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Tang H, Zhou H, Zhang L, Tang T, Li N. Molecular mechanism of MLCK1 inducing 5-Fu resistance in colorectal cancer cells through activation of TNFR2/NF-κB pathway. Discov Oncol 2024; 15:159. [PMID: 38735014 PMCID: PMC11089027 DOI: 10.1007/s12672-024-01019-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 05/07/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND AND AIMS Chemotherapy resistance in colorectal cancer have been faced with significant challenges in recent years. Particular interest is directed to tumor microenvironment function. Recent work has, identified a small molecule named Divertin that prevents myosin light chain kinase 1(MLCK1) recruitment to the perijunctional actomyosin ring(PAMR), restores barrier function after tumor necrosis factor(TNF)-induced barrier loss and prevents disease progression in experimental inflammatory bowel disease. Studies have shown that MLCK is a potential target for affecting intestinal barrier function, as well as for tumor therapy. However, the relative contributions of MLCK expression and chemotherapy resistance in colorectal cancers have not been defined. METHODS Statistical analysis of MYLK gene expression differences in colorectal cancer patients and normal population and prognosis results from The Cancer Genome Atlas(TCGA) data. Cell activity was detected by Cell counting Kit-8. Cell proliferation was detected by monoclonal plate. The apoptosis was detected by flow cytometry and western blot. Determine the role of MLCK1 in inducing 5-Fluorouracil(5-Fu) resistance in colorectal cancer cells was detected by overexpression of MLCK1 and knock-down expression of MLCK1. RESULTS MLCK1 is expressed at different levels in different colorectal cancer cells, high MLCK1 expressing cell lines are less sensitive to 5-Fu, and low MLCK1 expressing cell lines are more sensitive to 5-Fu. MLCK1 high expression enhances resistance to 5-Fu in colorectal cancer cells and the sensitivity to 5-Fu was increased after knocking down the expression of MLCK1, that might be closely correlated to TNFR2/NF-κB pathway. CONCLUSIONS MLCK1 high expression can enhance resistance to 5-Fu in colorectal cancer cells and the sensitivity to 5-Fu was increased after knocking down the expression of MLCK1, that might be closely correlated to TNFR2/NF-κB pathway, which will provide a new method for the treatment of colorectal cancer patients who are resistant to 5-Fu chemotherapy.
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Affiliation(s)
- Huifen Tang
- Department of Hematology, The Affiliated Hospital, Hangzhou Normal University, 126# Wenzhou Road, Hangzhou, 310015, Zhejiang, People's Republic of China
| | - Hui Zhou
- Department of Hematology, The Affiliated Hospital, Hangzhou Normal University, 126# Wenzhou Road, Hangzhou, 310015, Zhejiang, People's Republic of China
| | - Liang Zhang
- Department of Hematology, The Affiliated Hospital, Hangzhou Normal University, 126# Wenzhou Road, Hangzhou, 310015, Zhejiang, People's Republic of China
| | - Tingting Tang
- Department of Hematology, The Affiliated Hospital, Hangzhou Normal University, 126# Wenzhou Road, Hangzhou, 310015, Zhejiang, People's Republic of China
| | - Ning Li
- Department of Hematology, The Affiliated Hospital, Hangzhou Normal University, 126# Wenzhou Road, Hangzhou, 310015, Zhejiang, People's Republic of China.
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Kasprzak A. Prognostic Biomarkers of Cell Proliferation in Colorectal Cancer (CRC): From Immunohistochemistry to Molecular Biology Techniques. Cancers (Basel) 2023; 15:4570. [PMID: 37760539 PMCID: PMC10526446 DOI: 10.3390/cancers15184570] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/04/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and severe malignancies worldwide. Recent advances in diagnostic methods allow for more accurate identification and detection of several molecular biomarkers associated with this cancer. Nonetheless, non-invasive and effective prognostic and predictive testing in CRC patients remains challenging. Classical prognostic genetic markers comprise mutations in several genes (e.g., APC, KRAS/BRAF, TGF-β, and TP53). Furthermore, CIN and MSI serve as chromosomal markers, while epigenetic markers include CIMP and many other candidates such as SERP, p14, p16, LINE-1, and RASSF1A. The number of proliferation-related long non-coding RNAs (e.g., SNHG1, SNHG6, MALAT-1, CRNDE) and microRNAs (e.g., miR-20a, miR-21, miR-143, miR-145, miR-181a/b) that could serve as potential CRC markers has also steadily increased in recent years. Among the immunohistochemical (IHC) proliferative markers, the prognostic value regarding the patients' overall survival (OS) or disease-free survival (DFS) has been confirmed for thymidylate synthase (TS), cyclin B1, cyclin D1, proliferating cell nuclear antigen (PCNA), and Ki-67. In most cases, the overexpression of these markers in tissues was related to worse OS and DFS. However, slowly proliferating cells should also be considered in CRC therapy (especially radiotherapy) as they could represent a reservoir from which cells are recruited to replenish the rapidly proliferating population in response to cell-damaging factors. Considering the above, the aim of this article is to review the most common proliferative markers assessed using various methods including IHC and selected molecular biology techniques (e.g., qRT-PCR, in situ hybridization, RNA/DNA sequencing, next-generation sequencing) as prognostic and predictive markers in CRC.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Swiecicki Street 6, 60-781 Poznan, Poland
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3
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Jain A, Bhardwaj V. Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities. World J Gastroenterol 2021; 27:6527-6550. [PMID: 34754151 PMCID: PMC8554400 DOI: 10.3748/wjg.v27.i39.6527] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/22/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. Although chemotherapeutic regimens such as gemcitabine+ nab-paclitaxel and FOLFIRINOX (FOLinic acid, 5-Fluroruracil, IRINotecan, and Oxaliplatin) significantly improve patient survival, the prevalence of therapy resistance remains a major roadblock in the success of these agents. This review discusses the molecular mechanisms that play a crucial role in PDAC therapy resistance and how a better understanding of these mechanisms has shaped clinical trials for pancreatic cancer chemotherapy. Specifically, we have discussed the metabolic alterations and DNA repair mechanisms observed in PDAC and current approaches in targeting these mechanisms. Our discussion also includes the lessons learned following the failure of immunotherapy in PDAC and current approaches underway to improve tumor's immunological response.
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Affiliation(s)
- Aditi Jain
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Vikas Bhardwaj
- Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, United States
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Lin LW, Lai PS, Chen YY, Chen CY. Expression of astrocyte-elevated gene-1 indicates prognostic value of fluoropyrimidine-based adjuvant chemotherapy in resectable stage III colorectal cancer. Pathol Int 2021; 71:752-764. [PMID: 34528330 DOI: 10.1111/pin.13160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 08/12/2021] [Indexed: 11/30/2022]
Abstract
It is unclear which prognostic factor such as pathological features and gene mutation are majorly relevant for stage III disease and whether they aid in determining patients who will be benefit from postoperative adjuvant chemotherapy. The expression of astrocyte-elevated gene-1 (AEG-1), thymidylate synthase (TS), excision repair cross-complementation group 1 (ERCC1), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) was examined to investigate their role in adjuvant chemotherapy for patients with resectable stage III colorectal cancer (CRC). A significant positive correlation was observed between AEG-1, TS, ERCC1, EGFR, and VEGF gene expression levels in CRC cell lines, and low AEG-1 and TS expression were highly sensitive to 5-fluorouracil treatment. Our results showed that AEG-1 expression was high in T4 and caused CRC recurrence or metastasis. Patients with T4, high AEG-1, TS and VEGF expression had a significantly short disease-free survival and overall survival. In multivariate Cox regression analysis, high AEG-1 expression could be an independent prognostic factor indicating poor survival in patients with resectable stage III CRC treated with adjuvant chemotherapy. In conclusion, AEG-1 expression and tumor grade are potential prognostic factors for recurrence and survival in patients with stage III CRC receiving adjuvant fluoropyrimidine-based chemotherapy.
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Affiliation(s)
- Long-Wei Lin
- Department of Pathology, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan
| | - Peng-Sheng Lai
- Department of Surgery, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan
| | - Ying-Yin Chen
- Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan
| | - Chung-Yu Chen
- Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan.,Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
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Merloni F, Ranallo N, Scortichini L, Giampieri R, Berardi R. Tailored therapy in patients treated with fluoropyrimidines: focus on the role of dihydropyrimidine dehydrogenase. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2019; 2:787-802. [PMID: 35582578 PMCID: PMC8992529 DOI: 10.20517/cdr.2018.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 03/01/2019] [Accepted: 06/04/2019] [Indexed: 01/19/2023]
Abstract
Fluoropyrimidines are widely used in the treatment of solid tumors, mainly gastrointestinal, head and neck and breast cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for catabolism of 5-FU and it is encoded by DPYD gene. To date, many known polymorphisms cause DPD deficiency and subsequent increase of 5-FU toxicity. In addition, reduced inactivation of 5-FU could lead to increased 5-FU intracellular concentration and augmented efficacy of this drugs. Therefore DPD expression, particularly intratumoral, has been investigated as predictive and prognostic marker in 5-FU treated patients. There also seems to be a tendency to support the correlation between DPD expression and response/survival in patients treated with fluoropyrimidine even if definitive conclusions cannot be drawn considering that some studies are conflicting. Therefore, the debate on intratumoral DPD expression as a potential predictor and prognostic marker in patients treated with fluoropyrimidines is still open. Four DPD-polymorphisms are the most relevant for their frequency in population and clinical relevance. Many studies demonstrate that treating a carrier of one of these polymorphisms with a full dose of fluoropyrimidine can expose patient to a severe, even life-threatening, toxicity. Severe toxicity is reduced if this kind of patients received a dose-adjustment after being genotyped. CPIC (Clinical Pharmacogenetics Implementation Consortium) is an International Consortium creating guidelines for facilitating use of pharmacogenetic tests for patient care and helps clinicians ensuring a safer drug delivery to the patient. Using predictive DPD deficiency tests in patients receiving 5FU-based chemotherapy, in particular for colorectal cancer, has proven to be a cost-effective strategy.
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Affiliation(s)
- Filippo Merloni
- Scuola di Specializzazione in Oncologia, Università Politecnica delle Marche, Ancona 60121, Italy
| | - Nicoletta Ranallo
- Scuola di Specializzazione in Oncologia, Università Politecnica delle Marche, Ancona 60121, Italy
| | - Laura Scortichini
- Scuola di Specializzazione in Oncologia, Università Politecnica delle Marche, Ancona 60121, Italy
| | - Riccardo Giampieri
- Clinica Oncologica, Università Politecnica delle Marche, AOU Ospedali Riuniti, Ancona 60126, Italy
| | - Rossana Berardi
- Clinica Oncologica, Università Politecnica delle Marche, AOU Ospedali Riuniti, Ancona 60126, Italy
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Ntavatzikos A, Spathis A, Patapis P, Machairas N, Vourli G, Peros G, Papadopoulos I, Panayiotides I, Koumarianou A. TYMS/KRAS/BRAF molecular profiling predicts survival following adjuvant chemotherapy in colorectal cancer. World J Gastrointest Oncol 2019; 11:551-566. [PMID: 31367274 PMCID: PMC6657223 DOI: 10.4251/wjgo.v11.i7.551] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 04/30/2019] [Accepted: 06/12/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Patients with stage II-III colorectal cancer (CRC) treated with adjuvant chemotherapy, gain a 25% survival benefit. In the context of personalized medicine, there is a need to identify patients with CRC who may benefit from adjuvant chemotherapy. Molecular profiling could guide treatment decisions in these patients. Thymidylate synthase (TYMS) gene polymorphisms, KRAS and BRAF could be included in the molecular profile under consideration. AIM To investigate the association of TYMS gene polymorphisms, KRAS and BRAF mutations with survival of CRC patients treated with chemotherapy. METHODS A retrospective study studied formalin-fixed paraffin-embedded tissues (FFPEs) of consecutive patients treated with adjuvant chemotherapy during January/2005-January/2007. FFPEs were analysed with PCR for the detection of TYMS polymorphisms, mutated KRAS (mKRAS) and BRAF (mBRAF). Patients were classified into three groups (high, medium and low risk) according to 5'UTR TYMS polymorphisms Similarly, based on 3'UTR polymorphism ins/loss of heterozygosity (LOH) patients were allocated into two groups (high and low risk of relapse, respectively). Cox regression models examined the associated 5-year survival outcomes. RESULTS One hundred and thirty patients with early stage CRC (stage I-II: 55 patients; stage III 75 patients; colon: 70 patients; rectal: 60 patients) were treated with surgery and chemotherapy. The 5-year disease free survival and overall survival rate was 61.6% and 73.9% respectively. 5'UTR polymorphisms of intermediate TYMS polymorphisms (2RG/3RG, 2RG/LOH, 3RC/LOH) were associated with lower risk for relapse [hazard ratio (HR) 0.320, P = 0.02 and HR 0.343, P = 0.013 respectively] and death (HR 0.368, P = 0.031 and HR 0.394, P = 0.029 respectively). The 3'UTR polymorphism ins/LOH was independently associated with increased risk for disease recurrence (P = 0.001) and death (P = 0.005). mBRAF (3.8% of patients) was associated with increased risk of death (HR 4.500, P = 0.022) whereas mKRAS (39% of patients) not. CONCLUSION Prospective validating studies are required to confirm whether 2RG/3RG, 2RG/LOH, 3RC/LOH, absence of ins/LOH and wild type BRAF may indicate patients at lower risk of relapse following adjuvant chemotherapy.
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Affiliation(s)
- Anastasios Ntavatzikos
- Hematology-Oncology Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Athens 12462, Greece
| | - Aris Spathis
- Department of Cytopathology, National and Kapodistrian University of Athens, Medical School, “ATTIKON” University Hospital, Athens 12462, Greece
| | - Paul Patapis
- 3rd Department of Surgery, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Athens 12462, Greece
| | - Nikolaos Machairas
- 3rd Department of Surgery, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Athens 12462, Greece
| | - Georgia Vourli
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - George Peros
- Department of Surgery, Medical School, National and Kapodistrian University of Athens, Evgenideio Therapeutirio S.A., “I AGIA TRIAS”, Athens 11528, Greece
| | - Iordanis Papadopoulos
- Department of Surgery, Medical School, National and Kapodistrian University of Athens, Evgenideio Therapeutirio S.A., “I AGIA TRIAS”, Athens 11528, Greece
| | - Ioannis Panayiotides
- 2nd Department of Pathology, University of Athens, Medical School, “ATTIKON” University Hospital, Athens 12462, Greece
| | - Anna Koumarianou
- Hematology-Oncology Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Athens 12462, Greece
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Kugimiya N, Harada E, Suehiro Y, Suga A, Takemoto Y, Hamano K. Determination of thymidine phosphorylase expression level facilitates recurrence risk stratification in stage II/III colorectal cancer following adjuvant chemotherapy with oral fluoropyrimidines. Oncol Lett 2019; 17:5267-5274. [PMID: 31186743 DOI: 10.3892/ol.2019.10181] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 03/18/2019] [Indexed: 01/13/2023] Open
Abstract
The present study aimed to prospectively clarify the prognostic effect of the expression of several genes that are known to modulate 5-fluorouracil effects in 63 patients who underwent curative resection for stage II/III colorectal cancer following adjuvant chemotherapy with oral fluoropyrimidines between 2008 and 2012. Thymidine phosphorylase (TP) expression in primary tumours was significantly lower in the recurrence group compared with the no-recurrence group (P=0.03), whereas, expression levels of genes that encoded thymidylate synthase, dihydropyrimidine dehydrogenase, folylpolyglutamate synthase, γ-glutamyl hydrolase and dihydrofolate reductase were not statistically different in tumours from the recurrence and no-recurrence groups. In the multivariate analysis using stepwise Cox proportional hazards regression, the following factors were significantly associated with shorter relapse-free survival following adjuvant chemotherapy with oral fluoropyrimidines: Venous invasion [present; hazard ratio (HR)=6.51; 95% confidence interval (CI): 1.55-27.4; P=0.01), Tumour-Node-Metastasis stage (3b; HR=6.18; 95% CI: 1.36-28.2; P=0.02) and TP expression (low; HR=9.61; 95% CI: 1.81-51.0; P=0.04). Patients with two or more risk characteristics had significantly shorter 5-year relapse-free survival compared with patients with one or no risk characteristics (55.8 vs. 91.8%; log-rank P=0.0006). We concluded that low TP expression is an independent predictive factor for poor prognosis in colorectal cancer. Therefore, determining TP expression may help to improve recurrence risk stratification in patients with stage II/III colorectal cancer following adjuvant chemotherapy with oral fluoropyrimidines.
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Affiliation(s)
- Naruji Kugimiya
- Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Eijiro Harada
- Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Yuki Suehiro
- Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Atsushi Suga
- Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Yoshihiro Takemoto
- Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Kimikazu Hamano
- Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
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Sun X, Guo S. The Prognostic and Predictive Value of Dihydropyrimidine Dehydrogenase-Related Indicators in Clinical Outcomes of Chemotherapy in Colorectal Cancer Patients: a Systematic Review and Meta-Analysis. Pathol Oncol Res 2018; 26:121-131. [PMID: 30519982 DOI: 10.1007/s12253-018-00563-3] [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] [Received: 06/19/2018] [Accepted: 11/26/2018] [Indexed: 10/27/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. Predictive biomarkers are needed to predict patients' outcomes and to select a chemotherapy regimen. We assessed whether dihydropyrimidine dehydrogenase (DPD)-related indicators can predict CRC patients' outcomes. We searched the studies in PubMed, EmBase, and the Cochrane Library up to March 4, 2018. We mainly analyzed different CRC patients' outcomes according to specific DPD-related indicators. Twenty-five articles were included in the meta-analysis. The results showed that for disease-free survival (DFS), low DPD expression was significantly superior to high expression (I2 = 72%; HR: 1.59; 95%CI: 1.21-2.09; p = 0.001). However, this result had a potential publication bias (Begg's test: p = 0.007; Egger's test: p = 0.004). Among patients treated with chemotherapy, a high thymidylate phosphorylase (TP)/DPD ratio was advantageous for DFS (I2 = 63.7%; HR: 0.65; 95%CI: 0.46-0.92; p = 0.015), and this result did not have a publication bias. For overall survival (OS), low DPD expression was superior to high expression (I2 = 74.4%; HR: 2.11; 95%CI: 1.48-3.00; p < 0.001), although this result had a publication bias (Egger's test: p = 0.003; Begg's test: p = 0.010). There was no difference in OS according to the TP/DPD ratio (I2 = 0%; HR: 0.92; 95%CI: 0.75-1.13; p = 0.420). DFS and OS were better in CRC patients with low DPD expression than in those with high DPD expression. However, because of publication bias, more DPD indicator-related studies, especially with negative results, are still needed. Patients with a high TP/DPD ratio have better DFS but not OS.
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Affiliation(s)
- Xiaojun Sun
- Inpatients department, Nanjing Qi-xia Xi-gang community health service centers, Nanjing, 210033, Jiangsu, China
| | - Shilei Guo
- R&D department, Nanjing Regenerative Medicine Engineering and Technology Research Center, No.108, Ganjiabian East, Qixia District, Nanjing, 210046, Jiangsu, China.
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Minegaki T, Suzuki A, Mori M, Tsuji S, Yamamoto S, Watanabe A, Tsuzuki T, Tsunoda T, Yamamoto A, Tsujimoto M, Nishiguchi K. Histone deacetylase inhibitors sensitize 5-fluorouracil-resistant MDA-MB-468 breast cancer cells to 5-fluorouracil. Oncol Lett 2018; 16:6202-6208. [PMID: 30333885 DOI: 10.3892/ol.2018.9388] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 08/23/2018] [Indexed: 11/06/2022] Open
Abstract
Resistance to 5-fluorouracil (5-FU) is a serious problem in cancer therapy and overcoming it is required in order to improve the efficacy of cancer chemotherapy. Histone deacetylase (HDAC) inhibitors are used in cancer treatments and, recently, it has been reported that HDAC inhibitors can overcome resistance to various anti-cancer drugs in vitro. In the present study, a 5-FU-resistant breast cancer cell line was established, and the effects of HDAC inhibitors in these cells were examined. The 5-FU-resistant cell line MDA-MB-468 (MDA468/FU) was established by continuous exposure of the parental cells to 5-FU. This subline was characterized by high resistance to 5-FU, higher mRNA expression levels of thymidylate synthetase and dihydropyrimidine dehydrogenase (DPD), and lower mRNA expression levels of uridine monophosphate synthetase (UMPS) than the parental cells. Gimeracil, a DPD inhibitor, did not affect the sensitivity of MDA468/FU cells to 5-FU. Oteracil, a UMPS inhibitor, decreased the cytotoxicity of 5-FU in MDA468 cells, but not in MDA468/FU cells. The HDAC inhibitors, valproic acid and suberanilohydroxamic acid sensitized the two cell lines to 5-FU in a concentration-dependent manner. In conclusion, the results of the present study revealed that HDAC inhibitors increase the sensitivity to 5-FU in 5-FU-sensitive and -resistant cells.
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Affiliation(s)
- Tetsuya Minegaki
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Ai Suzuki
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Misato Mori
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Shiori Tsuji
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Satoshi Yamamoto
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Airi Watanabe
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Tomoyo Tsuzuki
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Takaki Tsunoda
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Asuka Yamamoto
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Masayuki Tsujimoto
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Kohshi Nishiguchi
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
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10
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Gajjar KK, Vora HH, Kobawala TP, Trivedi TI, Ghosh NR. Deciphering the potential value of 5-fluorouracil metabolic enzymes in predicting prognosis and treatment response of colorectal cancer patients. Int J Biol Markers 2018; 33:180-188. [DOI: 10.1177/1724600817748539] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Introduction: 5-flourouracil (5-FU) is one of the standard chemotherapeutic drugs used today in the treatment of colorectal cancer patients. Disruption of 5-FU metabolic pathway may contribute to altered effectiveness towards 5-FU-based therapy. Hence, the study of 5-FU metabolizing enzymes might have the potential efficacy to predict survival and response to treatment in colorectal cancer patients. Materials and methods: Immunohistochemical localization of 5-FU metabolic enzymes (TS, MTHFR, DPYD, and TP) was evaluated in 143 untreated patients with colorectal cancer; their prognostic and predictive values were also evaluated. Results: Immuno-positivity for TS, MTHFR, DPYD, and TP was observed in 77%, 75%, 88%, and 96% of colorectal cancer patients, respectively. Univariate survival analysis in total patients showed that low DPYD expression significantly predicted adverse overall survival ( P=0.042). Moreover, subgroup of colon cancer patients with low TS expression was associated with unfavorable prognosis. TP expression also emerged as a prognosticator in the subgroup of early and advanced stage patients. Additionally, when effect of co-expression of 5-FU metabolic enzymes was evaluated in total patients, low coexpression of all four proteins was predictive of poor overall survival than for individuals expressing high coexpression of these proteins ( P=0.045). In contrast, none of the 5-FU metabolic enzymes—either singly or on coexpression—emerged as a useful biomarker of potential therapeutic value when evaluated in the subgroup of patients treated with 5-FU alone or 5-FU plus oxaliplatin. Conclusion: The above findings suggest that coexpression of 5-FU metabolic enzymes possess significant prognostic value and could be useful biomarkers in colorectal cancer patients.
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Affiliation(s)
- Kinjal K. Gajjar
- Tumor Biology Lab 2, Cancer Biology Department, The Gujarat Cancer & Research Institute, NCH Compound, Asarwa, Ahmedabad, Gujarat- India
| | - Hemangini H. Vora
- Immuno-haematology Lab 1, Cancer Biology Department, The Gujarat Cancer & Research Institute, NCH Compound, Asarwa, Ahmedabad, Gujarat- India
| | - Toral P. Kobawala
- Tumor Biology Lab 2, Cancer Biology Department, The Gujarat Cancer & Research Institute, NCH Compound, Asarwa, Ahmedabad, Gujarat- India
| | - Trupti I. Trivedi
- Clinical Carcinogenesis Lab 3, Cancer Biology Department, The Gujarat Cancer & Research Institute, NCH Compound, Asarwa, Ahmedabad, Gujarat- India
| | - Nandita R. Ghosh
- Tumor Biology Lab 2, Cancer Biology Department, The Gujarat Cancer & Research Institute, NCH Compound, Asarwa, Ahmedabad, Gujarat- India
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Prediction of novel target genes and pathways involved in irinotecan-resistant colorectal cancer. PLoS One 2017; 12:e0180616. [PMID: 28749961 PMCID: PMC5531462 DOI: 10.1371/journal.pone.0180616] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 06/14/2017] [Indexed: 01/02/2023] Open
Abstract
Background Acquired drug resistance to the chemotherapeutic drug irinotecan (the active metabolite of which is SN-38) is one of the significant obstacles in the treatment of advanced colorectal cancer (CRC). The molecular mechanism or targets mediating irinotecan resistance are still unclear. It is urgent to find the irinotecan response biomarkers to improve CRC patients’ therapy. Methods Genetic Omnibus Database GSE42387 which contained the gene expression profiles of parental and irinotecan-resistant HCT-116 cell lines was used. Differentially expressed genes (DEGs) between parental and irinotecan-resistant cells, protein-protein interactions (PPIs), gene ontologies (GOs) and pathway analysis were performed to identify the overall biological changes. The most common DEGs in the PPIs, GOs and pathways were identified and were validated clinically by their ability to predict overall survival and disease free survival. The gene-gene expression correlation and gene-resistance correlation was also evaluated in CRC patients using The Cancer Genomic Atlas data (TCGA). Results The 135 DEGs were identified of which 36 were upregulated and 99 were down regulated. After mapping the PPI networks, the GOs and the pathways, nine genes (GNAS, PRKACB, MECOM, PLA2G4C, BMP6, BDNF, DLG4, FGF2 and FGF9) were found to be commonly enriched. Signal transduction was the most significant GO and MAPK pathway was the most significant pathway. The five genes (FGF2, FGF9, PRKACB, MECOM and PLA2G4C) in the MAPK pathway were all contained in the signal transduction and the levels of those genes were upregulated. The FGF2, FGF9 and MECOM expression were highly associated with CRC patients’ survival rate but not PRKACB and PLA2G4C. In addition, FGF9 was also associated with irinotecan resistance and poor disease free survival. FGF2, FGF9 and PRKACB were positively correlated with each other while MECOM correlated positively with FGF9 and PLA2G4C, and correlated negatively with FGF2 and PRKACB after doing gene-gene expression correlation. Conclusion Targeting the MAPK signal transduction pathway through the targeting of the FGF2, FGF9, MECOM, PLA2G4C and PRKACB might increase tumor responsiveness to irinotecan treatment.
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12
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Bera H, Chigurupati S. Recent discovery of non-nucleobase thymidine phosphorylase inhibitors targeting cancer. Eur J Med Chem 2016; 124:992-1003. [PMID: 27783978 DOI: 10.1016/j.ejmech.2016.10.032] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2016] [Revised: 10/14/2016] [Accepted: 10/15/2016] [Indexed: 01/19/2023]
Abstract
Thymidine phosphorylase (TP, EC 2.4.2.4), an enzyme involved in pyrimidine salvage pathway, is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and gliostatin. It is extremely upregulated in a variety of solid tumours. The TP amplification is associated with concomitant overexpression of many angiogenic factors such as matrix metalloproteases (MMPs), interleukins (ILs), vascular endothelial growth factor (VEGF) etc., resulting in promotion of angiogenesis and cancer metastasis. In addition, overshooting TP level protects tumour cells from apoptosis and helps cell survival. Thus, TP is identified as a prime target for developing novel anticancer therapies. Pioneering research activities investigated a large number of TP inhibitors, most of which are pyrimidine or purine analogues. Recently, an array of structurally diverse non-nucleobase derivatives was designed, synthesized and established as promising TP inhibitors. This review, following an outline on the TP structure and functions, gives an overview of the recent advancement of various non-nucleobase TP inhibitors as novel anti-cancer agents.
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Affiliation(s)
- Hriday Bera
- Faculty of Pharmacy, AIMST University, Semeling, Kedah, 08100, Malaysia.
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13
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Gmeiner WH, Debinski W, Milligan C, Caudell D, Pardee TS. The applications of the novel polymeric fluoropyrimidine F10 in cancer treatment: current evidence. Future Oncol 2016; 12:2009-20. [PMID: 27279153 DOI: 10.2217/fon-2016-0091] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
F10 is a novel polymeric fluoropyrimidine drug candidate with strong anticancer activity in multiple preclinical models. F10 has strong potential for impacting cancer treatment because it displays high cytotoxicity toward proliferating malignant cells with minimal systemic toxicities thus providing an improved therapeutic window relative to traditional fluoropyrimidine drugs, such as 5-fluorouracil. F10 has a unique mechanism that involves dual targeting of thymidylate synthase and Top1. In this review, the authors provide an overview of the studies that revealed the novel aspects of F10's cytotoxic mechanism and summarize results obtained in preclinical models of acute myeloid leukemia, acute lymphocytic leukemia, glioblastoma and prostate cancer that demonstrate the strong potential of F10 to improve treatment outcomes.
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Affiliation(s)
- William H Gmeiner
- Wake Forest Baptist Medical Center Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.,Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Waldemar Debinski
- Wake Forest Baptist Medical Center Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.,Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.,Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Carol Milligan
- Wake Forest Baptist Medical Center Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.,Department of Neurobiology & Anatomy, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - David Caudell
- Wake Forest Baptist Medical Center Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.,Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Timothy S Pardee
- Wake Forest Baptist Medical Center Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.,Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.,Department of Hematology/Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
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14
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Jin G, Yang Y, Liu H, Liu K, Zhao J, Chen X, Zhang X, Zhang Y, Lu J, Dong Z. Genome-wide analysis of the effect of esophageal squamous cell carcinoma on human umbilical vein endothelial cells. Oncol Rep 2016; 36:155-64. [PMID: 27222202 DOI: 10.3892/or.2016.4816] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 02/05/2016] [Indexed: 11/06/2022] Open
Abstract
A large volume of data indicates that controlling tumor-associated angiogenesis is a promising therapy against cancer. However, angiogenesis is a complex process, little is known about the differential gene expression in the process of normal endothelial cell differentiation toward tumor vascular endothelial cells induced by tumor microenvironment. The aim of this study is to investigate the effect of tumor microenvironment simulated by the supernatant of esophageal squamous cancer cells (KYSE70) on normal endothelial cells (HUVECs) at the whole genome level. The gene expression profile was studied through gene ontology and signal pathway analysis. Compared with the normal HUVECs, a total of 3769 differentially expressed genes in induced HUVECs were detected, including 1609 upregulated genes and 2160 downregulated genes. Moreover, the microarray data analysis showed that 11 significant biological processes and 10 significant signaling pathways changed most, which are associated with angiogenesis and cell differentiation. According to the different expression levels in the microarrays and their functions, four differentially expressed genes involved in tumor angiogenesis and cell differentiation (IL6, VEGFA, S1PR1, TYMP) were selected and analyzed by qRT-PCR. The qRT-PCR results were consistent with the microarray data. Furthermore, we simulated the tumor microenvironment by human esophageal carcinoma tissue homogenate to investigate its effect on HUVECs, the qRT-PCR results indicated that the above genes were highly expressed in HUVECs after induction by esophageal carcinoma tissue homogenate. In conclusion, tumor microenvironment impact on normal endothelial cells differentiated toward tumor vascular endothelial cells, and the selected genes, which are associated with tumor angiogenesis, would be anti-angiogenesis targets against esophageal carcinoma.
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Affiliation(s)
- Guoguo Jin
- Department of Pathophysiology, Basic Medical College, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Yi Yang
- Department of Pathophysiology, Basic Medical College, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Hangfan Liu
- Department of Pathophysiology, Basic Medical College, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Kangdong Liu
- Department of Pathophysiology, Basic Medical College, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Jimin Zhao
- Department of Pathophysiology, Basic Medical College, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Xinhuan Chen
- Department of Pathophysiology, Basic Medical College, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Xiaoyan Zhang
- Department of Pathophysiology, Basic Medical College, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Yanyan Zhang
- Department of Pathophysiology, Basic Medical College, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Jing Lu
- Department of Pathophysiology, Basic Medical College, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Ziming Dong
- Department of Pathophysiology, Basic Medical College, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
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Buhl IK, Gerster S, Delorenzi M, Jensen T, Jensen PB, Bosman F, Tejpar S, Roth A, Brunner N, Hansen A, Knudsen S. Cell Line Derived 5-FU and Irinotecan Drug-Sensitivity Profiles Evaluated in Adjuvant Colon Cancer Trial Data. PLoS One 2016; 11:e0155123. [PMID: 27171152 PMCID: PMC4865183 DOI: 10.1371/journal.pone.0155123] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 04/25/2016] [Indexed: 02/06/2023] Open
Abstract
PURPOSE This study evaluates whether gene signatures for chemosensitivity for irinotecan and 5-fluorouracil (5-FU) derived from in vitro grown cancer cell lines can predict clinical sensitivity to these drugs. METHODS To test if an irinotecan signature and a SN-38 signature could identify patients who benefitted from the addition of irinotecan to 5-FU, we used gene expression profiles based on cell lines and clinical tumor material. These profiles were applied to expression data obtained from pretreatment formalin fixed paraffin embedded (FFPE) tumor tissue from 636 stage III colon cancer patients enrolled in the PETACC-3 prospective randomized clinical trial. A 5-FU profile developed similarly was assessed by comparing the PETACC-3 cohort with a cohort of 359 stage II colon cancer patients who underwent surgery but received no adjuvant therapy. RESULTS There was no statistically significant association between the irinotecan or SN-38 profiles and benefit from irinotecan. The 5-FU sensitivity profile showed a statistically significant association with relapse free survival (RFS) (hazard ratio (HR) = 0.54 (0.41-0.71), p<1e-05) and overall survival (HR = 0.47 (0.34-0.63), p<1e-06) in the PETACC-3 subpopulation. The effect of the 5-FU profile remained significant in a multivariable Cox Proportional Hazards model, adjusting for several relevant clinicopathological parameters. No statistically significant effect of the 5-FU profile was observed in the untreated cohort of 359 patients (relapse free survival, p = 0.671). CONCLUSION The irinotecan predictor had no predictive value. The 5-FU predictor was prognostic in stage III patients in PETACC-3 but not in stage II patients with no adjuvant therapy. This suggests a potential predictive ability of the 5-FU sensitivity profile to identify colon cancer patients who may benefit from 5-FU, however, any biomarker predicting benefit for adjuvant 5-FU must be rigorously evaluated in independent cohorts. Given differences between the two study cohorts, the present results should be further validated.
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Affiliation(s)
- Ida Kappel Buhl
- Section for Molecular Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Medical Prognosis Institute, Hoersholm, Denmark
| | - Sarah Gerster
- Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Mauro Delorenzi
- Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
- Ludwig Center for Cancer Research and Oncology Department, University of Lausanne, Lausanne, Switzerland
| | | | | | - Fred Bosman
- University of Lausanne, University Institute of Pathology, Lausanne, Switzerland
| | - Sabine Tejpar
- University Hospital Gasthuisberg, Digestive Oncology Unit, Leuven, Belgium
| | - Arnaud Roth
- University Hospital of Geneva, Oncosurgery Unit, Geneva, Switzerland
| | - Nils Brunner
- Section for Molecular Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Johnson B, Vanderwalde A, Javadi N, Feldman R, Reddy SB. Molecular profiling of a case of advanced pancreatic cancer identifies an active and tolerable combination of targeted therapy with backbone chemotherapy. J Gastrointest Oncol 2016; 7:E6-E12. [PMID: 27034805 PMCID: PMC4783749 DOI: 10.3978/j.issn.2078-6891.2015.091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 08/01/2015] [Indexed: 12/11/2022] Open
Abstract
Typical survival with common 1(st)-line regimens for pancreatic cancer range from 6-11 months. We report a case of a patient with stage IVB pancreatic adenocarcinoma treated with gemcitabine and erlotinib who stopped therapy after 3 months without achieving a response due to intolerance. To decide upon additional treatment options, molecular analysis was performed on liver metastasis which revealed KRAS, FBXW7, APC, and ATM mutations, with thymidylate synthase (TS) negativity and PD-1 positivity. Based on this profile of TS negativity and ATM mutation, a combination strategy was devised consisting of capecitabine, oxaliplatin, bevacizumab and vorinostat. The patient had a near complete response to therapy with this regimen. In refractory metastatic pancreatic cancer, responses of this magnitude are rarely seen. To our knowledge, this represents the first demonstrated activity of this combination in the metastatic setting which could prompt further investigation of its use in large scale clinical trials.
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17
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A prognostic analysis of 895 cases of stage III colon cancer in different colon subsites. Int J Colorectal Dis 2015; 30:1173-83. [PMID: 26054387 DOI: 10.1007/s00384-015-2273-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/31/2015] [Indexed: 02/04/2023]
Abstract
PURPOSE Stage III colon cancer is currently treated as an entity with a unified therapeutic principle. The aim of the retrospective study is to explore the clinicopathological characteristics and outcomes of site-specific stage III colon cancers and the influences of tumor location on prognosis. METHODS Eight hundred ninety-five patients with stage III colon cancer treated with radical operation and subsequent adjuvant chemotherapy (5-fluorouracil/oxaliplatin) were divided into seven groups according to colon segment (cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, and sigmoid colon). Expression of excision repair cross-complementing group 1 (ERCC1) and thymidylate synthase (TS) was examined by immunohistochemistry. We assessed if differences exist in patient characteristics and clinic outcomes between the seven groups. RESULTS There were significant differences in tumor differentiation (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) stage (P < 0.001), metachronous liver metastasis (P < 0.001), metachronous lung metastasis (P < 0.001), and ERCCI expression (P < 0.001) between the seven groups. Both 5-year recurrence-free survival (RFS) and 5-year overall survival (OS) exhibited significant differences (both P < 0.001) with survival gradually decreasing from cecum to sigmoid colon. Cox regression analyses identified that tumor location was an independent prognostic factor for RFS and OS. CONCLUSIONS Stage III colon cancer located proximally carried a poorer survival than that located distally. Different efficacies of FOLFOX adjuvant chemotherapy may be an important factor affecting survival of site-specific stage III colon cancers.
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Wakasa K, Kawabata R, Nakao S, Hattori H, Taguchi K, Uchida J, Yamanaka T, Maehara Y, Fukushima M, Oda S. Dynamic modulation of thymidylate synthase gene expression and fluorouracil sensitivity in human colorectal cancer cells. PLoS One 2015; 10:e0123076. [PMID: 25881233 PMCID: PMC4400010 DOI: 10.1371/journal.pone.0123076] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 02/27/2015] [Indexed: 11/18/2022] Open
Abstract
Biomarkers have revolutionized cancer chemotherapy. However, many biomarker candidates are still in debate. In addition to clinical studies, a priori experimental approaches are needed. Thymidylate synthase (TS) expression is a long-standing candidate as a biomarker for 5-fluorouracil (5-FU) treatment of cancer patients. Using the Tet-OFF system and a human colorectal cancer cell line, DLD-1, we first constructed an in vitro system in which TS expression is dynamically controllable. Quantitative assays have elucidated that TS expression in the transformant was widely modulated, and that the dynamic range covered 15-fold of the basal level. 5-FU sensitivity of the transformant cells significantly increased in response to downregulated TS expression, although being not examined in the full dynamic range because of the doxycycline toxicity. Intriguingly, our in vitro data suggest that there is a linear relationship between TS expression and the 5-FU sensitivity in cells. Data obtained in a mouse model using transformant xenografts were highly parallel to those obtained in vitro. Thus, our in vitro and in vivo observations suggest that TS expression is a determinant of 5-FU sensitivity in cells, at least in this specific genetic background, and, therefore, support the possibility of TS expression as a biomarker for 5-FU-based cancer chemotherapy.
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Affiliation(s)
- Kentaro Wakasa
- Clinical Research Institute, National Kyushu Cancer Center, Fukuoka, Japan
| | - Rumi Kawabata
- Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Seiki Nakao
- Clinical Research Institute, National Kyushu Cancer Center, Fukuoka, Japan
| | | | - Kenichi Taguchi
- Clinical Research Institute, National Kyushu Cancer Center, Fukuoka, Japan
| | - Junji Uchida
- Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics, Yokohama City University, Yokohama, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masakazu Fukushima
- Clinical Research Institute, National Kyushu Cancer Center, Fukuoka, Japan
| | - Shinya Oda
- Clinical Research Institute, National Kyushu Cancer Center, Fukuoka, Japan
- * E-mail:
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Er TK, Bujanda L, Rodrigo M, Herreros-Villanueva M. Pharmacogenomic biomarkers for colorectal cancer treatment. CANCER TREATMENT COMMUNICATIONS 2015; 4:121-127. [DOI: 10.1016/j.ctrc.2015.08.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2023]
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Yoon YS, Kim JC. Recent applications of chemosensitivity tests for colorectal cancer treatment. World J Gastroenterol 2014; 20:16398-16408. [PMID: 25469008 PMCID: PMC4248183 DOI: 10.3748/wjg.v20.i44.16398] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Revised: 07/08/2014] [Accepted: 08/13/2014] [Indexed: 02/06/2023] Open
Abstract
The evaluation of therapeutic efficacy is necessary to predict the outcome of patients with metastatic colorectal cancer (CRC). In these patients, there is a critical need for predictive chemosensitivity assays and biomarkers to optimize efficacy and minimize toxicity. The introduction of targeted agents has improved the progression-free survival and overall survival of patients with metastatic disease. However, approximately 50% of patients do not show a positive response to chemotherapy and the selection of patients likely to respond to a specific regimen remains challenging. Cell culture-based chemosensitivity tests use autologous viable tumor cells to evaluate susceptibility to specific agents in vitro and predict their direct effects. Adenosine triphosphate-based assays and methyl thiazolyl-diphenyl-tetrazolium bromide-based assays are used widely as sensitivity tests because of their short assay period, technical simplicity, and the requirement of small amount of specimen. Among protein- and gene-based chemosensitivity assays, assessment of KRAS mutation status predicts the response to epidermal growth factor receptor-targeted therapy in CRC patients. The validation of predictive and prognostic markers enables the selection of therapeutic regimens with optimal efficacy and minimal toxicity for each patient, which has been termed personalized treatment. This review summarizes currently available predictive and prognostic chemosensitivity tests for metastatic CRC.
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Wang WB, Yang Y, Zhao YP, Zhang TP, Liao Q, Shu H. Recent studies of 5-fluorouracil resistance in pancreatic cancer. World J Gastroenterol 2014; 20:15682-15690. [PMID: 25400452 PMCID: PMC4229533 DOI: 10.3748/wjg.v20.i42.15682] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Revised: 05/04/2014] [Accepted: 07/25/2014] [Indexed: 02/06/2023] Open
Abstract
Resistance to 5-fluorouracil (5-FU), an important anticancer drug, is a serious challenge in the treatment of pancreatic cancer. Equilibrative nucleoside transporter 1 and multidrug-resistance protein (MRP) 5 and MRP8, rather than P-glycoprotein, play important roles in 5-FU transport. Thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase and thymidine phosphorylase are four key enzymes involved in 5-FU metabolism. Other metabolic enzymes, including uridine monophosphate synthetase, also contribute to chemoresistance. Intracellular signaling pathways are an integrated network, and nuclear factor kappa-light-chain-enhancer of activated B cells, AKT and extracellular signal-regulated kinases are signaling pathways that are particularly relevant to 5-FU resistance. In addition, recent reports indicate that STAT-3 is a crucial survival protein. Proteomic assays provide a powerful tool for identifying target proteins and understanding the role of microRNAs and stromal factors to facilitate the development of strategies to combat 5-FU resistance.
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Kataoka K, Kanazawa A, Nakajima A, Yamaguchi A, Arimoto A. Prognostic value of biomarkers in metastatic colorectal cancer patients. J Surg Res 2014; 194:343-350. [PMID: 25456112 DOI: 10.1016/j.jss.2014.10.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/09/2014] [Accepted: 10/03/2014] [Indexed: 12/25/2022]
Abstract
BACKGROUNDS The prognostic value of biomarkers in metastatic colorectal cancer (mCRC) patients with liver metastases remains unclear. We assessed the difference of expression of biomarkers between primary tumors and liver metastases treated with chemotherapy in mCRC patients, as well as the prognostic value of these markers. METHODS Forty-three mCRC patients with liver-limited disease from January 2007-November 2011 were analyzed. They all received resection of primary tumors followed by oxaliplatin-based chemotherapy. After chemotherapy, they all received hepatic resection. Forty-three paired primary and metastatic tumor specimens were collected to measure the messenger RNA expression of six biomarkers by the Danenberg tumor profile method (thymidylate synthase, dihydropyrimidine dehydrogenase [DPD], excision repair cross-complementing gene1, thymidine phosphorylase [TP], folylpolyglutamate synthase, and regenerating islet-derived family, member 4). RESULTS Thirty-six patients' messenger RNA was used for analysis. All markers showed similar expression between primary and metastatic sites. The low-expression group of Danenberg tumor profile and TP in the primary tumor showed significantly higher overall survival than the high-expression group (P < 0.001 and P = 0.033), but for DPD and TP in liver metastases, there were no significant differences of overall survival between the two groups. The ratios of marker expression in liver metastatic site to that in primary site of DPD and TP were significantly higher in chemo-responders than in non-chemo-responders (P = 0.034 and P = 0.022). CONCLUSIONS Biomarkers' expressions in liver metastases were similar to those in the primary tumor. DPD and TP in the primary lesion may be a prognostic factor in chemotherapy-naïve mCRC patients with liver-limited disease, but those in liver tumor were not. Further validated analysis to our results would be warranted.
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Affiliation(s)
- Kozo Kataoka
- Department of Surgery, Osaka Red-Cross Hospital, Osaka, Japan.
| | - Akiyoshi Kanazawa
- Department of Gastroenterological Surgery and Oncology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan
| | - Akio Nakajima
- Department of Surgery, Osaka Red-Cross Hospital, Osaka, Japan
| | - Ayane Yamaguchi
- Department of Surgery, Osaka Red-Cross Hospital, Osaka, Japan
| | - Akira Arimoto
- Department of Surgery, Osaka Red-Cross Hospital, Osaka, Japan
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Monte AA, Brocker C, Nebert DW, Gonzalez FJ, Thompson DC, Vasiliou V. Improved drug therapy: triangulating phenomics with genomics and metabolomics. Hum Genomics 2014; 8:16. [PMID: 25181945 PMCID: PMC4445687 DOI: 10.1186/s40246-014-0016-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 08/05/2014] [Indexed: 12/23/2022] Open
Abstract
Embracing the complexity of biological systems has a greater likelihood to improve prediction of clinical drug response. Here we discuss limitations of a singular focus on genomics, epigenomics, proteomics, transcriptomics, metabolomics, or phenomics-highlighting the strengths and weaknesses of each individual technique. In contrast, 'systems biology' is proposed to allow clinicians and scientists to extract benefits from each technique, while limiting associated weaknesses by supplementing with other techniques when appropriate. Perfect predictive modeling is not possible, whereas modeling of intertwined phenomic responses using genomic stratification with metabolomic modifications may greatly improve predictive values for drug therapy. We thus propose a novel-integrated approach to personalized medicine that begins with phenomic data, is stratified by genomics, and ultimately refined by metabolomic pathway data. Whereas perfect prediction of efficacy and safety of drug therapy is not possible, improvements can be achieved by embracing the complexity of the biological system. Starting with phenomics, the combination of linking metabolomics to identify common biologic pathways and then stratifying by genomic architecture, might increase predictive values. This systems biology approach has the potential, in specific subsets of patients, to avoid drug therapy that will be either ineffective or unsafe.
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Affiliation(s)
- Andrew A Monte
- University of Colorado Department of Emergency Medicine, Leprino Building, 7th Floor Campus Box B-215, 12401 E. 17th Avenue, Aurora, CO, 80045, USA.
- Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, 80045, USA.
- Rocky Mountain Poison & Drug Center, Denver, CO, 80204, USA.
| | - Chad Brocker
- Laboratory of Metabolism, Center for Cancer Research, National Institute of Cancer, Bethesda, MD, 20892, USA.
| | - Daniel W Nebert
- Division of Human Genetics, Department of Pediatrics and Molecular Developmental Biology, University of Cincinnati Medical Center, Cincinnati, OH, 45220, USA.
- Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45220, USA.
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Institute of Cancer, Bethesda, MD, 20892, USA.
| | - David C Thompson
- Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, 80045, USA.
| | - Vasilis Vasiliou
- Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, 80045, USA.
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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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Lindskog EB, Derwinger K, Gustavsson B, Falk P, Wettergren Y. Thymidine phosphorylase expression is associated with time to progression in patients with metastatic colorectal cancer. BMC Clin Pathol 2014; 14:25. [PMID: 24936150 PMCID: PMC4058433 DOI: 10.1186/1472-6890-14-25] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 05/28/2014] [Indexed: 02/06/2023] Open
Abstract
Background 5-Fluorouracil (5-FU) is the cornerstone of chemotherapeutic treatment for patients with colorectal cancer. The enzyme thymidine phosphorylase (TP) catalyzes the conversion of 5-FU to its active metabolite, 5-fluoro-2’-deoxyuridine. TP is expressed in tumour epithelial cells and stromal cells, particularly in tumour-associated macrophages. These macrophages may affect sensitivity to chemotherapy. Previously, we identified TP as a predictive factor in microdissected tumour samples of patients with advanced colorectal cancer. In the present study, we analysed TP expression in tissues and associated stromal cells from patients with advanced colorectal cancer and associated TP levels to tumour response and time-to-event variables during first-line chemotherapy treatment. We also investigated the association between serum TP levels at the time of surgery and gene expression in primary tumour tissues. Methods This study included 125 patients with metastatic colorectal cancer treated with first-line 5-FU-based chemotherapy. To quantify TP gene expression levels in tumour tissues, real-time polymerase chain reaction was performed using the 7500 Fast Real-Time PCR system (Applied Biosystems, Foster City, CA, USA). TP protein concentration in matched serum samples was determined using an enzyme-linked immunosorbent assay system (USCN Life Science Inc.). Results The tumour response rate was 31%, and 30% of patients exhibited stable disease. No associations between TP expression level and age or gender were observed. Levels of TP mRNA in mucosa and tumours were positively correlated (r = 0.41, p < 0.01). No correlation between TP expression and tumour response rate was observed. Time to progression was significantly longer in patients with high TP expression (p < 0.01). Serum TP protein levels were not associated with tumour response or time-to-event variables and did not correlate with gene expression in tumour tissues. Conclusions High TP gene expression in non-microdissected tumour tissues of patients with advanced colorectal cancer correlates with longer time to progression, which could be related to treatment. These results are in contrast to previous studies where microdissected tumour cells were analysed and may be due to the presence of adjacent stromal cells. Serum TP protein expression does not correlate to TP gene expression in tissues of patients with advanced colorectal cancer.
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Affiliation(s)
- Elinor Bexe Lindskog
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg 416 85, Sweden
| | - Kristoffer Derwinger
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg 416 85, Sweden
| | - Bengt Gustavsson
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg 416 85, Sweden
| | - Peter Falk
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg 416 85, Sweden
| | - Yvonne Wettergren
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg 416 85, Sweden
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Diakos CI, Chua W, Charles KA, Howell VM, Clarke SJ. Predicting chemotherapeutic response and toxicity in colorectal cancer. COLORECTAL CANCER 2013. [DOI: 10.2217/crc.13.39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
SUMMARY While treatment for colorectal cancer has evolved significantly over the past 10 years with the introduction of active chemotherapeutic agents and targeted therapies, this has been at the cost of increased toxicity for patients; and significant financial burden for governments and patients. Predicting clinical outcomes, especially given the largely elderly patient population involved, is therefore paramount. This review seeks to summarize existing data regarding the prediction of response and toxicity to chemotherapy agents currently used in the treatment of colorectal cancer.
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Affiliation(s)
- Connie I Diakos
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Wei Chua
- Department of Medical Oncology, Liverpool Hospital, Liverpool, NSW, Australia
| | - Kellie A Charles
- School of Medical Sciences (Pharmacology), Sydney Medical School, University of Sydney, NSW, Australia
| | - Viive M Howell
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Stephen J Clarke
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW, Australia.
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Santos C, Vilar E, Capella G, Salazar R. Molecular markers in colorectal cancer: clinical relevance in stage II colon cancer. COLORECTAL CANCER 2013. [DOI: 10.2217/crc.13.24] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
SUMMARY Colorectal cancer is the second most common cause of cancer death in developed countries. Adjuvant chemotherapy is standard for stage III colorectal cancer but its use in stage II is controversial. Several clinicopathological factors have been described to define a high-risk group among stage II colon cancers, which can aid the selection of patients who may benefit from chemotherapy. Local tumor invasion (T4), high histological grade, obstruction and perforation at diagnosis, and number of lymph nodes removed are the most widely accepted factors. Several molecular factors have been also investigated as prognostic candidate biomarkers. DNA ploidy, KRAS and TP53 mutations, thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, loss of heterozygosity on chromosome 18q and microsatellite instability have been widely investigated. The aim of this review is to analyze the current evidence and clinical applications of the classical molecular biomarkers as well as new ones such as BRAF, circulating tumor cells, genome expression signatures and DNA methylation.
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Affiliation(s)
- Cristina Santos
- Department of Medical Oncology, Institut Català d’Oncologia – Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08907, Spain
- Translational Research Laboratory, Institut Català d’Oncologia – Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08907, Spain
| | - Eduardo Vilar
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Gabriel Capella
- Translational Research Laboratory, Institut Català d’Oncologia – Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08907, Spain
| | - Ramon Salazar
- Translational Research Laboratory, Institut Català d’Oncologia – Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08907, Spain
- Department of Medical Oncology, Institut Català d’Oncologia – Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08907, Spain
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Donada M, Bonin S, Barbazza R, Pettirosso D, Stanta G. Management of stage II colon cancer - the use of molecular biomarkers for adjuvant therapy decision. BMC Gastroenterol 2013; 13:36. [PMID: 23446022 PMCID: PMC3599045 DOI: 10.1186/1471-230x-13-36] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Accepted: 02/25/2013] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND There is uncertainty on the benefit of adjuvant chemotherapy in patients with stage II colorectal cancers. The aim of this study is to investigate the combined role of clinical, pathological and molecular parameters to identify those stage II patients who better benefit from adjuvant therapy. METHODS We examined 120 stage II colon cancer patients. Of these, 60 patients received adjuvant 5-FU chemotherapy after surgery and the other 60 did not receive therapy. Immunohistochemical (IHC) analyses were performed to evaluate the expressions of Thymidylate synthetase (TYMS), TP53 (p53), β-catenin (CTNNB1) and CD8. For TYMS, its mRNA expression levels were also investigated by real time qRT-PCR. The entire case study was characterized by the presence of a defect in the MMR (mismatch repair) system, the presence of the CpG island methylator phenotype (CIMP or CIMP-High) and for the V600E mutation in the BRAF gene. At the histo-pathological level, the depth of tumour invasion, lymphovascular invasion, invasion of large veins, host lymphocytic response and tumour border configuration were recorded. RESULTS The presence of the V600E mutation in the BRAF gene was a poor prognostic factor for disease free and overall survival (DFS; hazard ratio [HR], 2.57; 95% CI: 1.03 -6.37; p = 0.04 and OS; HR, 3.68; 95% CI: 1.43-9.47; p < 0.01 respectively), independently of 5-FU treatment. Adjuvant therapy significantly improved survival in patients with high TYMS levels (p = 0.04), while patients with low TYMS had a better outcome if treated by surgery alone (DFS; HR, 6.07; 95% CI, 0.82 to 44.89; p = 0.04). In patients with a defect in the MMR system (dMMR), 5-FU therapy was associated to reduced survival (DFS; HR, 37.98; 95% CI, 1.04 to 1381.31; p = 0.04), while it was beneficial for CIMP-High associated tumours (DFS; HR, 0.17; 95% CI, 0.02 to 1.13; p = 0.05). CONCLUSIONS Patients' characterization according to MMR status, CIMP phenotype and TYMS mRNA expression may provide a more tailored approach for adjuvant therapy in stage II colon cancer.
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Affiliation(s)
- Marisa Donada
- DSM Department (Department of medical, surgical and health sciences), University of Trieste, Surgical Pathology Bldg, Strada di Fiume 447, I-34149, Trieste, Italy
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Role of conventional chemosensitivity test and tissue biomarker expression in predicting response to treatment of peritoneal carcinomatosis from colon cancer. Clin Colorectal Cancer 2013; 12:122-7. [PMID: 23332421 DOI: 10.1016/j.clcc.2012.11.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Revised: 10/02/2012] [Accepted: 11/26/2012] [Indexed: 01/28/2023]
Abstract
UNLABELLED Peritoneal carcinomatosis (PC) is observed in approximately 10% of patients with colorectal cancer at the time of primary cancer resection. Most of these patients receive 5-fluorouracil (5-FU)- or oxaliplatin-containing chemotherapy regimens as first-, second-, or third-line treatment. In the present study, sensitivity and resistance to drugs used to treat PC were better defined by a conventional chemosensitivity test than by biomarker expression. BACKGROUND 5-Fluorouracil- or oxaliplatin-based regimens are the treatments of choice in patients with PC from colon cancer. There are currently no useful preclinical evaluations to guide the decision-making process for tailored therapy. The aim of the present study was to compare the advantages and limits of a conventional in vitro chemosensitivity test with those of a panel of biomolecular markers in predicting clinical response to different drugs used to treat colon cancer-derived PC. PATIENTS AND METHODS Fresh surgical biopsy specimens were obtained from 28 patients with peritoneal carcinomatosis from colon cancer. TS, TP, DPD, MDR1, MRP-1, MGMT, BRCA1, ERCC1, GSTP1, and XPD gene expression levels were determined by real-time reverse transcription polymerase chain reaction. An in vitro chemosensitivity test was used to define a sensitivity or resistance profile to the drugs used to treat each patient. RESULTS Expression levels of the genes analyzed were generally poorly related to each other. TS and ERCC1 expression was inversely related to response to 5-FU-and/or oxaliplatin-containing regimens. Significant predictivity in terms of sensitivity but poor predictivity of resistance (56.2%) (P=.037) were observed for ERCC1 expression (90%), and high predictivity of resistance (100%) but very low predictivity of sensitivity (40%) (P=.014) were registered for TS. The best overall and significant predictivity was observed for chemosensitivity test results (62.5% sensitivity and 89% resistance; P=.005). CONCLUSIONS Sensitivity and resistance to drugs used in vivo was better defined by the chemosensitivity test than by biomarker expression.
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Mori T, Ohue M, Takii Y, Hashizume T, Kato T, Kotake K, Sato T, Tango T. Factors predicting the response to oral fluoropyrimidine drugs: a phase II trial on the individualization of postoperative adjuvant chemotherapy using oral fluorinated pyrimidines in stage III colorectal cancer treated by curative resection (ACT-01 Study). Oncol Rep 2012; 29:437-44. [PMID: 23232805 DOI: 10.3892/or.2012.2177] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Accepted: 10/18/2012] [Indexed: 11/06/2022] Open
Abstract
We evaluated the predictive relevance of several biomarkers on the survival of patients with stage III colorectal cancer treated with adjuvant chemotherapy of oral fluoropyrimidines. This was a multicenter phase II trial on adult patients with histologically confirmed resected stage III (Dukes' C) colorectal cancer. Patients received oral doxifluridine (800 mg/m2/day) in 3 divided doses, or oral uracil/tegafur (UFT) (400 mg/m2/day) in 2 divided doses for 5 days, every 7 days for 12 months with a 5-year follow-up. Outcome measures were disease-free survival and tissue markers [thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) protein levels and TP, DPD, thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT) mRNA levels in tumor samples and TS tandem-repeat type in blood samples]. There was a significant association between the intratumoral TP/DPD enzyme ratio and disease-free survival when the model included the drug, the parameter and the interactions between them [hazard ratio (HR)=2.76; P=0.00469]. The 5-year disease-free survival rate was statistically significantly higher in patients with high TP/DPD ratios [median ≥2.63: 71.9%; 95% confidence interval (CI) 61.4-80.0] compared to patients with low TP/DPD ratios (<2.63: 57.0%; 95% CI 46.3-66.3) (log-rank P=0.0277) following adjuvant therapy with oral fluoropyrimidines. No significant association was observed between the intratumoral TP/DPD enzyme ratio (cut-off value 2.0) and the disease-free survival rate in the doxifluridine group; primary endpoint (log-rank P=0.6850). The magnitude of the intratumoral TP/DPD enzyme ratio may be a potential indicator for the individualization of postoperative adjuvant chemotherapy with oral fluoropyrimidines for stage III colorectal cancer.
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Affiliation(s)
- Takeo Mori
- Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Tokyo, Japan.
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Quidde J, Arnold D, Stein A. Clinical management of localized colon cancer with capecitabine. Clin Med Insights Oncol 2012; 6:363-73. [PMID: 23170068 PMCID: PMC3498969 DOI: 10.4137/cmo.s8194] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Large randomized trials demonstrated a benefit of adjuvant chemotherapy after resection of the primary colon cancer. It improves overall survival and reduces the risk of death, by 5% in UICC (Union Internationale Contre le Cancer) stage II and approximately 15%-20% in stage III. Fluoropyrimidines have been the standard drugs for the treatment of colon cancer since large randomized controlled trials demonstrated their efficacy and safety in treating patients suffering from this disease. Capecitabine is an orally administered fluoropyrimidine, which is preferably activated in tumor tissue to the active moiety 5-fluorouracil (5FU) and is cytotoxic through inhibition of DNA synthesis. It has proven equivalent efficacy and tolerability despite a changed toxicity profile compared to 5FU with less myelosuppression but more hand-and-foot syndrome. Capecitabine is well tolerated in elderly patients. The oral route of administration avoids frequent clinical visits as well as insertion of central venous catheters. The impact of the particular drug features on daily clinical practice is discussed in this review.
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Affiliation(s)
- J. Quidde
- Hubertus Wald Tumor Center, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Germany
| | - D. Arnold
- Hubertus Wald Tumor Center, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Germany
| | - A. Stein
- Hubertus Wald Tumor Center, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Germany
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Minegaki T, Takara K, Hamaguchi R, Tsujimoto M, Nishiguchi K. Factors affecting the sensitivity of human-derived esophageal carcinoma cell lines to 5-fluorouracil and cisplatin. Oncol Lett 2012; 5:427-434. [PMID: 23420099 PMCID: PMC3573136 DOI: 10.3892/ol.2012.1014] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Accepted: 10/26/2012] [Indexed: 02/04/2023] Open
Abstract
Effective chemotherapy against esophageal carcinoma is considered achievable with a combination of 5-fluorouracil (5-FU) and cisplatin (CDDP). However, chemo-therapy remains ineffective in certain patients. The aim of this study was to clarify the factors which affect sensitivity to 5-FU and CDDP. The effects of factors known to influence sensitivity to 5-FU and CDDP, namely transporters, DNA repair enzymes and metabolic enzymes, were examined. mRNA levels of four transporters, SLC22A2, SLC23A2, ABCB1 and ABCC2, two DNA repair-related enzymes, Rad51 and MSH2, and one metabolic enzyme, dihydropyrimidine dehydrogenase (DPYD), showed a strong correlation (|r|>0.7) with IC50 values for 5-FU. In addition, the mRNA levels of ABCC2, MSH2 and DPYD showed a strong correlation (|r|>0.7) with the IC50 values for CDDP. Gimeracil, a DPYD inhibitor, enhanced the sensitivity of some cells to 5-FU but decreased the sensitivity of all the cells to CDDP. The inhibitory effects of ABCC2 with MK571 did not correspond to those observed in the correlation analysis. In conclusion, mRNA levels of SLC22A2, SLC23A2, ABCB1, ABCC2, Rad51, MSH2 and DPYD were confirmed to be strongly correlated with IC50 values for 5-FU, and mRNA levels of ABCC2, MSH2 and DPYD were confirmed to be strongly correlated with IC50 values for CDDP. In addition, the inhibition of DPYD appeared to affect the cytotoxicity of CDDP.
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Affiliation(s)
- Tetsuya Minegaki
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414
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Lindskog EB, Wettergren Y, Odin E, Gustavsson B, Derwinger K. Thymidine Phosphorylase Gene Expression in Stage III Colorectal Cancer. CLINICAL MEDICINE INSIGHTS-ONCOLOGY 2012; 6:347-53. [PMID: 23115484 PMCID: PMC3480868 DOI: 10.4137/cmo.s10226] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND The thymidine phosphorylase (TP) enzyme has several tumor-promoting functions. The aim of this study was to explore TP gene expression in relation to clinical and histopathological data obtained from patients with stage III colorectal cancer. METHODS AND RESULTS TP gene expression was analyzed by real-time quantitative PCR in tumor and mucosa samples from 254 patients. TP gene expression in tumors correlated with lymph node staging, with higher expression relating to a higher number of positive nodes and a worse N-stage. Higher TP expression was also associated with a worse histological tumor grade. Patients with rectal cancer had significantly higher TP expression in mucosa and tumors compared with patients having colon cancer. CONCLUSION Higher intratumoral TP expression appears to be related to a worse N stage, and thus, with a worse prognosis. TP gene expression measured in a preoperative biopsy could be of interest in preoperative staging.
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Affiliation(s)
- Elinor B Lindskog
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
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Chen Y, Yi C, Liu L, Li B, Wang Y, Wang X. Thymidylate synthase expression and prognosis in colorectal cancer: a meta-analysis of colorectal cancer survival data. Int J Biol Markers 2012; 27:e203-e211. [PMID: 23015402 DOI: 10.5301/jbm.2012.9584] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2012] [Indexed: 02/08/2023]
Abstract
BACKGROUND Although many studies have investigated the prognostic effect of thymidylate synthase (TS) in colorectal cancer, no consensus has been reached. The aim of this meta-analysis was to obtain a more precise estimate of the prognostic significance of TS expression in localized cancers treated by curative resection and adjuvant chemotherapy. MATERIALS AND METHOD Seventeen eligible studies reporting survival in 2,893 patients stratified by TS expression were pooled using a fixed- or random-effects model. The main outcome measure was hazard ratio (HR). RESULTS The overall HR for overall survival was 1.01 (95% CI 0.74-1.39, p=0.947), with an I2 of 64.4%. The total HR for disease-free survival was 1.36 (95% CI 0.97-1.89, p=0.072), with an I2 of 75.8%. In the TS protein-tested subgroup, the total HR for disease-free survival was 1.72 (95% CI 1.02-2.89, p=0.042), with an I2 of 81.3%. CONCLUSION Our meta-analysis showed that, in the adjuvant setting, TS expression does not predict a poorer disease-free survival or a worse overall survival. Therefore, we believe that it is inappropriate to regard TS expression as a prognostic factor for patients with stage II and stage III colorectal cancer treated by surgery and adjuvant chemotherapy.
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Affiliation(s)
- Yao Chen
- Shandong University, Jinan, PR China
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Monte AA, Vasiliou V, Heard KJ. Omics Screening for Pharmaceutical Efficacy and Safety in Clinical Practice. JOURNAL OF PHARMACOGENOMICS & PHARMACOPROTEOMICS 2012; S5:001. [PMID: 23264882 PMCID: PMC3526192 DOI: 10.4172/2153-0645.s5-001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
As molecular techniques have improved, investigators have attempted to improve pharmaceutical efficacy and safety by making trait associations with genomic, epigenomic, transcriptomic, proteomic, and metabolomic polymorphisms. The 'omics era has seen screening assays for pharmaceutical efficacy and safety translated into clinical practice. This manuscript will discuss each 'omic field and the screening assays available to the clinician. While success has been demonstrated in each 'omic field, many challenges remain. Assays need wider availability, predictive values remain low, and costs remain high. In order for clinicians to realize improved efficacy and safety due 'omic screens, development of improved techniques, combining of 'omic assays, and increased clinical utilization is necessary. This is an exciting time for investigators and clinicians that desire improved pharmaceutical therapy.
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Affiliation(s)
- Andrew A. Monte
- Rocky Mountain Poison and Drug Center, Denver, CO, USA
- University of Colorado School of Medicine, Department of Emergency Medicine Aurora, CO, USA
| | - Vasilis Vasiliou
- Molecular Toxicology & Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA
| | - Kennon J. Heard
- Rocky Mountain Poison and Drug Center, Denver, CO, USA
- University of Colorado School of Medicine, Department of Emergency Medicine Aurora, CO, USA
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Jensen NF, Smith DH, Nygård SB, Rømer MU, Nielsen KV, Brünner N. Predictive biomarkers with potential of converting conventional chemotherapy to targeted therapy in patients with metastatic colorectal cancer. Scand J Gastroenterol 2012; 47:340-55. [PMID: 22181013 DOI: 10.3109/00365521.2012.640835] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The availability of systemic chemotherapy regimens for the treatment of patients with metastatic colorectal cancer (mCRC) is based on the results from large prospective, randomized studies. The main chemotherapeutic drugs used in treatment of mCRC are the fluoropyrimidines (5-fluorouracil (5-FU); capecitabine) in combination with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI). The objective response rate to either combination is approximately 50%, where no significant differences with regard to progression free survival or overall survival have been observed. Interestingly, a number of preclinical and clinical studies have indicated lack of full cross resistance between oxaliplatin based and irinotecan based treatment. Therefore, it is possible that certain mCRC patient subpopulations would benefit more from one drug combination rather than the other. To address this clinical problem there has been much focus on development and validation of predictive biomarkers for these three drugs. Here, we present a thorough review on the current status of predictive biomarkers for 5-FU, oxaliplatin and irinotecan treatment of mCRC patients. The overall conclusions were as follows: Several promising biomarker candidates were identified, notably thymidylate synthase for 5-FU, topoisomerase I for irinotecan and ERCC1 for oxaliplatin. However, these candidates warrant further analysis, where assay performance and clinical trial design should be in focus.
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Affiliation(s)
- Niels Frank Jensen
- Department of Veterinary Disease Biology, Section for Pathobiology, Faculty of Life Sciences, University of Copenhagen, Frederiksberg C, Denmark
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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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Vande Voorde J, Liekens S, McGuigan C, Murziani PG, Slusarczyk M, Balzarini J. The cytostatic activity of NUC-3073, a phosphoramidate prodrug of 5-fluoro-2′-deoxyuridine, is independent of activation by thymidine kinase and insensitive to degradation by phosphorolytic enzymes. Biochem Pharmacol 2011; 82:441-52. [DOI: 10.1016/j.bcp.2011.05.024] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2011] [Revised: 05/20/2011] [Accepted: 05/23/2011] [Indexed: 11/29/2022]
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Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer mortality worldwide. In the last decade, median overall survival has increased significantly with the introduction of new cytotoxics and biologic therapies. Notably, the definition of molecular markers predicting benefit with epidermal growth factor receptor (EGFR)-targeted agents has led to important advances in the personalized treatment of CRC. Data derived from multiple phase III trials have indicated that KRAS mutations can be considered a highly specific negative biomarker of response to anti-EGFR monoclonal antibodies. The predictive value of additional mutations and deregulations of the signaling pathways downstream of the EGFR such as BRAF, NRAS, PIK3CA, or PTEN is under intensive investigation. In addition, status of microsatellite instability and molecular markers related to the metabolism of chemotherapy agents has shown promising ability to select patients with higher chances of response to cytotoxic agents. Although attempts to identify predictive factors for efficacy to antiangiogenic therapies have been disappointing, further research on this field will maximize their therapeutic index. Determination of molecular predictive factors before selection of chemotherapy is rapidly approaching us to the paradigm of individualized treatment of CRC.
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Sun J, Liu BR, Wei J, Qian XP, Yu LX, Guo RH, Shen H, Wang TS, Shu YQ. The extract of Paris polyphylla exerts apoptotic induction and synergic antiproliferative effect with anticancer drugs in SMMC-7721 human liver cancer cells. ACTA ACUST UNITED AC 2011. [DOI: 10.1016/j.bionut.2011.06.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
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Fariña-Sarasqueta A, Gosens MJEM, Moerland E, van Lijnschoten I, Lemmens VEPP, Slooter GD, Rutten HJT, van den Brule AJC. TS gene polymorphisms are not good markers of response to 5-FU therapy in stage III colon cancer patients. Cell Oncol (Dordr) 2011; 34:327-35. [PMID: 21630057 DOI: 10.1007/s13402-011-0030-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/04/2010] [Indexed: 02/06/2023] Open
Abstract
AIM Although the predictive and prognostic value of thymidylate synthase (TS) expression and gene polymorphism in colon cancer has been widely studied, the results are inconclusive probably because of methodological differences. With this study, we aimed to elucidate the role of TS gene polymorphisms genotyping in therapy response in stage III colon carcinoma patients treated with 5-FU adjuvant chemotherapy. PATIENTS AND METHODS 251 patients diagnosed with stage III colon carcinoma treated with surgery followed by 5-FU based adjuvant therapy were selected. The variable number of tandem repeats (VNTR) and the single nucleotide polymorphism (SNP) in the 5'untranslated region of the TS gene were genotyped. RESULTS There was a positive association between tumor T stage and the VNTR genotypes (p = 0.05). In both univariate and multivariate survival analysis no effects of the studied polymorphisms on survival were found. However, there was an association between both polymorphisms and age. Among patients younger than 60 years, the patients homozygous for 2R seemed to have a better overall survival, whereas among the patients older than 67 this longer survival was seen by the carriers of other genotypes. CONCLUSION We conclude that the TS VNTR and SNP do not predict response to 5-FU therapy in patients with stage III colon carcinoma. However, age appears to modify the effects of TS polymorphisms on survival.
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Komori S, Osada S, Yoshida K. Novel strategy with gemcitabine for advanced pancreatic cancer. ISRN ONCOLOGY 2011; 2011:936893. [PMID: 22091436 PMCID: PMC3200206 DOI: 10.5402/2011/936893] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2011] [Accepted: 04/08/2011] [Indexed: 01/06/2023]
Abstract
5-fluorouracil (5-FU) is widely used in chemotherapy for gastric and colorectal cancer, but gemcitabine (GEM), and not 5-FU, is approved as a standard drug for use in pancreatic cancer. Interindividual variation in the enzyme activity of the GEM metabolic pathway can affect the extent of GEM metabolism and the efficacy of GEM chemotherapy. Human equilibrative nucleoside transporter 1 (hENT1) is recognized as a major transporter of GEM into cells. In addition, a factor that activates hENT1 is the inhibition of thymidylate synthase (TS), one of the 5-FU metabolic enzymes; TS inhibition mediates depleting intracellular nucleotide pools, resulting in the activation of the salvage pathway mediated through hENT1. In this paper, the role of 5-FU in GEM-based chemotherapy for pancreatic cancer is discussed with special emphasis on enzymes involved in the 5-FU and GEM metabolic pathways and in the correlation between GEM responsiveness and the expression of 5-FU and GEM metabolic enzymes.
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Affiliation(s)
- Shuji Komori
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Yanagido, 1-1 Yanagido, Gifu 501-1194, Japan
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De Mattos-Arruda L, Dienstmann R, Tabernero J. Development of molecular biomarkers in individualized treatment of colorectal cancer. Clin Colorectal Cancer 2011; 10:279-89. [PMID: 21729679 DOI: 10.1016/j.clcc.2011.03.030] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Revised: 03/11/2011] [Accepted: 03/15/2011] [Indexed: 12/13/2022]
Abstract
Colorectal cancer is a leading cause of cancer mortality despite recent expansion of treatment options in metastatic colorectal cancer (mCRC). Our knowledge about key signaling pathways in colorectal tumors has contributed to the identification of specific molecular markers of response to targeted agents. In this review we discuss well-established and potential predictive biomarkers of benefit with epidermal growth factor receptor (EGFR) inhibitors. Data derived from multiple phase III trials have indicated that KRAS mutations can be considered a highly specific negative biomarker of response to anti-EGFR monoclonal antibodies. Other molecular aberrations in pathways downstream of EGFR such as BRAF, NRAS, and PIK3CA mutations, and PTEN loss are also reviewed. Moreover biomarkers of efficacy to classic chemotherapeutic agents as well as recent advances regarding high-throughput technologies and circulating tumor cells are also considered. Personalized cancer medicine in the mCRC scenario seems to be near reality, but validation of many biomarkers in prospective clinical trials is urgently warranted.
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Affiliation(s)
- Leticia De Mattos-Arruda
- Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
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Zhou F, Zhang J, Li P, Niu F, Wu X, Wang G, Roberts MS. Toward a new age of cellular pharmacokinetics in drug discovery. Drug Metab Rev 2011; 43:335-45. [PMID: 21395404 DOI: 10.3109/03602532.2011.560607] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Pharmacokinetics, pharmacology, and toxicology are the major determinants of the success or failure of candidates during drug development. Because inappropriate pharmacokinetics often leads to inefficacy, even toxicity, pharmacokinetics studies have been regarded as crucial components in drug preclinical and clinical research. However, new data increasingly reveal that drug concentrations in plasma or tissues cannot totally explain the efficacy of drug on the target organ. For most drugs that interact with targets localized in cells, intracellular penetration, accumulation, distribution, and elimination are important parameters governing the efficacy in the target cells. So, there is a pressing need to clarify the cellular pharmacokinetics and thus evaluate the efficacy of drugs in the target cells. This review provides a general overview regarding current knowledge about cellular pharmacokinetics in some specific cells and also summarizes the factors that can influence cellular pharmacokinetics. It concludes by discussing potential strategies for optimizing cellular pharmacokinetics and advocating that global cellular pharmacokinetics studies be conducted in future research toward improving drug efficacy.
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Affiliation(s)
- Fang Zhou
- Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing
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Donada M, Bonin S, Nardon E, De Pellegrin A, Decorti G, Stanta G. Thymidilate synthase expression predicts longer survival in patients with stage II colon cancer treated with 5-flurouracil independently of microsatellite instability. J Cancer Res Clin Oncol 2011; 137:201-210. [PMID: 20387074 DOI: 10.1007/s00432-010-0872-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2009] [Accepted: 03/22/2010] [Indexed: 12/11/2022]
Abstract
BACKGROUND 5-Fluorouracil (5-FU) is the most commonly used therapeutic agent for colon cancer treatment. Several studies have evaluated in patients with colon cancer, either the role of genes involved in the 5-FU pathway, such as thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) or the role of microsatellite instability (MSI) as prognostic or predictive markers for adjuvant chemotherapy efficacy, with discordant results. In this study we investigated the combined effect of TS, TP, DPD mRNA expression and MSI status in primary tumors of patients with colon cancer, all treated with 5-FU adjuvant therapy. METHODS TS, TP and DPD expression levels were investigated by real-time quantitative RT-PCR on RNA extracts from formalin-fixed and paraffin-embedded tissues of 55 patients with colon adenocarcinoma. In the same case study MSI status was assessed on DNA extracts. RESULTS A higher TS expression was significantly associated with a longer survival for patients with cancers of stage II (P < 0.01), but not for those with stage III (P = 0.68). In addition, in multivariate analysis, a higher TS expression was significantly associated with a decreased risk of death (HR 0.13, 95% CI 0.03-0.59, P < 0.01), while the MSI status did not have effects on patients' survival. CONCLUSIONS This retrospective investigation suggests that TS gene expression at mRNA level can be a useful marker of better survival in patients (especially of those with cancers of stage II) receiving 5-FU adjuvant chemotherapy, independently of the MSI status.
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Affiliation(s)
- Marisa Donada
- ACADEM Department, Cattinara Hospital, University of Trieste, Surgical Pathology Bldg, Strada di Fiume 447, 34149 Trieste, Italy
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Scartozzi M, Maccaroni E, Giampieri R, Pistelli M, Bittoni A, Del Prete M, Berardi R, Cascinu S. 5-Fluorouracil pharmacogenomics: still rocking after all these years? Pharmacogenomics 2011; 12:251-265. [PMID: 21332317 DOI: 10.2217/pgs.10.167] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The 5-fluorouracil (5-FU) metabolic pathway is mainly dependent on the activity of several intracellular enzymes. Among them, four in particular; thymidylate synthase, methylenetetrahydrofolate reductase, dihydropyrimidine dehydrogenase and thymidine phosphorylase are considered the key points in determining sensitivity or resistance to this drug. These enzymes are needed to metabolize the drug in its active form (thymidylate phosphorylase) or to drop the concentration of the active drug in the cell (dihydropyrimidine dehydrogenase) or both (thymidylate synthase and methylenetetrahydrofolate reductase). Several different studies have tried to investigate the relationship between the presence of mutations in these enzymes and a reduced/improved activity of treatment based on 5-FU or its derivatives. In this article, we will focus on the often contradictory results of these studies.
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Affiliation(s)
- Mario Scartozzi
- Clinica di Oncologia Medica, AO Ospedali Riuniti-Ancona, Università Politecnica delle Marche, Ancona, Italy.
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Kurdistani SK. Histone modifications in cancer biology and prognosis. PROGRESS IN DRUG RESEARCH. FORTSCHRITTE DER ARZNEIMITTELFORSCHUNG. PROGRES DES RECHERCHES PHARMACEUTIQUES 2011; 67:91-106. [PMID: 21141726 DOI: 10.1007/978-3-7643-8989-5_5] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Cancer is a disease of genome sequence alterations as well as epigenetic changes. Epigenetics refers in part to the mechanisms by which histones affect various DNA-based processes, such as gene regulation. Histones are proteins around which the DNA wraps itself to form chromatin--the physiologically relevant form of the human genome. Histones are modified extensively by posttranslational modifications that alter chromatin structure and serve to recruit to or exclude protein complexes from DNA. Aberrations in histone modifications occur frequently in cancer including changes in their levels and distribution at gene promoters, gene coding regions, repetitive DNA sequences, and other genomic elements. Locus-specific alterations in histone modifications may have adverse effects on expression of nearby genes but so far have not been shown to have clinical utility. Cancer cells also exhibit alterations in global levels of specific histone modifications, generating an additional layer of epigenetic heterogeneity at the cellular level in tumor tissues. Unlike locus-specific changes, the cellular epigenetic heterogeneity can be used to define previously unrecognized subsets of cancer patients with distinct clinical outcomes. In general, increased prevalence of cells with lower global levels of histone modifications is prognostic of poorer clinical outcome such as increased risk of tumor recurrence and/or decreased survival probability. Prognostic utility of histone modifications has been demonstrated independently for multiple cancers including those of prostate, lung, kidney, breast, ovary, and pancreas, suggesting a fundamental association between global histone modification levels and tumor aggressiveness, regardless of cancer tissue of origin. Cellular levels of histone modifications may also predict response to certain chemotherapeutic agents, serving as predictive biomarkers that could inform clinical decisions on choice and course of therapy. The challenge before us is to understand how global levels of histone modifications are established and maintained and what their mechanistic links are to the cancer clinical behavior.
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Affiliation(s)
- Siavash K Kurdistani
- Department of Biological Chemistry and Pathology, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
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Lee SJ, Choi YL, Park YH, Kim ST, Cho EY, Ahn JS, Im YH. Thymidylate synthase and thymidine phosphorylase as predictive markers of capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Cancer Chemother Pharmacol 2010; 68:743-51. [PMID: 21170649 DOI: 10.1007/s00280-010-1545-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2010] [Accepted: 12/01/2010] [Indexed: 01/12/2023]
Abstract
PURPOSE The primary purpose of this study was to evaluate the role of thymidylate synthase (TS) and thymidine phosphorylase (TP) as biomarkers to predict clinical outcomes of capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC). METHODS Of the patients who were previously treated with anthracycline and taxane regimens, 90 patients who had available tissue block for immunohistochemistry with measurable lesions were included. All patients received capecitabine (2,500 mg/m(2)/day) for 14 days every 3 weeks. RESULTS High TS expression was more common among patients with triple-negative (TN) subtype than among patients with other subtypes (33% for hormone receptor+, 8% for HER2+, and 58% for TN, P = 0.023). The median PFS was significantly lower in patients with high TS (6.6 vs. 3.0 months; P = 0.017) and low TP expressions (6.0 vs. 3.3 months; P = 0.013). A high TS and a low TP expressions were identified as unfavorable independent risk factors for PFS to capecitabine monotherapy in multivariate analysis (hazard ratio [HR], 1.7, P = 0.037 for high TS score; HR, 1.8, P = 0.014 for low TP score). CONCLUSIONS Our data suggest that high TS and low TP scores correlate with a shorter PFS for capecitabine monotherapy in patients with anthracycline- and taxane-pretreated MBC.
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Affiliation(s)
- Su Jin Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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50
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Chua W, Kho PS, Moore MM, Charles KA, Clarke SJ. Clinical, laboratory and molecular factors predicting chemotherapy efficacy and toxicity in colorectal cancer. Crit Rev Oncol Hematol 2010; 79:224-50. [PMID: 20719530 DOI: 10.1016/j.critrevonc.2010.07.012] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2010] [Revised: 07/05/2010] [Accepted: 07/15/2010] [Indexed: 12/20/2022] Open
Abstract
Colorectal cancer (CRC) treatment has evolved significantly over the last ten years with the use of active chemotherapeutic agents including fluoropyrimidines, oxaliplatin and irinotecan plus targeted monoclonal antibodies bevacizumab, cetuximab and panitumumab. The addition of newer chemotherapeutic agents and targeted therapies has improved patient outcomes at the cost of increased toxicity with not all patients benefiting from these treatments. It is necessary for clinicians to more accurately predict clinical outcomes particularly in the predominantly elderly CRC patient population. This review aims to summarise existing data regarding the use of clinical and laboratory variables plus molecular markers in predicting response, survival and toxicity to chemotherapy agents and targeted monoclonal antibodies currently used in the treatment of CRC.
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Affiliation(s)
- Wei Chua
- Sydney Cancer Centre, Concord Repatriation General Hospital, Hospital Road, Concord, NSW 2139, Australia
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