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Su BC, Chen GY, Yang CM, Chuang WT, Lin MC, Hsu PL, Lee CW, Cheng CC, Wu SY, Pan BS, Yu HH. Impacts of hyperthermic chemotherapeutic agent on cytotoxicity, chemoresistance-related proteins and PD-L1 expression in human gastric cancer cells. Int J Hyperthermia 2024; 41:2310017. [PMID: 38350654 DOI: 10.1080/02656736.2024.2310017] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/17/2024] [Accepted: 01/22/2024] [Indexed: 02/15/2024] Open
Abstract
Objective: Gastric cancer with peritoneal metastasis is considered to be final stage gastric cancer. One current treatment approach for this condition is combined cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). However, the therapeutic mechanisms of HIPEC remain largely undescribed. Method: In order to assess the cellular effects of HIPEC in vitro, we treated AGS human gastric adenocarcinoma cells with or without 5-fluorouracil (5-Fu) at 37 °C or at 43 °C (hyperthermic temperature) for 1 h followed by incubation at 37 °C for 23 h. The impacts of hyperthermia/5-Fu on apoptosis, cell survival signals, oxidative stress, chemoresistance-related proteins and programmed death-ligand 1 (PD-L1) expression were measured. Results: Our results showed that hyperthermia potentiates 5-Fu-mediated cytotoxicity in AGS cells. Furthermore, the combination of 5-Fu and hyperthermia reduces levels of both phosphorylated STAT3 and STAT3, while increasing the levels of phosphorylated Akt and ERK. In addition, 5-Fu/hyperthermia enhances reactive oxygen species and suppresses superoxide dismutase 1. Chemoresistance-related proteins, such as multidrug resistance 1 and thymidylate synthase, are also suppressed by 5-Fu/hyperthermia. Interestingly, hyperthermia enhances 5-Fu-mediated induction of glycosylated PD-L1, but 5-Fu-mediated upregulation of PD-L1 surface expression is prevented by hyperthermia. Conclusion: Taken together, our findings provide insights that may aid in the development of novel therapeutic strategies and enhanced therapeutic efficacy of HIPEC.
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Affiliation(s)
- Bor-Chyuan Su
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Guan-Yu Chen
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Chun-Ming Yang
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Wei-Ting Chuang
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Meng-Chieh Lin
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Pei-Ling Hsu
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chu-Wan Lee
- Department of Nursing, National Tainan Junior College of Nursing, Tainan, Taiwan
| | - Chih-Cheng Cheng
- Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Shih-Ying Wu
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston-Salem, NC, USA
| | - Bo-Syong Pan
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA
| | - Hsin-Hsien Yu
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
- Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
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Ulker D, Ozyurt R, Erkasap N, Butun V. Magnetic Targeting of 5-Fluorouracil-Loaded Liposome-Nanogels for In Vivo Breast Cancer Therapy and the Cytotoxic Effects on Liver and Kidney. AAPS PharmSciTech 2022; 23:289. [DOI: 10.1208/s12249-022-02438-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 10/03/2022] [Indexed: 02/06/2023] Open
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Venkatasamy A, Guerin E, Blanchet A, Orvain C, Devignot V, Jung M, Jung AC, Chenard MP, Romain B, Gaiddon C, Mellitzer G. Ultrasound and Transcriptomics Identify a Differential Impact of Cisplatin and Histone Deacetylation on Tumor Structure and Microenvironment in a Patient-Derived In Vivo Model of Gastric Cancer. Pharmaceutics 2021; 13:1485. [PMID: 34575561 PMCID: PMC8467189 DOI: 10.3390/pharmaceutics13091485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/09/2021] [Accepted: 09/13/2021] [Indexed: 01/06/2023] Open
Abstract
The reasons behind the poor efficacy of transition metal-based chemotherapies (e.g., cisplatin) or targeted therapies (e.g., histone deacetylase inhibitors, HDACi) on gastric cancer (GC) remain elusive and recent studies suggested that the tumor microenvironment could contribute to the resistance. Hence, our objective was to gain information on the impact of cisplatin and the pan-HDACi SAHA (suberanilohydroxamic acid) on the tumor substructure and microenvironment of GC, by establishing patient-derived xenografts of GC and a combination of ultrasound, immunohistochemistry, and transcriptomics to analyze. The tumors responded partially to SAHA and cisplatin. An ultrasound gave more accurate tumor measures than a caliper. Importantly, an ultrasound allowed a noninvasive real-time access to the tumor substructure, showing differences between cisplatin and SAHA. These differences were confirmed by immunohistochemistry and transcriptomic analyses of the tumor microenvironment, identifying specific cell type signatures and transcription factor activation. For instance, cisplatin induced an "epithelial cell like" signature while SAHA favored a "mesenchymal cell like" one. Altogether, an ultrasound allowed a precise follow-up of the tumor progression while enabling a noninvasive real-time access to the tumor substructure. Combined with transcriptomics, our results underline the different intra-tumoral structural changes caused by both drugs that impact differently on the tumor microenvironment.
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Affiliation(s)
- Aina Venkatasamy
- Streinth Lab (Stress Response and Innovative Therapies), Strasbourg University, Inserm UMR_S 1113 IRFAC (Interface Recherche Fondamental et Appliquée à la Cancérologie), 67200 Strasbourg, France; (A.V.); (E.G.); (A.B.); (C.O.); (V.D.); (A.C.J.); (B.R.)
- IHU-Strasbourg (Institut Hospitalo-Universitaire), 67091 Strasbourg, France
| | - Eric Guerin
- Streinth Lab (Stress Response and Innovative Therapies), Strasbourg University, Inserm UMR_S 1113 IRFAC (Interface Recherche Fondamental et Appliquée à la Cancérologie), 67200 Strasbourg, France; (A.V.); (E.G.); (A.B.); (C.O.); (V.D.); (A.C.J.); (B.R.)
| | - Anais Blanchet
- Streinth Lab (Stress Response and Innovative Therapies), Strasbourg University, Inserm UMR_S 1113 IRFAC (Interface Recherche Fondamental et Appliquée à la Cancérologie), 67200 Strasbourg, France; (A.V.); (E.G.); (A.B.); (C.O.); (V.D.); (A.C.J.); (B.R.)
| | - Christophe Orvain
- Streinth Lab (Stress Response and Innovative Therapies), Strasbourg University, Inserm UMR_S 1113 IRFAC (Interface Recherche Fondamental et Appliquée à la Cancérologie), 67200 Strasbourg, France; (A.V.); (E.G.); (A.B.); (C.O.); (V.D.); (A.C.J.); (B.R.)
| | - Véronique Devignot
- Streinth Lab (Stress Response and Innovative Therapies), Strasbourg University, Inserm UMR_S 1113 IRFAC (Interface Recherche Fondamental et Appliquée à la Cancérologie), 67200 Strasbourg, France; (A.V.); (E.G.); (A.B.); (C.O.); (V.D.); (A.C.J.); (B.R.)
| | | | - Alain C. Jung
- Streinth Lab (Stress Response and Innovative Therapies), Strasbourg University, Inserm UMR_S 1113 IRFAC (Interface Recherche Fondamental et Appliquée à la Cancérologie), 67200 Strasbourg, France; (A.V.); (E.G.); (A.B.); (C.O.); (V.D.); (A.C.J.); (B.R.)
- Laboratoire de Biologie Tumorale, ICANS, 67200 Strasbourg, France
| | - Marie-Pierre Chenard
- Pathology Department, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France;
| | - Benoit Romain
- Streinth Lab (Stress Response and Innovative Therapies), Strasbourg University, Inserm UMR_S 1113 IRFAC (Interface Recherche Fondamental et Appliquée à la Cancérologie), 67200 Strasbourg, France; (A.V.); (E.G.); (A.B.); (C.O.); (V.D.); (A.C.J.); (B.R.)
- Digestive Surgery Department, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
| | - Christian Gaiddon
- Streinth Lab (Stress Response and Innovative Therapies), Strasbourg University, Inserm UMR_S 1113 IRFAC (Interface Recherche Fondamental et Appliquée à la Cancérologie), 67200 Strasbourg, France; (A.V.); (E.G.); (A.B.); (C.O.); (V.D.); (A.C.J.); (B.R.)
| | - Georg Mellitzer
- Streinth Lab (Stress Response and Innovative Therapies), Strasbourg University, Inserm UMR_S 1113 IRFAC (Interface Recherche Fondamental et Appliquée à la Cancérologie), 67200 Strasbourg, France; (A.V.); (E.G.); (A.B.); (C.O.); (V.D.); (A.C.J.); (B.R.)
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Isoforms of the p53 Family and Gastric Cancer: A Ménage à Trois for an Unfinished Affair. Cancers (Basel) 2021; 13:cancers13040916. [PMID: 33671606 PMCID: PMC7926742 DOI: 10.3390/cancers13040916] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/06/2021] [Accepted: 02/17/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary The p53 family is a complex family of transcription factors with different cellular functions that are involved in several physiological processes. A massive amount of data has been accumulated on their critical role in the tumorigenesis and the aggressiveness of cancers of different origins. If common features are observed, there are numerous specificities that may reflect particularities of the tissues from which the cancers originated. In this regard, gastric cancer tumorigenesis is rather remarkable, as it is induced by bacterial and viral infections, various chemical carcinogens, and familial genetic alterations, which provide an example of the variety of molecular mechanisms responsible for cell transformation and how they impact the p53 family. This review summarizes the knowledge gathered from over 40 years of research on the role of the p53 family in gastric cancer, which still displays one of the most elevated mortality rates amongst all types of cancers. Abstract Gastric cancer is one of the most aggressive cancers, with a median survival of 12 months. This illustrates its complexity and the lack of therapeutic options, such as personalized therapy, because predictive markers do not exist. Thus, gastric cancer remains mostly treated with cytotoxic chemotherapies. In addition, less than 20% of patients respond to immunotherapy. TP53 mutations are particularly frequent in gastric cancer (±50% and up to 70% in metastatic) and are considered an early event in the tumorigenic process. Alterations in the expression of other members of the p53 family, i.e., p63 and p73, have also been described. In this context, the role of the members of the p53 family and their isoforms have been investigated over the years, resulting in conflicting data. For instance, whether mutations of TP53 or the dysregulation of its homologs may represent biomarkers for aggressivity or response to therapy still remains a matter of debate. This uncertainty illustrates the lack of information on the molecular pathways involving the p53 family in gastric cancer. In this review, we summarize and discuss the most relevant molecular and clinical data on the role of the p53 family in gastric cancer and enumerate potential therapeutic innovative strategies.
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Derieux S, Svrcek M, Manela S, Lagorce-Pages C, Berger A, André T, Taieb J, Paye F, Voron T. Evaluation of the prognostic impact of pathologic response to preoperative chemotherapy using Mandard's Tumor Regression Grade (TRG) in gastric adenocarcinoma. Dig Liver Dis 2020; 52:107-114. [PMID: 31427088 DOI: 10.1016/j.dld.2019.07.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 07/14/2019] [Accepted: 07/16/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Perioperative chemotherapy is the gold standard in gastric cancer management. The prognostic significance of pathological response has been investigated in many malignancies, using Tumor Regression Grade (TRG). Its prognostic value in gastric cancer remains poorly known. AIMS This study aimed to assess the prognostic value of pathological response to chemotherapy, using Mandard's TRG in gastric cancer, and to identify factors predictive of response to chemotherapy. METHODS We retrospectively identified patients with gastric adenocarcinoma from two institutional surgical databases, with preoperative chemotherapy and subsequent gastrectomy. Pathological response was centrally reviewed using Mandard's TRG. RESULTS From 325 patients resected from a gastric cancer between 1997 and 2016, 109 underwent a preoperative chemotherapy. 42% were pathologic responders (TRG1-3) and 58% non-responders (TRG4-5). Five-years overall survival (OS) was 35% for non-responders, and 73% for responders (p = 0,006). Five-years disease-free survival (DFS) was 34% for non-responders and 65% for responders (p = 0,013). In multivariate analysis, pathological response was an independent prognostic factor of poor OS: HR = 2.736 (CI95% = 1.335-5.608; p = 0.006) and DFS: HR = 2.241 (CI95% = 1.130-4.446; p = 0.021). CONCLUSION TRG after preoperative chemotherapy is an important prognostic factor in patients resected for a gastric adenocarcinoma. Further studies should be performed to evaluate if adjuvant therapy should be adapted to pathological response.
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Affiliation(s)
- Simon Derieux
- Sorbonne University, Digestive surgery department, AP-HP, St Antoine Hospital, Paris, France.
| | - Magali Svrcek
- Sorbonne University, Department of pathology, AP-HP, St Antoine Hospital, Paris, France
| | - Sarah Manela
- Department of pathology, AP-HP, Georges Pompidou European Hospital, Paris, France
| | | | - Anne Berger
- Digestive surgery department, AP-HP, Georges Pompidou European Hospital, Paris, France
| | - Thierry André
- Sorbonne University, Medical oncology department, AP-HP, Saint Antoine Hospital, Paris, France
| | - Julien Taieb
- Digestive oncology department, AP-HP, Georges Pompidou European Hospital, Paris, France
| | - François Paye
- Sorbonne University, Digestive surgery department, AP-HP, St Antoine Hospital, Paris, France
| | - Thibault Voron
- Sorbonne University, Digestive surgery department, AP-HP, St Antoine Hospital, Paris, France
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Varghese V, Magnani L, Harada-Shoji N, Mauri F, Szydlo RM, Yao S, Lam EWF, Kenny LM. FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression. Sci Rep 2019; 9:1505. [PMID: 30728402 PMCID: PMC6365533 DOI: 10.1038/s41598-018-38017-0] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 10/07/2018] [Indexed: 12/11/2022] Open
Abstract
Resistance to 5-Fluoruracil (5-FU) has been linked to elevated expression of the main target, thymidylate synthase (TYMS), which catalyses the de novo pathway for production of deoxythymidine monophosphate. The potent oncogenic forkhead box transcription factor, FOXM1 is is regulated by E2F1 which also controls TYMS. This study reveals a significant role of FOXM1 in 5-FU resistance. Overexpression and knock-down studies of FOXM1 in colon cancer cells suggest the importance of FOXM1 in TYMS regulation. ChIP and global ChIP-seq data also confirms that FOXM1 can also potentially regulate other 5-FU targets, such as TYMS, thymidine kinase 1 (TK-1) and thymidine phosphorylase (TYMP). In human colorectal cancer tissue specimens, a strong correlation of FOXM1 and TYMS staining was observed. Elevated FOXM1 and TYMS expression was also observed in acquired 5-FU resistant colon cancer cells (HCT116 5-FU Res). A synergistic effect was observed following treatment of CRC cells with an inhibitor of FOXM1, thiostrepton, in combination with 5-FU. The combination treatment decreased colony formation and migration, and induced cell cycle arrest, DNA damage, and apoptosis in CRC cell lines. In summary, this research demonstrated that FOXM1 plays a pivotal role in 5-FU resistance at least partially through the regulation of TYMS.
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Affiliation(s)
- Vidhya Varghese
- Department of Surgery and Cancer, Imperial College London, London, USA
| | - Luca Magnani
- Department of Surgery and Cancer, Imperial College London, London, USA
| | | | - Francesco Mauri
- Imperial College Healthcare NHS Trust, Imperial College London, London, USA
| | | | - Shang Yao
- Department of Surgery and Cancer, Imperial College London, London, USA
| | - Eric W-F Lam
- Department of Surgery and Cancer, Imperial College London, London, USA.
| | - Laura M Kenny
- Department of Surgery and Cancer, Imperial College London, London, USA.
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Li S, Li B, Wang J, Zhang D, Liu Z, Zhang Z, Zhang W, Wang Y, Bai D, Guan J, Zhang Y. Identification of Sensitivity Predictors of Neoadjuvant Chemotherapy for the Treatment of Adenocarcinoma of Gastroesophageal Junction. Oncol Res 2017; 25:93-97. [PMID: 28081737 PMCID: PMC7840763 DOI: 10.3727/096504016x14719078133564] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The identification of reliable predictors of chemotherapy sensitivity and early screening of adenocarcinoma of gastroesophageal junction (AGEJ) patients who are resistant to chemotherapy has become an important area of clinical and translational research. We aimed to investigate the predictive value of seven cancer-associated cellular proteins for neoadjuvant chemotherapy in AGEJ patients. Clinical data of 93 patients who received neoadjuvant chemotherapy for locally advanced AGEJ between June 2010 and December 2014 were reviewed. All patients were administered the combination regimen of S-1 and oxaliplatin (SOX). Expression of P-glycoprotein (P-gp), glutathione S-transferase-π (GST-π), topoisomerase II (topo II), multidrug resistance gene-associated protein (MRP), lung resistance-related protein (LRP), Ki-67, and p53 was determined by immunohistochemistry (IHC) in AGEJ tissues before neoadjuvant chemotherapy. Chemotherapeutic efficacy was evaluated according to RECIST 1.0 standards and histopathological results, and the relationship between the expression of the cellular proteins and chemotherapy efficacy was analyzed. The SOX regimen was associated with an overall response rate of 46.2%. The frequency of expression of the seven cancer-associated factors in the AGEJ tissues was as follows: P-gp, 64.5%; GST-π, 39.8%; topo II, 72.0%; MRP, 33.3%; LRP, 68.8%; Ki-67, 62.4%; and p53, 40.9%. Expression of Ki-67 (p = 0.003) and p53 (p = 0.009) was significantly correlated with chemotherapy sensitivity. Elevated Ki-67 expression and decreased p53 expression predict for SOX insensitivity in AGEJ, and the cellular expression of these respective proteins may provide a useful reference for designing individualized chemotherapy regimens for AGEJ patients in the future.
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He MM, Zhang DS, Wang F, Wang ZX, Yuan SQ, Wang ZQ, Luo HY, Ren C, Qiu MZ, Jin Y, Wang DS, Chen DL, Zeng ZL, Li YH, He YY, Hao YT, Guo P, Wang FH, Zeng YX, Xu RH. Phase II trial of S-1 plus leucovorin in patients with advanced gastric cancer and clinical prediction by S-1 pharmacogenetic pathway. Cancer Chemother Pharmacol 2016; 79:69-79. [PMID: 27913881 PMCID: PMC5225176 DOI: 10.1007/s00280-016-3209-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 11/24/2016] [Indexed: 01/10/2023]
Abstract
Background The first one-arm phase II trial aimed to evaluate and predict efficacy and safety of S-1 plus oral leucovorin (S-1/LV) as first-line chemotherapy for patients with advanced gastric cancer (AGC), using S-1 pharmacogenetic pathway approach. Patients and methods A total of 39 patients orally took S-1 at conventional dose and LV simultaneously at a dose of 25 mg twice daily for a week, within a 2-week cycle. The primary endpoint was overall response rate (ORR), while the secondary endpoints were progression-free survival (PFS), time to failure (TTF), overall survival (OS), disease control rate (DCR), and adverse events (AEs). Peripheral blood was sampled prospectively for baseline expression of dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP), and thymidylate synthase (TS), CYP2A6 gene polymorphisms, and 5-FU pharmacokinetics. Results The ORR and DCR were 41.0 and 76.9%. The median PFS, TTF, and OS were 4.13, 3.70, and 11.40 months. Grade 3–4 AEs occurred in only 13 patients, and grade 4 AEs occurred in only 1 of them. High OPRT/TS and peritoneal metastasis (vs. liver metastasis) independently predicted responding. High OPRT/DPD independently predicted grade 3–4 AEs. High AUC0–24h of 5-FU and metastatic/recurrent sites ≤2 (vs. >3) independently predicted prolonged PFS. Low baseline plasmic DPD independently predicted prolonged OS. Conclusions Two-week, oral S-1/LV regimen demonstrated promising efficacy and safety as first-line chemotherapy for AGC. ClinicalTrials.gov identifier NCT02090153 Electronic supplementary material The online version of this article (doi:10.1007/s00280-016-3209-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ming-Ming He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China
| | - Dong-Sheng Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China
| | - Feng Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China
| | - Zi-Xian Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China
| | - Shu-Qiang Yuan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China
| | - Zhi-Qiang Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China
| | - Hui-Yan Luo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China
| | - Chao Ren
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China
| | - Miao-Zhen Qiu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China
| | - Ying Jin
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China
| | - De-Shen Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China
| | - Dong-Liang Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China
| | - Zhao-Lei Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China
| | - Yu-Hong Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China
| | - Yang-Yang He
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yuan-Tao Hao
- Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Pi Guo
- Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Feng-Hua Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China
| | - Yi-Xin Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.,Beijing Hospital, Beijing, China
| | - Rui-Hua Xu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
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Naka A, Takeda R, Shintani M, Ogane N, Kameda Y, Aoyama T, Yoshikawa T, Kamoshida S. Organic cation transporter 2 for predicting cisplatin-based neoadjuvant chemotherapy response in gastric cancer. Am J Cancer Res 2015; 5:2285-2293. [PMID: 26328259 PMCID: PMC4548340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 06/10/2015] [Indexed: 06/04/2023] Open
Abstract
Some studies have shown the usability of neoadjuvant chemotherapy (NAC) in gastric cancer (GC). Nevertheless there are a few predictive markers of the effectiveness of NAC in GC. The aim of this study is to assess the predictive impact of organic cation transporter 2 (OCT2) expression on response to neoadjuvant chemotherapy (NAC) in gastric cancer. We retrospectively assessed 66 patients with advanced gastric cancer received NAC with S-1/cisplatin or paclitaxel/cisplatin. Expression levels of OCT2 were assessed by immunohistochemistry in pre-chemotherapy biopsies and correlated with clinicopathologic parameters including pathologic response. High expression level of OCT2 (OCT2(high)) was significantly associated with intestinal type according to Laurén classification (P = 0.03) and low histologic grade (P = 0.03). In univariate analysis of the entire cohort, no variables showed any significant association with a response, although intestinal type (P = 0.09), low histologic grade (P = 0.09), and OCT2(high) (P = 0.07) tended to be more frequent in responders compared with non-responders. When the two treatment groups were separately assessed in the univariate analysis, a significantly higher rate of OCT2(high) was observed in responders compared with non-responders in the S-1/cisplatin group (P = 0.001). In addition, multivariate analysis identified OCT2(high) as the sole independent predictor of response (P = 0.04). However, in the paclitaxel/cisplatin group, no variables were associated with response. Taken together, our results suggest that OCT2(high) may represent a potential predictor of response to NAC with S-1/cisplatin in gastric cancer.
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Affiliation(s)
- Ayano Naka
- Department of Medical Biophysics, Laboratory of Pathology, Kobe University Graduate School of Health Sciences7-10-2 Tomogaoka, Suma, Kobe, Hyogo 654-0142, Japan
| | - Risa Takeda
- Department of Medical Biophysics, Laboratory of Pathology, Kobe University Graduate School of Health Sciences7-10-2 Tomogaoka, Suma, Kobe, Hyogo 654-0142, Japan
| | - Michiko Shintani
- Department of Medical Biophysics, Laboratory of Pathology, Kobe University Graduate School of Health Sciences7-10-2 Tomogaoka, Suma, Kobe, Hyogo 654-0142, Japan
| | - Naoki Ogane
- Department of Pathology, Kanagawa Prefectural Ashigarakami Hospital866-1 Matsudasoryo, Matsuda-cho, Ashigarakami-gun, Kanagawa 258-0003, Japan
| | - Yoichi Kameda
- Department of Pathology, Kanagawa Prefectural Ashigarakami Hospital866-1 Matsudasoryo, Matsuda-cho, Ashigarakami-gun, Kanagawa 258-0003, Japan
- Department of Pathology, Kanagawa Cancer Center Hospital1-1-2 Nakao, Asahi-ku 241-0815, Japan
| | - Toru Aoyama
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center Hospital1-1-2 Nakao, Asahi-ku, Yokohama 241-0815, Japan
| | - Takaki Yoshikawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center Hospital1-1-2 Nakao, Asahi-ku, Yokohama 241-0815, Japan
| | - Shingo Kamoshida
- Department of Medical Biophysics, Laboratory of Pathology, Kobe University Graduate School of Health Sciences7-10-2 Tomogaoka, Suma, Kobe, Hyogo 654-0142, Japan
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10
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Xu HY, Xu WL, Wang LQ, Chen MB, Shen HL. Relationship between p53 status and response to chemotherapy in patients with gastric cancer: a meta-analysis. PLoS One 2014; 9:e95371. [PMID: 24740294 PMCID: PMC3989310 DOI: 10.1371/journal.pone.0095371] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 03/25/2014] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Previous studies have yielded conflicting results regarding the relationship between p53 status and response to chemotherapy in patients with gastric cancer. We therefore performed a meta-analysis to expound the relationship between p53 status and response to chemotherapy. METHODS/FINDINGS Thirteen previously published eligible studies, including 564 cases, were identified and included in this meta-analysis. p53 positive status (high expression of p53 protein and/or a mutant p53 gene) was associated with improved response in gastric cancer patients who received chemotherapy (good response: risk ratio [RR] = 0.704; 95% confidence intervals [CI] = 0.550-0.903; P = 0.006). In further stratified analyses, association with a good response remained in the East Asian population (RR = 0.657; 95% CI = 0.488-0.884; P = 0.005), while in the European subgroup, patients with p53 positive status tended to have a good response to chemotherapy, although this did not reach statistical significance (RR = 0.828, 95% CI = 0.525-1.305; P = 0.417). As five studies used neoadjuvant chemotherapy (NCT) and one used neoadjuvant chemoradiotherapy (NCRT), we also analyzed these data, and found that p53 positive status was associated with a good response in gastric cancer patients who received chemotherapy-based neoadjuvant treatment (RR = 0.675, 95% CI = 0.463-0.985; P = 0.042). CONCLUSION This meta-analysis indicated that p53 status may be a useful predictive biomarker for response to chemotherapy in gastric cancer. Further prospective studies with larger sample sizes and better study designs are required to confirm our findings.
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Affiliation(s)
- Hai-Yuan Xu
- Department of Medical Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, People's Republic of China
| | - Wen-Lin Xu
- Department of Central Laboratory, Zhenjiang Fourth People's Hospital Affiliated to Jiangsu University, Zhenjiang, People's Republic of China
| | - Li-Qiang Wang
- Department of Medical Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, People's Republic of China
| | - Min-Bin Chen
- Department of Medical Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, People's Republic of China
| | - Hui-Ling Shen
- Department of Medical Oncology, Zhenjiang First People's Hospital Affiliated to Jiangsu University, Zhenjiang, People's Republic of China
- * E-mail:
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11
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Ku GY, Ilson DH. Multimodality therapy for the curative treatment of cancer of the esophagus and gastroesophageal junction. Expert Rev Anticancer Ther 2014; 8:1953-64. [DOI: 10.1586/14737140.8.12.1953] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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12
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A pilot study to investigate the role of thymidylate synthase as a marker of prognosis for neoadjuvant chemotherapy in gastric and gastro-oesophageal junction adenocarcinoma. Gastroenterol Res Pract 2013; 2013:502153. [PMID: 23533389 PMCID: PMC3603715 DOI: 10.1155/2013/502153] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2012] [Accepted: 01/25/2013] [Indexed: 01/02/2023] Open
Abstract
Aims and Background. Patients in the United Kingdom with operable gastric and gastro-oesophageal junction (GOJ) tumours receive neoadjuvant chemotherapy. Our aim was to study the expression of thymidylate synthase (TS) enzyme in pre-treatment diagnostic biopsy specimens and investigate its clinical usefulness. Methods. A single-centre study was carried out in 45 patients with gastric and GOJ adenocarcinoma treated with neo-adjuvant chemotherapy according to the MAGIC protocol. TS expression was determined using immunohistochemistry. >10% tumour nuclei expression of TS was used as cut-off for positivity. Results. Forty-one (91%) of the 45 tumours expressed TS. There was no association between TS expression and lymph node status (P = 0.80), histological response (P = 0.30), and recurrence (P = 0.55). On univariate analysis, only N-stage (P = 0.02) and vascular invasion (P = 0.04) were associated with a poor prognosis. Patients with negative tumour TS expression had better outcome than those with positive expression. The overall 5-year survival rate was 100% in the TS negative versus 56% in TS positive group, but the difference was not statistically significant (P = 0.17). Conclusion. TS expression should be studied in a larger series of gastro-oesophageal cancers as a potential prognostic marker of prognosis to neo-adjuvant chemotherapy.
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13
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Li B, Wang L, Chi B. Upregulation of periostin prevents P53-mediated apoptosis in SGC-7901 gastric cancer cells. Mol Biol Rep 2012; 40:1677-83. [PMID: 23076534 DOI: 10.1007/s11033-012-2218-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Accepted: 10/09/2012] [Indexed: 12/11/2022]
Abstract
Periostin is frequently upregulated in human cancers including gastric cancer and implicated in cancer cell proliferation, invasion, and epithelial-mesenchymal transition. This study was undertaken to investigate the effects of periostin overexpression on the chemosensitivity of gastric cancer cells. We constructed a stable cell line overexpressing periostin in SGC-7901 human gastric cancer cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed that periostin had no influence on the proliferation of SGC-7901 cells. Compared to empty vector-transfected cells, overexpression of periostin rendered SGC-7901 cells more resistant to cisplatin or 5-fluorouracil (5-FU)-induced apoptosis, accompanying with less release of cytochrome c from mitochondria and diminished cleavage of caspase-3 and poly (ADP-ribose) polymerase. Periostin-overexpressing cells treated with cisplatin or 5-FU showed significantly (p < 0.05) decreased expression of Bax and p53 proteins and increased expression of Bcl-2 protein, when compared to drug-treated mock counterparts. Restoration of p53 expression by delivering wild-type p53 gene resulted in a marked increase in drug-induced apoptosis in periostin-overexpressing SGC-7901 cells. Periostin overexpression elevated the phosphorylation of Akt. Pretreatment of periostin-overexpressing cells with an Akt inhibitor, MK-2206, partially rescued periostin-mediated inhibition of p53 expression and drug resistance. Taken together, our data indicate that periostin confers protection against cisplatin or 5-FU-induced apoptosis in SGC-7901 cells, likely through modulating the Akt/p53 pathway, and thus represents a potential therapeutic target in gastric cancer.
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Affiliation(s)
- Bin Li
- Department of Gastroenterology, The First Affiliated Hospital, Jilin University, Jilin, 1300112, China
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14
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Naito S, Eto M, Shinohara N, Tomita Y, Fujisawa M, Namiki M, Nishikido M, Usami M, Tsukamoto T, Akaza H. Multicenter Phase II Trial of S-1 in Patients With Cytokine-Refractory Metastatic Renal Cell Carcinoma. J Clin Oncol 2010; 28:5022-9. [DOI: 10.1200/jco.2010.29.1203] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose This phase II multicenter trial was conducted to evaluate the activity and safety of S-1 in Japanese patients with metastatic renal cell carcinoma (mRCC). We also examined the relation between response and mRNA expression levels of enzymes involved in the metabolism of fluorouracil (FU). Methods Patients with mRCC who had received nephrectomy in whom cytokine-based immunotherapy was ineffective or contraindicated were studied. S-1 was administered orally at 80-, 100-, or 120-mg daily, assigned according to body surface area, on days 1 to 28 of a 42-day cycle. The primary end point was the objective response rate. The mRNA expression levels of FU-related enzymes were measured by reverse-transcriptase polymerase chain reaction in formalin-fixed, paraffin-embedded specimens of tumors obtained at nephrectomy. Results A total of 45 eligible patients were enrolled. Eleven (24.4%) of 45 patients had partial responses to S-1, and 28 (62.2%) had stable disease. Median progression-free survival was 9.2 months. The severity of most adverse events was mild to moderate. The most common grade 3/4 drug-related adverse events were neutropenia (8.9%) and anorexia (8.9%). The expression level of thymidylate synthase (TS) mRNA was significantly lower in patients who responded to treatment (t-test, P = .048), and progression-free survival was significantly longer in patients whose TS mRNA expression levels were below the median value, as compared with those with higher levels (log-rank test, P = .006). Conclusion S-1 is active against cytokine-refractory mRCC. Quantification of TS mRNA levels in tumors before treatment may facilitate prediction of the response of mRCC to S-1.
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Affiliation(s)
- Seiji Naito
- From Graduate School of Medical Sciences, Kyushu University, Fukuoka; Hokkaido University Graduate School of Medicine, Sapporo; Yamagata University Faculty of Medicine, Yamagata; Kobe University Graduate School of Medicine, Kobe; Kanazawa University Hospital, Kanazawa; Nagasaki University School of Medicine, Nagasaki; Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; Sapporo Medical University School of Medicine, Sapporo; and Graduate School of Comprehensive Human Science, University of
| | - Masatoshi Eto
- From Graduate School of Medical Sciences, Kyushu University, Fukuoka; Hokkaido University Graduate School of Medicine, Sapporo; Yamagata University Faculty of Medicine, Yamagata; Kobe University Graduate School of Medicine, Kobe; Kanazawa University Hospital, Kanazawa; Nagasaki University School of Medicine, Nagasaki; Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; Sapporo Medical University School of Medicine, Sapporo; and Graduate School of Comprehensive Human Science, University of
| | - Nobuo Shinohara
- From Graduate School of Medical Sciences, Kyushu University, Fukuoka; Hokkaido University Graduate School of Medicine, Sapporo; Yamagata University Faculty of Medicine, Yamagata; Kobe University Graduate School of Medicine, Kobe; Kanazawa University Hospital, Kanazawa; Nagasaki University School of Medicine, Nagasaki; Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; Sapporo Medical University School of Medicine, Sapporo; and Graduate School of Comprehensive Human Science, University of
| | - Yoshihiko Tomita
- From Graduate School of Medical Sciences, Kyushu University, Fukuoka; Hokkaido University Graduate School of Medicine, Sapporo; Yamagata University Faculty of Medicine, Yamagata; Kobe University Graduate School of Medicine, Kobe; Kanazawa University Hospital, Kanazawa; Nagasaki University School of Medicine, Nagasaki; Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; Sapporo Medical University School of Medicine, Sapporo; and Graduate School of Comprehensive Human Science, University of
| | - Masato Fujisawa
- From Graduate School of Medical Sciences, Kyushu University, Fukuoka; Hokkaido University Graduate School of Medicine, Sapporo; Yamagata University Faculty of Medicine, Yamagata; Kobe University Graduate School of Medicine, Kobe; Kanazawa University Hospital, Kanazawa; Nagasaki University School of Medicine, Nagasaki; Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; Sapporo Medical University School of Medicine, Sapporo; and Graduate School of Comprehensive Human Science, University of
| | - Mikio Namiki
- From Graduate School of Medical Sciences, Kyushu University, Fukuoka; Hokkaido University Graduate School of Medicine, Sapporo; Yamagata University Faculty of Medicine, Yamagata; Kobe University Graduate School of Medicine, Kobe; Kanazawa University Hospital, Kanazawa; Nagasaki University School of Medicine, Nagasaki; Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; Sapporo Medical University School of Medicine, Sapporo; and Graduate School of Comprehensive Human Science, University of
| | - Masaharu Nishikido
- From Graduate School of Medical Sciences, Kyushu University, Fukuoka; Hokkaido University Graduate School of Medicine, Sapporo; Yamagata University Faculty of Medicine, Yamagata; Kobe University Graduate School of Medicine, Kobe; Kanazawa University Hospital, Kanazawa; Nagasaki University School of Medicine, Nagasaki; Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; Sapporo Medical University School of Medicine, Sapporo; and Graduate School of Comprehensive Human Science, University of
| | - Michiyuki Usami
- From Graduate School of Medical Sciences, Kyushu University, Fukuoka; Hokkaido University Graduate School of Medicine, Sapporo; Yamagata University Faculty of Medicine, Yamagata; Kobe University Graduate School of Medicine, Kobe; Kanazawa University Hospital, Kanazawa; Nagasaki University School of Medicine, Nagasaki; Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; Sapporo Medical University School of Medicine, Sapporo; and Graduate School of Comprehensive Human Science, University of
| | - Taiji Tsukamoto
- From Graduate School of Medical Sciences, Kyushu University, Fukuoka; Hokkaido University Graduate School of Medicine, Sapporo; Yamagata University Faculty of Medicine, Yamagata; Kobe University Graduate School of Medicine, Kobe; Kanazawa University Hospital, Kanazawa; Nagasaki University School of Medicine, Nagasaki; Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; Sapporo Medical University School of Medicine, Sapporo; and Graduate School of Comprehensive Human Science, University of
| | - Hideyuki Akaza
- From Graduate School of Medical Sciences, Kyushu University, Fukuoka; Hokkaido University Graduate School of Medicine, Sapporo; Yamagata University Faculty of Medicine, Yamagata; Kobe University Graduate School of Medicine, Kobe; Kanazawa University Hospital, Kanazawa; Nagasaki University School of Medicine, Nagasaki; Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; Sapporo Medical University School of Medicine, Sapporo; and Graduate School of Comprehensive Human Science, University of
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15
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Zhang J, He XH, Xie XY, Hu X, He C. The potential for serum p53 to predict the response to chemotherapy of patients with gastric cancer. J Int Med Res 2010; 38:423-31. [PMID: 20515556 DOI: 10.1177/147323001003800205] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
This study was designed to investigate the relationship between serum p53, tissue p53 and tissue permeability glycoprotein (P-gp) levels in gastric cancer. Serum levels of p53 were detected by enzyme-linked immunosorbent assay, and tissue p53 and P-gp levels were analysed by immunohistochemistry. In total, 63.0% of gastric cancer tissue samples tested positive for P-gp and 58.7% of samples tested positive for p53. Tissue P-gp immunoreactivity was significantly correlated with tissue p53 immunoreactivity, and both tissue p53 and P-gp immunoreactivity were significantly correlated to the degree of cancer cell differentiation. The percentage of gastric cancer patients with serum positive for p53 was 36.2%, which was significantly higher than the rate in non-cancerous gastric disease patients. Serum p53 was significantly correlated to tissue p53 and tissue P-gp, inferring that the presence of p53 in the serum could indicate the status of tissue p53 and P-gp. This could, therefore, be useful for screening for the most appropriate (lowest toxicity and highest effectiveness) drugs to use ahead of (neo)-adjuvant chemotherapy.
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Affiliation(s)
- J Zhang
- Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China
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16
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Fareed KR, Al-Attar A, Soomro IN, Kaye PV, Patel J, Lobo DN, Parsons SL, Madhusudan S. Tumour regression and ERCC1 nuclear protein expression predict clinical outcome in patients with gastro-oesophageal cancer treated with neoadjuvant chemotherapy. Br J Cancer 2010; 102:1600-7. [PMID: 20461087 PMCID: PMC2883154 DOI: 10.1038/sj.bjc.6605686] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Aims: Neoadjuvant chemotherapy followed by surgery is the standard of care for patients with gastro-oesophageal adenocarcinoma. Previously, we validated the utility of the tumour regression grade (TRG) as a histopathological marker of tumour downstaging in patients receiving platinum-based neoadjuvant chemotherapy. In this study we profiled key DNA repair and damage signalling factors and correlated them with clinicopathological outcomes, including TRG response. Methods and results: Formalin-fixed human gastro-oesophageal cancers were constructed into tissue microarrays (TMAs). The first set consisted of 142 gastric/gastro-oesophageal cancer cases not exposed to neoadjuvant chemotherapy and the second set consisted of 103 gastric/gastro-oesophageal cancer cases exposed to preoperative platinum-based chemotherapy. Expressions of ERCC1, XPF, FANCD2, APE1 and p53 were investigated using immunohistochemistry. In patients who received neoadjuvant chemotherapy, favourable TRG response (TRG 1, 2 or 3) was associated with improvement in disease-specific survival (P=0.038). ERCC1 nuclear expression correlated with lack of histopathological response (TRG 4 or 5) to neoadjuvant chemotherapy (P=0.006) and was associated with poor disease-specific (P=0.020) and overall survival (P=0.040). Conclusions: We provide evidence that tumour regression and ERCC1 nuclear protein expression evaluated by immunohistochemistry are promising predictive markers in gastro-oesophageal cancer patients receiving neoadjuvant platinum-based chemotherapy.
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Affiliation(s)
- K R Fareed
- Laboratory of Molecular Oncology, Academic Unit of Oncology, School of Molecular Medical Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
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17
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Li Y, Li X, Dai H, Sun X, Li J, Yang F, Gu H, Yang Y, Jin Z, Chu Y, Jin X, Kakehi Y, Wu X. Thymidylate synthase was associated with patient prognosis and the response to adjuvant therapy in bladder cancer. BJU Int 2008; 103:547-52. [PMID: 18990150 DOI: 10.1111/j.1464-410x.2008.08099.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To investigate the expression of thymidylate synthase (TS), a key enzyme in DNA synthesis that is over-expressed in several cancer cells, in bladder cancer and its association with patient prognosis and the response to adjuvant therapy. PATIENTS AND METHODS In all, 67 bladder tissue specimens were obtained from patients who had undergone transurethral resection (TUR). TS expression in bladder cancer and normal bladder tissue was analysed by immunohistochemistry. RESULTS Of the 67 bladder tissue specimens, 47 (70%) and 10 (15%) had positive expression for TS in cancer and normal tissues, respectively. TS expression was greater in patients with Grade 3 (16/17, 94%) than in Grade 1 and 2 (31/50, 64%; P = 0.002). It was also greater in Stage T1 (14/14) than in Stage Ta (33/53, 62%; P = 0.001). Furthermore, patients with negative TS expression had a longer postoperative recurrence-free survival (RFS) than those with positive expression during the 5 year follow-up (P = 0.028). In the patients with positive TS-expressing tumours, adjuvant therapy significantly improved RFS (P < 0.001). CONCLUSIONS High TS expression might be a marker of poor prognosis for patients with bladder cancer. In addition, patients with high TS expression might also be benefit from adjuvant therapy.
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Affiliation(s)
- Yongnan Li
- Department of Preventive Medicine, Mudanjiang Medical College, Mudanjiang, China.
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18
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Sakurai Y, Kamoshida S, Furuta S, Sunagawa R, Inaba K, Isogaki J, Komori Y, Uyama I, Tsutsumi Y. Levels and expressions of orotate phosphoribosyltransferase in gastric carcinoma and normal gastric mucosa tissues. Gastric Cancer 2008; 10:234-40. [PMID: 18095079 DOI: 10.1007/s10120-007-0440-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2007] [Accepted: 10/17/2007] [Indexed: 02/07/2023]
Abstract
BACKGROUND Orotate phosphoribosyltransferase (OPRT; EC 2.4.2.10), a key enzyme that catalyzes one of the primary steps in the phosphorylation of fluoropyrimidine, was recently recognized as an important enzyme that determines the anticancer effects of the dihydropyrimidine dehydrogenase-inhibitory fluoropyrimidine, S-1. METHODS Levels of OPRT were examined in 97 gastric carcinoma tissues and 65 normal gastric mucosa tissues obtained from patients with gastric carcinoma. The relation between OPRT levels and clinicopathological variables was evaluated, and correlations of OPRT with thymidylate synthase and dihydropyrimidine dehydrogenase levels in gastric carcinoma tissues were evaluated. RESULTS Although OPRT levels were high in well-differentiated and localized carcinomas, they were not correlated with other clinicopathological variables or with the pathological stage of gastric carcinoma. Levels of OPRT were significantly higher in gastric carcinoma tissue than in normal gastric mucosa. OPRT levels were not correlated with levels of either thymidylate synthase or dihydropyrimidine dehydrogenase. In samples of gastric carcinoma tissues and normal gastric mucosa tissues obtained simultaneously from 24 patients, no correlation was found between OPRT levels in gastric carcinoma and levels in normal gastric mucosa. CONCLUSION These results suggest that the OPRT level is significantly higher in gastric carcinoma tissue than in normal gastric mucosa and that the OPRT level in gastric carcinoma is a novel variable that is independent of the levels of other previously known enzymes related to 5-fluorouracil (FU) metabolism.
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Affiliation(s)
- Yoichi Sakurai
- Department of Surgery, Fujita Health University School of Medicine, 1-98 Dengakugakubo Kutsukake-cho, Toyoake, 470-1192, Japan
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Jakob C, Liersch T, Meyer W, Becker H, Baretton GB, Aust DE. Predictive value of Ki67 and p53 in locally advanced rectal cancer: Correlation with thymidylate synthase and histopathological tumor regression after neoadjuvant 5-FU-based chemoradiotherapy. World J Gastroenterol 2008; 14:1060-6. [PMID: 18286688 PMCID: PMC2689409 DOI: 10.3748/wjg.14.1060] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the predictive value of Ki67 and p53 and their correlation with thymidylate synthase (TS) gene expression in a rectal cancer patient cohort treated according to a standardized recommended neoadjuvant treatment regimen.
METHODS: Formalin fixed, paraffin embedded pre-therapeutical tumor biopsies (n = 22) and post-therapeutical resection specimens (n = 40) from patients with rectal adenocarcinoma (clinical UICC stage II/III) receiving standardized neoadjuvant 5-fluorouracil (5-FU) based chemoradiotherapy were studied for Ki67 and p53 expression by immunohistochemistry and correlated with TS mRNA expression by quantitative TaqMan real-time PCR after laser microdissection. The results were compared with histopathological tumor regression according to a standardized semiquantitative score grading system.
RESULTS: Responders (patients with high tumor regression) showed a significantly lower Ki67 expression than non-responders in the pre-therapeutical tumor biopsies (81.2% vs 16.7%; P < 0.05) as well as in the post-therapeutical resection specimens (75.8% vs 14.3%; P < 0.01). High TS mRNA expression was significantly correlated with a high Ki67 index and low TS mRNA expression was significantly correlated with a low Ki67 index in the pre-therapeutical tumor biopsies (corr. coef. = 0.46; P < 0.01) as well as in the post-therapeutical resection specimens (corr. coef. = 0.40; P < 0.05). No significant association was found between p53 and TS mRNA expression or tumor regression.
CONCLUSION: Ki67 has, like TS, predictive value in rectal cancer patients after neoadjuvant 5-FU based chemoradiotherapy. The close correlation between Ki67 and TS indicates that TS is involved in active cell cycle processes.
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Zhang D, Fan D. Multidrug resistance in gastric cancer: recent research advances and ongoing therapeutic challenges. Expert Rev Anticancer Ther 2007; 7:1369-78. [PMID: 17944563 DOI: 10.1586/14737140.7.10.1369] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Gastric cancer is the second leading cause of cancer mortality worldwide. The major cause of treatment failure for gastric cancer is the development of multidrug resistance (MDR) to chemotherapy, which is currently one of the primary treatment options. Recently, research into the MDR of gastric cancer has revealed that, in addition to the classical ATP-binding cassette transporters, such as P-glycoprotein (P-gp) and MDR-associated protein (MRP)1, a number of other molecules might mediate the drug resistance of human gastric cancer. The absence of P-gp and MRP1 expression in some gastric cancer cases also indicates that there might be other mechanisms responsible for human gastric cancer MDR. These molecules belong to different functional families and might work together to confer MDR phenotypes. The new findings may provide new clues to the mechanisms of MDR and enable the selection of new candidates for targeting MDR in human gastric cancer.
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Affiliation(s)
- Dexin Zhang
- Institute of Digestive Disease & State Key Laboratory of Cancer Biology, Xjing Hospital, The Fourth Military Medical University, 15 West Chang-Le Road, Xi'an, Shaanxi 710032, PR China.
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