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Panczyk M. Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years. World J Gastroenterol 2014; 20:9775-827. [PMID: 25110414 PMCID: PMC4123365 DOI: 10.3748/wjg.v20.i29.9775] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 01/17/2014] [Accepted: 04/21/2014] [Indexed: 02/07/2023] Open
Abstract
During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation, as a result of large international research projects (Human Genome Project, the 1000 Genomes Project International HapMap Project, and Programs for Genomic Applications NHLBI-PGA). This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer. For clinical use in the treatment of patients with colorectal cancer (CRC), in addition to fluoropyrimidines, another two new cytostatic drugs were allowed: irinotecan and oxaliplatin. Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted. The last 20 years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance. One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells. Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine. Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics. Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential. This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy. The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review.
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Zhao HY, Ma GW, Zou BY, Li M, Lin SX, Zhao LP, Guo Y, Huang Y, Tian Y, Xie D, Zhang L. Prognostic significance of thymidylate synthase in postoperative non-small cell lung cancer patients. Onco Targets Ther 2014; 7:1301-10. [PMID: 25114572 PMCID: PMC4109640 DOI: 10.2147/ott.s65067] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The aim of the present study was to investigate the clinicopathologic/prognostic significance of thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT), and thymidine phosphorylase (TP) proteins in postoperative non-small cell lung cancer (NSCLC) patients. Microarray slides from a set of 178 NSCLC patients were used for the detection of TS, OPRT, and TP expression by immunohistochemistry. The correlation between clinicopathologic factors and protein expression of three proteins was analyzed. Ninety seven carcinomas (57.4%) were TS-positive, 90 carcinomas (53.9%) were OPRT-positive, and 102 carcinomas (69.4%) were TP-positive. Compared with the TS-positive patients, the overall survival (OS) was significantly lower in the TS-negative patients (hazard ratio [HR] =1.766, 95% confidence interval [CI] =1.212–2.573, P=0.003). Significant differences between TS-positive and TS-negative patients was also observed in the following stratified analyses: 1) adenocarcinoma subgroup (HR =2.079, 95% CI =1.235–3.500, P=0.006); 2) less than 60-year-old subgroup (HR =1.890, 95% CI =1.061–3.366, P=0.031); 3) stage II/III subgroup (HR =1.594, 95% CI =1.036–2.453, P=0.034); and 4) surgery plus adjuvant therapy subgroup (HR =1.976, 95% CI =1.226–3.185, P=0.005). However, the OS was not significantly correlated with OPRT or TP protein expression. This study demonstrates that the TS level in tumor tissues may be a useful marker to predict the postoperative OS in NSCLC patients.
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Affiliation(s)
- Hong-Yun Zhao
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Guo-Wei Ma
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Ben-Yan Zou
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Mei Li
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Su-Xia Lin
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Li-Ping Zhao
- Department of Medical Oncology, Zhongshan Hospital of Sun Yat-Sen University, Zhongshan People's City Hospital, Zhongshan, People's Republic of China
| | - Ying Guo
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Yan Huang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Ying Tian
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Dan Xie
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Li Zhang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
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Sarac SB, Rasmussen CH, Afzal S, Thirstrup S, Jensen SA, Colding-Jørgensen M, Poulsen HE, Mosekilde E. Data-driven assessment of the association of polymorphisms in 5-Fluorouracil metabolism genes with outcome in adjuvant treatment of colorectal cancer. Basic Clin Pharmacol Toxicol 2012; 111:189-97. [PMID: 22448752 DOI: 10.1111/j.1742-7843.2012.00885.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Accepted: 03/19/2012] [Indexed: 11/28/2022]
Abstract
A major challenge in the assessment of medicines, treatment options, etc., is to establish a framework for the comparison of risks and benefits of many different types and magnitudes, a framework that at the same time allows a clear distinction between the roles played by the statistical analyses of data and by judgements based on personal experience and expertise. The purpose of this study was to demonstrate how clinical data can be weighted, scored and presented by the use of an eight-step data-driven benefit-risk assessment method, where two genetic profiles are compared. Our aim was to present a comprehensive approach that is simple to apply, allows direct comparison of different types of risks and benefits, quantifies the clinical relevance of data and is tailored for the comparison of different options. We analysed a cohort of 302 patients with colorectal cancer treated with 5-Fluorouracil (5-FU). Endpoints were cure rate, survival rate, time-to-death (TTD), time-to-relapse (TTR) and main adverse drug reactions. Multifactor dimensionality reduction (MDR) was used to identify genetic interaction profiles associated with outcome. We have been able to demonstrate that a specific MDR-derived combination (the MDR-1 group) of dihydropyrimidine dehydrogenase and thymidylate synthase polymorphisms is associated with increased and clinically significant difference for cure and survival rates, TTD and probably also for TTR, which are seen as the most important endpoints. An inferior profile was observed for severe myocardial ischaemia. A probably inferior profile was seen for severe arthralgia/myalgia and severe infections. A clear superior profile was seen for severe mucositis/stomatitis. The proposed approach offers comprehensive, data-driven assessment that can facilitate decision processes, for example, in a clinical setting. It employs descriptive statistical methods to highlight the clinically relevant differences between options.
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Afzal S, Gusella M, Jensen SA, Vainer B, Vogel U, Andersen JT, Brødbæk K, Petersen M, Jimenez-Solem E, Adleff V, Budai B, Hitre E, Láng I, Orosz E, Bertolaso L, Barile C, Padrini R, Kralovánszky J, Pasini F, Poulsen HE. The association of polymorphisms in 5-fluorouracil metabolism genes with outcome in adjuvant treatment of colorectal cancer. Pharmacogenomics 2012; 12:1257-67. [PMID: 21919605 DOI: 10.2217/pgs.11.83] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
AIM The purpose of this study was to investigate whether specific combinations of polymorphisms in 5-fluorouracil (5-FU) metabolism-related genes were associated with outcome in 5-FU-based adjuvant treatment of colorectal cancer. METHODS We analyzed two cohorts of 302 and 290 patients, respectively, one cohort for exploratory analyses and another cohort for validating the exploratory analyses. A total of ten polymorphisms in genes involved in 5-FU pharmacodynamics and pharmacokinetics were studied. End points were disease-free survival (DFS) and overall survival. Multifactor dimensionality reduction was used to identify genetic interaction profiles associated with outcome. RESULTS Low-expression alleles in thymidylate synthase (TYMS) were associated with decreased DFS and overall survival (DFS:hazard ratio [HR] exploration 2.65 [1.40-4.65]; p = 0.004, HR validation 1.69 [1.03-2.66]; p = 0.03). A specific multifactor dimensionality reduction derived combination of dihydropyrimidine dehydrogenase and TYMS polymorphisms was associated with increased DFS (HR exploration 0.69 [0.49-0.98]; p = 0.04, HR validation 0.66 [0.45-0.95]; p = 0.03). Specific combinations of functional polymorphisms in DPYD and TYMS were demonstrated to be associated with DFS and overall survival in patients receiving adjuvant 5-FU-based treatment. Specifically high TYMS expression alleles seem to be associated with decreased DFS.
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Fariña-Sarasqueta A, van Lijnschoten G, Rutten HJT, van den Brule AJC. Value of gene polymorphisms as markers of 5-FU therapy response in stage III colon carcinoma: a pilot study. Cancer Chemother Pharmacol 2010; 66:1167-71. [PMID: 20665215 DOI: 10.1007/s00280-010-1403-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2010] [Accepted: 07/11/2010] [Indexed: 01/31/2023]
Abstract
PURPOSE The role of pharmacogenetics in chemotherapy response in colon carcinoma is controversial. We studied the value of known SNPs in genes involved in 5-FU metabolism as biomarkers of chemotherapy response in patients with stage III colon carcinoma. METHODS DNA was isolated from normal colonic tissue of 60 patients with stage III colon carcinoma treated adjuvantly with 5-FU combined with leucovorin. The tested SNPs were validated SNPs on the OPRT, TYMS and DPYD genes and a synonymous SNP on the TYMP gene. Real-time PCR, sequencing and RFLP were used for genotyping. RESULTS None of the studied genotypes was associated with any of the tumor or patient characteristics. Moreover, none of the genotypes studied had effect on patient survival. CONCLUSION In conclusion, the tested SNPs are not biomarkers of chemotherapy response in our stage III colon cancer patients group.
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Affiliation(s)
- Arantza Fariña-Sarasqueta
- Department of Molecular Diagnostics, PAMM Laboratory of Pathology, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands
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Kawahara A, Akagi Y, Hattori S, Mizobe T, Shirouzu K, Ono M, Yanagawa T, Kuwano M, Kage M. Higher expression of deoxyuridine triphosphatase (dUTPase) may predict the metastasis potential of colorectal cancer. J Clin Pathol 2008; 62:364-9. [PMID: 19052026 PMCID: PMC2656677 DOI: 10.1136/jcp.2008.060004] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Aims: 5-Fluorouracil (5-FU) is one of the most widely used anticancer drugs; however, the activity of 5-FU is determined by the presence of several enzymes that limit its activation or degradation, and these include dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), thymidine kinase (TK), thymidine phosphorylase (TP) and deoxyuridine triphosphatase (dUTPase). The aim of this study was to compare the expression levels of these enzymes between the primary colorectal cancer of patients with and without distant metastases. Furthermore, there was a comparison of these expression levels between the primary tumour and the corresponding metastasis. Methods: Of 55 patients with colorectal cancer, 20 had no metastasis and the other 35 had distant metastasis. A strong expression was classified as positive, while weak to moderate or no expression was negative by immunohistochemistry. Results: Of the six 5-FU-related enzymes, the numbers of patients with expression of dUTPase (54% versus 15%; p = 0.005), TK (26% versus 0%; p = 0.019) and DPD (17% versus 45%; p = 0.033) were significantly different in those with primary tumours with metastasis compared with those with non-metastasis, respectively. The altered expression of OPRT (34.3%), TS (40.0%) and dUTPase (42.9%) was significantly greater from primary to metastasis among the 35 patients with metastasis. By contrast, the expression of OPRT, TS and dUTPase was decreased in 6, 5 and 7 patients, respectively, in metastatic sites. Conclusions: From this comparative study of the six 5-FU-related enzymes in colorectal cancer, the expression of dUTPase was most significantly different between primary tumours and their corresponding metastatic tumour. It is suggested that dUTPase may be a predictive biomarker for the metastatic potential of colorectal cancer.
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Affiliation(s)
- A Kawahara
- Department of Diagnostic Pathology, Kurume University Hospital, Japan.
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Sakamoto E, Nagase H, Kobunai T, Oie S, Oka T, Fukushima M, Oka T. Orotate phosphoribosyltransferase expression level in tumors is a potential determinant of the efficacy of 5-fluorouracil. Biochem Biophys Res Commun 2007; 363:216-22. [PMID: 17854773 DOI: 10.1016/j.bbrc.2007.08.164] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2007] [Accepted: 08/24/2007] [Indexed: 11/19/2022]
Abstract
Although the intratumoral expression levels of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are known to affect the antitumor activity of 5-fluorouracil (5-FU), the importance of orotate phosphoribosyltransferase (OPRT) has remained unclear. This study investigated the relationship between intratumoral OPRT expression and the antitumor activity of 5-FU using human NCI60 cell lines with similar levels of TS and DPD messenger RNAs, as well as 31 tumor xenografts. The OPRT mRNA level was positively correlated with the 5-FU efficacy in these cell lines. In vitro, the 50% growth-inhibitory concentrations of 5-FU were closely correlated with the OPRT mRNA levels in cancer cell lines with similar levels of TS mRNAs when combined with a DPD inhibitor. Moreover, downregulation of OPRT with small-interfering RNA decreased the sensitivities of the cultured tumor cells to 5-FU. These results suggest that the OPRT expression level in tumors is an additional determinant of the efficacy of 5-FU.
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Affiliation(s)
- Etsuko Sakamoto
- Personalized Medicine Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2 Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan.
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Sanada Y, Yoshida K, Ohara M, Tsutani Y. Expression of orotate phosphoribosyltransferase (OPRT) in hepatobiliary and pancreatic carcinoma. Pathol Oncol Res 2007; 13:105-13. [PMID: 17607371 DOI: 10.1007/bf02893485] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2006] [Accepted: 04/10/2007] [Indexed: 12/29/2022]
Abstract
The purpose of this study was to clarify the role of orotate phosphoribosyltransferase (OPRT) in the progression of hepatobiliary and pancreatic carcinomas. Representative sections from 8 surgically resected pancreatic carcinomas, 5 gallbladder carcinomas and 19 hepatocellular carcinomas (HCCs) were examined microscopically. Sites of pancreatic intraepithelial neoplasia (PanIN) were counted, and histologic subtypes of invasive ductal carcinoma of the pancreas (IDC) were determined. Gallbladder carcinomas and HCCs were examined histologically, and the subtypes and spread patterns were assessed. Expression of OPRT was examined immunohistochemically. A total of 75 PanINs were identified. Expression of OPRT increased as lesions progressed from early to high-grade PanINs (PanIN-1A and -1B versus PanIN-2 and -3, p=0.0004). Three (37.5%) of the 8 pancreatic IDCs were positive for OPRT. In the remaining 5 cases, OPRT was expressed only in the neoplastic ducts adjacent to PanIN-3s. In gallbladder carcinomas, mucosal neoplastic epithelium showed dense cytoplasmic expression in 4 of the 5 cases, but expression was absent in the deeply invasive lesions. Among HCCs, 15 of the 19 cases were negative for OPRT in the central area of the tumor, but 8 of the 19 cases expressed OPRT in vascularly invasive lesions. Our data suggest that OPRT is involved in early events of pancreatic and gallbladder carcinogenesis and invasion of HCC.
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Affiliation(s)
- Yuichi Sanada
- Department of Surgical Oncology, Research Institution for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Minami-ku, 734-8551, Japan.
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