resulted in profound bone marrow and gastrointestinal toxicity, especially in those with absolute DPD deficiency. Other forms of toxicity such as myocardial ischaemia have been difficult to attribute directly to DPD deficiency. Efforts to improve outcomes with fluorouracil have included monitoring of fluorouracil concentrations and modifying fluorouracil administration techniques (e.g. from bolus injections to protracted intravenous infusions). In general, these moves have met with limited therapeutic advancement. The recognition that DPD deficiency increases toxicity has lead to the suggestion that genotypic or phenotypic assessment of DPD status prior to initiating fluorouracil may help predict outcomes. The gene that encodes for DPD expression is called DPYD. Approximately 1% of Caucasians are heterozygotes for the DPYD*2A mutation which is the variant allele that is most frequently implicated in DPD deficiency. Screening for this mutation may identify around 60% of individuals with absolute DPD deficiency who are at the greatest risk of toxicity. Another approach is to determine DPD activity in peripheral blood mononuclear cells, with low activity suggesting an increased risk of toxicity. Intratumoral DPD activity may also be assessed with high activity suggesting a poorer response to fluorouracil. Recently, drugs that inhibit DPD (e.g. eniluracil) have become available. These remove much of the variability in fluorouracil pharmacokinetics and may make assessment of DPD activity redundant. Despite the considerable inroads that have been made, further study is needed before the best means of optimising fluorouracil treatment is determined.
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Affiliation(s)
- Sharon J Gardiner
- Department of Clinical Pharmacology, Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand
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Kawasaki G, Yoshitomi I, Yanamoto S, Mizuno A. Thymidylate synthase and dihydropyrimidine dehydrogenase expression in oral squamous cell carcinoma: an immunohistochemical and clinicopathologic study. ORAL SURGERY, ORAL MEDICINE, ORAL PATHOLOGY, ORAL RADIOLOGY, AND ENDODONTICS 2002; 94:717-23. [PMID: 12464897 DOI: 10.1067/moe.2002.126912] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Thymidylate synthase (TS) is the target enzyme for 5-fluorouracil (5-FU), and dihydropyrimidine dehydrogenase (DPD) is the first enzyme that metabolizes 5-fluorouracil. Until now, only the enzyme activities of TS and DPD have been investigated; however, there are few reports about the immunohistochemistry of TS and DPD and none regarding oral carcinoma. The purpose of this article was to investigate the expression of TS and DPD in oral squamous cell carcinoma. STUDY DESIGN In this study, 109 oral squamous cell carcinomas were investigated for the immunohistochemical expression of TS and DPD proteins. RESULTS The expressions of TS in carcinoma cases was significantly higher than in controls (P <.05, t test). DPD was expressed both in carcinomas and in areas adjacent to the carcinomas. There was no correlation between the clinical factors and the TS labeling index or between the clinical factors and the DPD labeling index (DPD-LI). Pathologically, DPD-LI was significantly different in both the World Health Organization classification and Anneroth's classification. The TS labeling index was significantly correlated with the Ki-67 LI (P <.05, Pearson's correlation coefficient). Although TS showed no correlation between tegafur-uracil response and TS labeling index, there was a significant correlation between the tegafur-uracil response and DPD-LI. CONCLUSIONS TS may reveal tumor cell proliferation, but DPD-LI may correlate with a response to anticancer drug treatment.
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Affiliation(s)
- Goro Kawasaki
- Division of Oral and Maxillofacial Surgery, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan.
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Shirota Y, Ichikawa W, Uetake H, Yamada H, Nihei Z, Sugihara K. Intratumoral dihydropyrimidine dehydrogenase messenger RNA level reflects tumor progression in human colorectal cancer. Ann Surg Oncol 2002; 9:599-603. [PMID: 12095978 DOI: 10.1007/bf02573898] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Determination of intratumoral dihydropyrimidine dehydrogenase (DPD) is of clinical interest because increased DPD levels can influence the tumor response to 5-fluorouracil-based chemotherapy through increased inactivation of the agent in tumor cells. METHODS DPD messenger RNA (mRNA) levels were evaluated in 80 consecutive patients undergoing surgery for primary colorectal cancer and 12 cases of liver metastasis. RESULTS Higher DPD mRNA levels were associated with higher pathologic classification, corresponding to the T categories (r =.267; P =.003). The DPD mRNA level was statistically higher in tumors with microscopic lymph node metastasis than in those without (P =.002). Hence, the DPD mRNA level increased in accordance with Dukes' classification (r =.387; P =.0001). The DPD mRNA level of the liver metastasis from colorectal cancer was significantly higher than that of primary lesions (P =.002). In eight patients, the DPD mRNA level of the liver metastasis was significantly higher than that of the matched primary tumor (P =.017). CONCLUSIONS Increases of the DPD mRNA level in cancerous tissue seem to reflect tumor progression. High DPD mRNA levels in liver metastasis and advanced colorectal cancer may have clinical importance for 5-fluorouracil-based chemosensitivity.
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Affiliation(s)
- Yoshinori Shirota
- Department of Digestive Surgery, Tokyo Medical and Dental University, Japan.
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Takechi T, Fujioka A, Matsushima E, Fukushima M. Enhancement of the antitumour activity of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase activity (DPD) using 5-chloro-2,4-dihydroxypyridine (CDHP) in human tumour cells. Eur J Cancer 2002; 38:1271-7. [PMID: 12044515 DOI: 10.1016/s0959-8049(02)00048-5] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The purpose of this study was to evaluate the use of 5-chloro-2,4-dihydroxypyridine (CDHP), a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), to enhance the antitumour activity of the fluoropyrimidines. In an in vitro study, CDHP did not influence cell proliferation by itself. However, CDHP did inhibit 5-fluorouracil (5-FU) degradation and enhanced 5-FU cytotoxicity in a concentration-dependent manner in two human tumour cell lines (MIAPaCa-2 and HuTu80) with relatively high basal DPD activity. CDHP exhibited a maximum effect at a molar ratio (CDHP:5-FU) of more than 0.2. However, CDHP did not have any effect on 5-FU cytotoxicity in the CAL27 tumour cell line, which has a relatively low basal DPD activity, even at concentrations where the DPD activity is almost completely inhibited. In an in vivo study, the maximal tolerable doses (MTD) of tegafur (FT) and a combination of FT and CDHP at a molar ratio of 1:0.4 (FT/CDHP) for nude mice were determined by oral administration for 14 consecutive days. After a single oral administration of either FT or FT/CDHP at the MTD, the 5-FU serum concentration-time profiles were almost the same for both treatment strategies. When nude mice bearing subcutaneous (s.c.) MIAPaCa-2 cells were treated with either FT or FT/CDHP at the MTD, the FT/CDHP treatment showed a significantly higher antitumour effect than the FT treatment (tumour growth inhibition: FT/CDHP, 51+/-12%; FT, 21+/-25%; P<0.05). However, the host-body weight suppression induced by FT/CDHP and FT was equivalent. These findings suggest that the combination of fluoropyrimidine and CDHP for the treatment of tumours with a high basal DPD elicits a greater antitumour effect than treatment with fluoropyrimidines alone and we suggest that CDHP inhibits the degradation of 5-FU in the tumour.
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Affiliation(s)
- T Takechi
- Institute for Applied Oncology, Taiho Pharmaceutical Co., Ltd., 1-27 Misugidai, Hanno-city, Saitama, Japan.
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Fujiwaki R, Hata K, Nakayama K, Moriyama M, Iwanari O, Katabuchi H, Okamura H, Sakai E, Miyazaki K. Thymidine kinase in epithelial ovarian cancer: relationship with the other pyrimidine pathway enzymes. Int J Cancer 2002; 99:328-35. [PMID: 11992400 DOI: 10.1002/ijc.10319] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
TK is a pyrimidine metabolic pathway enzyme involved in salvage DNA synthesis. What roles TK may play in epithelial ovarian cancer and the relationships between TK and the other pyrimidine pathway enzymes remain unclear. We examined TK1 gene expression by RT-PCR and related it to gene expression of TS, TP and DPD in 69 samples from epithelial ovarian cancer, 8 low-malignant-potential tumors, 16 benign ovarian tumors and 34 normal ovaries. Additionally, cytosolic and serum TK activities were determined by radioenzymatic assay. TK1 gene expression, the ratio of TK1 to TS gene expression, that of TK1 to TP and that of TK1 to DPD were significantly higher in epithelial ovarian cancer than in normal ovaries. In epithelial ovarian cancer, TK1 gene expression correlated with cytosolic and serum TK activities, TS and TP gene expression and the ratio of TP to DPD gene expression. Patients with high-TK1 gene expression had a significantly poorer survival than those with low TK1 gene expression. Combined analysis demonstrated that the relative risk of cancer death for tumors with high TK1, high TS and high TP gene expression was greater than that for tumors with high TK1 gene expression alone. TK1 gene expression together with TS, TP and DPD gene expression may play important roles in influencing the malignant behavior of epithelial ovarian cancer. Combination therapy including TK inhibitor is a possible therapeutic intervention in patients with epithelial ovarian cancer.
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Affiliation(s)
- Ritsuto Fujiwaki
- Department of Obstetrics and Gynecology, Shimane Medical University, Izumo, Japan.
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Orr MS, Scherf U. Large-scale gene expression analysis in molecular target discovery. Leukemia 2002; 16:473-7. [PMID: 11960324 DOI: 10.1038/sj.leu.2402413] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2001] [Accepted: 11/30/2001] [Indexed: 01/21/2023]
Abstract
The evolution of simple arrays consisting of a few genes to ones composed of thousands of genes and/or ESTs has allowed investigators unprecedented views of the molecular mechanisms within cells. Due to the enormous quantities of information derived from microarray analysis, new types of problems have surfaced, such as where to store all of the data. The ability to solve database or statistical problems has required the bench biologist to collaborate with database developers, software designers and statisticians to determine solutions for storage, analysis and interpretation of microarray data. The collaborative effort between these extremely diverse disciplines has led to the development of creative database query and gene expression analysis tools, producing significant reductions in the time required by researchers to filter through the datasets and discover the key processes perturbed by the diseases of interest. Both unsupervised and supervised analysis methods have been applied to gene expression data leading to the discovery of novel therapeutic targets and diagnostic markers. Furthermore, tumor classification based on their respective molecular fingerprints has led to the classification of cancer subtypes and the discovery of novel molecular taxonomies that may eventually lead to improved patient stratification and superior therapeutic strategies.
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Affiliation(s)
- M S Orr
- Gene Logic Inc., Gaithersburg, MD 20878, USA
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Collie-Duguid ES, Johnston SJ, Boyce L, Smith N, Cowieson A, Cassidy J, Murray GI, McLeod HL. Thymidine phosphorylase and dihydropyrimidine dehydrogenase protein expression in colorectal cancer. Int J Cancer 2001; 94:297-301. [PMID: 11668512 DOI: 10.1002/ijc.1462] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
It is essential for actively proliferating cells to increase their rate of DNA synthesis to progress through the cell cycle. This is reflected in the increased uracil usage that is a common feature in solid tumours. Thymidine phosphorylase (TP) anabolises formation of pyrimidine nucleosides available for DNA synthesis, whereas dihydropyrimidine dehydrogenase (DPD) catabolises the degradation of pyrimidine bases, thereby reducing levels of uracil and thymine available for DNA synthesis. In addition, tissue levels of TP or DPD have been associated with the clinical efficacy of pyrimidine anti-metabolites commonly used in the treatment of colorectal cancer. There is little information, however, on the relative expression or degree of co-ordinated regulation of either protein in primary or metastatic colorectal cancer. DPD and TP protein levels were measured in 15 primary colorectal carcinomas, 10 colorectal liver metastases and 25 adjacent uninvolved tissues. DPD was reduced in 67% (10/15) of colorectal tumours (mean tumour/normal = 0.52) and in all liver metastases (mean tumour/normal = 0.41) compared with the corresponding normal tissue. In contrast, TP was increased in 80% (12/15) of colorectal tumours (mean tumour/normal = 18.91) and in all metastases (mean tumour/normal = 3.70). TP and DPD protein expression were highly variable in uninvolved and tumour tissues. The ratio of TP:DPD was higher in 87% of colorectal tumours and in all liver metastases compared with the adjacent uninvolved tissues. This suggests the presence of co-ordinated regulation of these pyrimidine metabolic enzymes and offers a strategy for optimising the use of pyrimidine-based chemotherapy.
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Affiliation(s)
- E S Collie-Duguid
- Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, Scotland.
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Abstract
The fluorinated pyrimidines have played a major role in the treatment of many common tumors since 5-fluorouracil (5FU) was first introduced. Studies of the cellular and clinical pharmacology of 5FU have led to an improved understanding of the mechanisms of action of this agent. This knowledge has allowed the optimal and rational development of fluoropyrimidine therapy, with significant therapeutic advances in recent years. Efforts to improve the therapeutic index of 5FU have included alteration of schedule, and the addition of biochemical modulators such as folinic acid. Although protracted continuous infusion of 5FU has led to better response rates and decreased toxicity, the administration of 5FU by protracted infusion is not only costly, but also inconvenient to the patient. Furthermore it is often associated with infectious and thrombotic complications related to the required indwelling intravenous catheter. Protracted oral administration is a rational route for administering 5FU, being preferred by the patient and the pharmaco-economist. The unpredictable and low oral bioavailability of 5FU initially discouraged this form of treatment. This problem has now been overcome by the new generation of oral fluoropyrimidines. Two main strategies have been pursued: 1) The administration of an inactive prodrug of 5FU, which is absorbed intact, and subsequently converted to 5FU. Capecitabine is converted to 5FU by a 3 step enzymatic process. 2) The administration of 5FU with an inhibitor of dihydropyrimidine dehydrogenase (DPD) to minimise the erratic absorption and variable clearance of 5FU: the preparations UFT, S1, and ethinyluracil/5FU contain an oral fluoropyrimidine co-administered orally with inhibitors of this enzyme. The development and characteristics of these agents are discussed.
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Affiliation(s)
- J S de Bono
- Cancer Research Campaign Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow, UK.
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Caponigro F, Avallone A, Budillon A, Comella P, Comella G. Raltitrexed/5-fluorouracil-based combination chemotherapy regimens in anticancer therapy. Anticancer Drugs 2001; 12:489-97. [PMID: 11459994 DOI: 10.1097/00001813-200107000-00001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Preclinical evidence of a schedule-dependent synergism between raltitrexed and 5-fluorouracil (5-FU) has prompted clinical studies of this combination. We review the main preclinical and clinical results of raltitrexed/5-FU-based combination chemotherapy regimens in anticancer therapy. Promising results include: response rates of 25 and 23% with combinations of raltitrexed/5-FU/levofolinic acid (LFA) as first-line treatment and oxaliplatin/raltitrexed/5-FU/LFA as second-line treatment of metastatic colorectal cancer, respectively; and a 67% response rate in a phase I study of cisplatin/raltitrexed/5-FU/LFA as first-line treatment of advanced head and neck cancer, including a 100% response rate at the recommended dose. These combinations were well tolerated, with neutropenia as the main dose-limiting toxicity, allowing the drugs to be combined at the doses used in monotherapy. These results suggest a role for raltitrexed within combination regimens in colorectal cancer therapy, as well as other tumors such as head and neck cancer. A further potential application of raltitrexed in combination therapies is within multidisciplinary chemo-radiotherapy strategies, mainly in rectal cancer. Phase II studies are planned/ongoing to investigate these interesting possibilities.
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Affiliation(s)
- F Caponigro
- Southern Italy Cooperative Oncology Group, c/o National Tumor Institute of Naples, Via M Semmola, 80131 Napoli, Italy.
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