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Gu Y, Sun M, Fang H, Shao F, Lin C, Liu H, Li H, He H, Li R, Wang J, Zhang H, Xu J. Impact of clonal TP53 mutations with loss of heterozygosity on adjuvant chemotherapy and immunotherapy in gastric cancer. Br J Cancer 2024; 131:1320-1327. [PMID: 39217196 PMCID: PMC11473753 DOI: 10.1038/s41416-024-02825-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 08/08/2024] [Accepted: 08/12/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND This study aimed to reveal the effect of TP53 status on clinical outcomes and underlying mechanism in gastric cancer (GC) patients. METHODS TP53 status was divided into three groups according to genome sequencing, namely clonal mutations with LOH (C-LOH), clonal diploid or subclonal mutations (CD-SC), and wild type (WT). The p53 protein activity was divided into over-expression (OE), Null and WT according to immunohistochemical staining. Four cohorts, including the TCGA, SMC, ZSHS and FUSCC cohort, were analyzed for association between TP53 mutation status and clinical outcomes and the underlying mechanism. RESULTS In TCGA cohort, TP53 CD-SC were associated with superior overall survival compared to TP53 C-LOH cases. GC patients could benefit from ACT only in TP53 CD-SC/ p53 OE and TP53/ p53 WT subgroups, and TP53 C-LOH subgroup demonstrated the worst response to pembrolizumab among three subgroups. Genomic and immunophenotypic deconvolution revealed that TP53 C-LOH, CD-SC and WT differed for genomic and immune-related features. CONCLUSIONS TP53 C-LOH GCs with genomic instability and immune evasion phenotype have poor clinical outcomes in patients treated with ACT or immunotherapy.
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Affiliation(s)
- Yun Gu
- Department of General Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Mengyao Sun
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Hanji Fang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Fei Shao
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chao Lin
- Department of Emergency Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hao Liu
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - He Li
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hongyong He
- Department of Emergency Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ruochen Li
- Department of Emergency Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jieti Wang
- Department of Endoscopy, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Heng Zhang
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jiejie Xu
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
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Rahmé R, Braun T, Manfredi JJ, Fenaux P. TP53 Alterations in Myelodysplastic Syndromes and Acute Myeloid Leukemia. Biomedicines 2023; 11:biomedicines11041152. [PMID: 37189770 DOI: 10.3390/biomedicines11041152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 03/30/2023] [Accepted: 04/06/2023] [Indexed: 05/17/2023] Open
Abstract
TP53 mutations are less frequent in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) than in solid tumors, except in secondary and therapy-related MDS/AMLs, and in cases with complex monosomal karyotype. As in solid tumors, missense mutations predominate, with the same hotspot mutated codons (particularly codons 175, 248, 273). As TP53-mutated MDS/AMLs are generally associated with complex chromosomal abnormalities, it is not always clear when TP53 mutations occur in the pathophysiological process. It is also uncertain in these MDS/AML cases, which often have inactivation of both TP53 alleles, if the missense mutation is only deleterious through the absence of a functional p53 protein, or through a potential dominant-negative effect, or finally a gain-of-function effect of mutant p53, as demonstrated in some solid tumors. Understanding when TP53 mutations occur in the disease course and how they are deleterious would help to design new treatments for those patients who generally show poor response to all therapeutic approaches.
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Affiliation(s)
- Ramy Rahmé
- Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Institut de Recherche Saint Louis (IRSL), INSERM U1131, Université Paris Cité, 75010 Paris, France
- Ecole Doctorale Hématologie-Oncogenèse-Biothérapies, Université Paris Cité, 75010 Paris, France
- Clinical Hematology Department, Avicenne Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Sorbonne Paris Nord, 93000 Bobigny, France
| | - Thorsten Braun
- Clinical Hematology Department, Avicenne Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Sorbonne Paris Nord, 93000 Bobigny, France
| | - James J Manfredi
- Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Pierre Fenaux
- Senior Hematology Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Cité, 75010 Paris, France
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Knockdown of RBBP6 enhances radiosensitivity of gastric cancer cells through p53 pathway. Mol Cell Toxicol 2022. [DOI: 10.1007/s13273-022-00233-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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TP53 in Acute Myeloid Leukemia: Molecular Aspects and Patterns of Mutation. Int J Mol Sci 2021; 22:ijms221910782. [PMID: 34639121 PMCID: PMC8509740 DOI: 10.3390/ijms221910782] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 09/28/2021] [Accepted: 09/29/2021] [Indexed: 01/10/2023] Open
Abstract
Mutation of the tumor suppressor gene, TP53, is associated with abysmal survival outcomes in acute myeloid leukemia (AML). Although it is the most commonly mutated gene in cancer, its occurrence is observed in only 5–10% of de novo AML, and in 30% of therapy related AML (t-AML). TP53 mutation serves as a prognostic marker of poor response to standard-of-care chemotherapy, particularly in t-AML and AML with complex cytogenetics. In light of a poor response to traditional chemotherapy and only a modest improvement in outcome with hypomethylation-based interventions, allogenic stem cell transplant is routinely recommended in these cases, albeit with a response that is often short lived. Despite being frequently mutated across the cancer spectrum, progress and enthusiasm for the development of p53 targeted therapeutic interventions is lacking and to date there is no approved drug that mitigates the effects of TP53 mutation. There is a mounting body of evidence indicating that p53 mutants differ in functionality and form from typical AML cases and subsequently display inconsistent responses to therapy at the cellular level. Understanding this pathobiological activity is imperative to the development of effective therapeutic strategies. This review aims to provide a comprehensive understanding of the effects of TP53 on the hematopoietic system, to describe its varying degree of functionality in tumor suppression, and to illustrate the need for the adoption of personalized therapeutic strategies to target distinct classes of the p53 mutation in AML management.
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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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Cumbo C, Tota G, Anelli L, Zagaria A, Specchia G, Albano F. TP53 in Myelodysplastic Syndromes: Recent Biological and Clinical Findings. Int J Mol Sci 2020; 21:E3432. [PMID: 32414002 PMCID: PMC7279310 DOI: 10.3390/ijms21103432] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 05/09/2020] [Accepted: 05/11/2020] [Indexed: 12/15/2022] Open
Abstract
TP53 dysregulation plays a pivotal role in the molecular pathogenesis of myelodysplastic syndromes (MDS), identifying a subgroup of patients with peculiar features. In this review we report the recent biological and clinical findings of TP53-mutated MDS, focusing on the molecular pathways activation and on its impact on the cellular physiology. In MDS, TP53 mutational status is deeply associated with del(5q) syndrome and its dysregulation impacts on cell cycle, DNA repair and apoptosis inducing chromosomal instability and the clonal evolution of disease. TP53 defects influence adversely the MDS clinical outcome and the treatment response rate, thus new therapeutic approaches are being developed for these patients. TP53 allelic state characterization and the mutational burden evaluation can therefore predict prognosis and identify the subgroup of patients eligible for targeted therapy. For these reasons, in the era of precision medicine, the MDS diagnostic workup cannot do without the complete assessment of TP53 mutational profile.
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Affiliation(s)
| | | | | | | | | | - Francesco Albano
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, 70124 Bari, Italy; (C.C.); (G.T.); (L.A.); (A.Z.); (G.S.)
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Pitolli C, Wang Y, Mancini M, Shi Y, Melino G, Amelio I. Do Mutations Turn p53 into an Oncogene? Int J Mol Sci 2019; 20:E6241. [PMID: 31835684 PMCID: PMC6940991 DOI: 10.3390/ijms20246241] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 11/26/2019] [Accepted: 12/05/2019] [Indexed: 02/06/2023] Open
Abstract
The key role of p53 as a tumor suppressor became clear when it was realized that this gene is mutated in 50% of human sporadic cancers, and germline mutations expose carriers to cancer risk throughout their lifespan. Mutations in this gene not only abolish the tumor suppressive functions of p53, but also equip the protein with new pro-oncogenic functions. Here, we review the mechanisms by which these new functions gained by p53 mutants promote tumorigenesis.
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Affiliation(s)
- Consuelo Pitolli
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (C.P.); (M.M.); (G.M.)
- MRC Toxicology Unit, University of Cambridge, Pathology Building, Tennis Court Road, Cambridge CB2 1PQ, UK
| | - Ying Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 100012, China; (Y.W.); (Y.S.)
| | - Mara Mancini
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (C.P.); (M.M.); (G.M.)
- IDI-IRCCS, Biochemistry Laboratory, 00167 Rome, Italy
| | - Yufang Shi
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 100012, China; (Y.W.); (Y.S.)
- Institutes for Translational Medicine, Soochow University, Suzhou 215006, China
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (C.P.); (M.M.); (G.M.)
- MRC Toxicology Unit, University of Cambridge, Pathology Building, Tennis Court Road, Cambridge CB2 1PQ, UK
| | - Ivano Amelio
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (C.P.); (M.M.); (G.M.)
- MRC Toxicology Unit, University of Cambridge, Pathology Building, Tennis Court Road, Cambridge CB2 1PQ, UK
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10
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Hunter AM, Sallman DA. Current status and new treatment approaches in TP53 mutated AML. Best Pract Res Clin Haematol 2019; 32:134-144. [PMID: 31203995 DOI: 10.1016/j.beha.2019.05.004] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 05/08/2019] [Indexed: 12/16/2022]
Abstract
Mutations in the essential tumor suppressor gene, TP53, are observed in only 5-10% of acute myeloid leukemia (AML) cases, but are highly associated with therapy-related AML and cases with complex karyotype. The mutational status of TP53 is a critical prognostic indicator, with dismal outcomes consistently observed across studies. Response rates to traditional cytotoxic chemotherapy are poor and long-term survival after allogeneic hematopoietic stem cell transplant is rare. Therapy with hypomethylating agents has resulted in a modest improvement in outcomes over intensive chemotherapy, but durable responses are seldom observed. In view of the intrinsic resistance to standard chemotherapies conferred by mutations in TP53, novel treatment approaches are required. In this review, we examine the current treatment landscape in TP53 mutated AML and discuss emerging therapeutic approaches currently under clinical investigation.
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Affiliation(s)
- Anthony M Hunter
- Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; University of South Florida, Morsani College of Medicine, Tampa, FL, USA
| | - David A Sallman
- Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
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11
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Man Z, Chen T, Zhu Z, Zhang H, Ao L, Xi L, Zhou J, Tang Z. High expression of TRIM36 is associated with radiosensitivity in gastric cancer. Oncol Lett 2019; 17:4401-4408. [PMID: 30944633 PMCID: PMC6444413 DOI: 10.3892/ol.2019.10122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 02/11/2019] [Indexed: 12/20/2022] Open
Abstract
Radiotherapy is one of the main adjuvant treatments for gastric cancer (GC) that can effectively reduce local recurrence and improve survival rates. However, radiotherapy may result in cytotoxicity and not benefit all patients. This highlights the requirement for identifying potential radiosensitivity genes in GC. The current study investigated the association between tripartite motif containing 36 (TRIM36) status and the prognosis of patients with GC receiving radiotherapy. A total of 371 patients with GC were selected from The Cancer Genome Atlas and randomly divided into test and the validation groups. The results revealed that TRIM36 expression was not associated with the overall survival (OS) rate. Patients who received radiotherapy with high TRIM36 expression had an improved OS rate compared with patients who did not receive radiotherapy in the test group, as demonstrated by univariate analysis [hazard ratio (HR), 0.062; 95% confidence interval (CI), 0.008–0.462; P=0.007] and multivariate analysis (HR, 0.095; 95% CI, 0.012–0.748; P=0.025). In the validation group, patients with high TRIM36 expression had decreased mortality risk when they received radiotherapy compared with patients who did not receive radiotherapy, as determined by univariate analysis (HR, 0.190; 95% CI, 0.067–0.540; P=0.002) and multivariate analysis (HR, 0.075; 95% CI, 0.020–0.276; P<0.001). However, for patients with low expression, no significant difference was identified in the overall survival rates between the radiotherapy and non-radiotherapy groups. Chi-squared analysis revealed that the expression status of TRIM36 was an independent factor and was not associated with clinicopathological factors. The results indicated that patients with high TRIM36 expression receiving radiotherapy exhibited an improved OS rate. TRIM36 may therefore be an important factor affecting the clinical prognosis of patients with GC receiving radiotherapy and may be considered as a potential radiosensitivity gene signature.
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Affiliation(s)
- Zhongsong Man
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Tao Chen
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Zhongwei Zhu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Haitao Zhang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Lei Ao
- Department of Biostatistics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Liting Xi
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Jin Zhou
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Zaixiang Tang
- Department of Biostatistics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
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Zhou X, Hao Q, Lu H. Mutant p53 in cancer therapy-the barrier or the path. J Mol Cell Biol 2019; 11:293-305. [PMID: 30508182 PMCID: PMC6487791 DOI: 10.1093/jmcb/mjy072] [Citation(s) in RCA: 163] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 11/14/2018] [Accepted: 11/14/2018] [Indexed: 12/11/2022] Open
Abstract
Since wild-type p53 is central for maintaining genomic stability and preventing oncogenesis, its coding gene TP53 is highly mutated in ~50% of human cancers, and its activity is almost abrogated in the rest of cancers. Approximately 80% of p53 mutations are single point mutations with several hotspot mutations. Besides loss of function and dominant-negative effect on the wild-type p53 activity, the hotspot p53 mutants also acquire new oncogenic functions, so-called 'gain-of-functions' (GOF). Because the GOF of mutant p53 is highly associated with late-stage malignance and drug resistance, these p53 mutants have become hot targets for developing novel cancer therapies. In this essay, we review some recent progresses in better understanding of the role of mutant p53 GOF in chemoresistance and the underlying mechanisms, and discuss the pros and cons of targeting mutant p53 for the development of anti-cancer therapies.
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Affiliation(s)
- Xiang Zhou
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, and Key Laboratory of Medical Epigenetics and Metabolism, Fudan University, Shanghai, China
| | - Qian Hao
- Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Hua Lu
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA
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Jin X, Jiang R, Xiang Y, Fan Z, Wu Z, Yang B, Yang L, Wei S, Yang Y. Overexpression of retinoblastoma‑binding protein 4 contributes to the radiosensitivity of AGS gastric cancer cells via phosphoinositide3‑kinase/protein kinase B pathway suppression. Mol Med Rep 2018; 18:1571-1581. [PMID: 29901205 PMCID: PMC6072197 DOI: 10.3892/mmr.2018.9153] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 05/04/2018] [Indexed: 12/16/2022] Open
Abstract
In the present study, the effects and underlying mechanism of RbAp48 on the radiosensitivity of AGS gastric cancer cells was investigated. Cell proliferation was determined with an MTT assay. Flow cytometry was performed to evaluate the cell cycle and apoptosis. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to detect mRNA and protein expression, respectively, including RbAp48, phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt). The results revealed that radiation enhanced the expression level of RbAp48 in AGS cells, and that RbAp48 combined with radiation reduced AGS cell proliferation. In addition, RbAp48 combined with radiation resulted in G2 phase arrest and induced apoptosis via regulation of the PI3K/Akt pathway. In conclusion, it was demonstrated that overexpression of RbAp48 enhanced the radiosensitivity of AGS gastric cancer cells via suppression of PI3K/Akt pathway activity, suggesting that RbAp48 may hold potential as a gene therapeutic strategy in the future, aiding in the treatment of gastric cancer.
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Affiliation(s)
- Xiaoxi Jin
- Laboratory Department, Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. China
| | - Rui Jiang
- Department of Hematology, Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. China
| | - Yongsheng Xiang
- Department of Hematology, Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. China
| | - Zhen Fan
- Department of Hematology, Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. China
| | - Zhiwei Wu
- Department of Hematology, Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. China
| | - Bo Yang
- Department of Hematology, Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. China
| | - Lujun Yang
- Department of Hematology, Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. China
| | - Shanshan Wei
- Department of Hematology, Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. China
| | - Yan Yang
- Laboratory Department, Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. China
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Spoerl S, Novotny A, Al-Batran SE, Lordick F, Thuss-Patience P, Pauligk C, Haller B, Feith M, Lorenzen S. Histopathological regression predicts treatment outcome in locally advanced esophagogastric adenocarcinoma. Eur J Cancer 2018; 90:26-33. [DOI: 10.1016/j.ejca.2017.11.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 11/10/2017] [Accepted: 11/19/2017] [Indexed: 02/08/2023]
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Historical and Clinical Experiences of Gene Therapy for Solid Cancers in China. Genes (Basel) 2017; 8:genes8030085. [PMID: 28245595 PMCID: PMC5368689 DOI: 10.3390/genes8030085] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 01/19/2017] [Indexed: 02/05/2023] Open
Abstract
Based on the theoretical and clinical development of modern medicines, gene therapy has been a promising treatment strategy for cancer and other diseases. The practice of gene therapy is nearly 27 years old, since the first authorized gene transfer study took place at the National Institute of Health in 1989. However, gene therapy was not readily adopted worldwide, until recently. Several gene therapy clinical trials have been carried out in China since 1998, and medical research in China has flourished. In this report, we review the history of gene therapy in China, focusing on treatment protocol, the administration cycle, dosage calculation, and the evaluation of therapeutic effects, in order to provide more information for the additional development of this promising treatment strategy.
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Du J, Wang Y, Chen D, Ji G, Ma Q, Liao S, Zheng Y, Zhang J, Hou Y. BAY61-3606 potentiates the anti-tumor effects of TRAIL against colon cancer through up-regulating DR4 and down-regulating NF-κB. Cancer Lett 2016; 383:145-153. [DOI: 10.1016/j.canlet.2016.10.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 09/28/2016] [Accepted: 10/02/2016] [Indexed: 02/02/2023]
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Pirollo KF, Nemunaitis J, Leung PK, Nunan R, Adams J, Chang EH. Safety and Efficacy in Advanced Solid Tumors of a Targeted Nanocomplex Carrying the p53 Gene Used in Combination with Docetaxel: A Phase 1b Study. Mol Ther 2016; 24:1697-706. [PMID: 27357628 DOI: 10.1038/mt.2016.135] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 06/21/2016] [Indexed: 01/10/2023] Open
Abstract
Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, occurs in most human cancers. SGT-53 is a liposomal nanocomplex designed for systemic, tumor-targeting delivery of the wt p53 gene. In this nanodelivery system, an anti-transferrin receptor single-chain antibody fragment serves as the targeting moiety. In an initial phase 1 trial in patients with advanced solid tumors, SGT-53 demonstrated tumor-specific targeting, was shown to be well tolerated, and was associated with an antitumor effect in several patients. Our preclinical studies have also demonstrated enhanced antitumor activity with the combination of SGT-53 and docetaxel. Thus, this dose-escalation trial was undertaken to assess the combination of SGT-53 and docetaxel for safety and potential efficacy in 14 advanced cancer patients. Results reveal that the combination of SGT-53 (maximum dose, 3.6 mg DNA/infusion) and docetaxel (75 mg/m(2)/infusion) was well tolerated. Moreover, clinical activity involving 12 evaluable patients was observed. Three of these patients achieved RECIST-verified partial responses with tumor reductions of -47%, -51%, and -79%. Two others had stable disease with significant shrinkage (-25% and -16%). These results support phase 2 testing of SGT-53 in combination with docetaxel.
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Affiliation(s)
- Kathleen F Pirollo
- Department of Oncology, Experimental Therapeutics Division, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - John Nemunaitis
- Mary Crowley Cancer Research Centers, Dallas, Texas, USA.,Gradalis, Dallas, Texas, USA.,Texas Oncology PA, Dallas, Texas, USA.,Medical City Dallas Hospital, Dallas, Texas, USA
| | - Po Ki Leung
- SynerGene Therapeutics, Potomac, Maryland, USA
| | - Robert Nunan
- Mary Crowley Cancer Research Centers, Dallas, Texas, USA
| | - Jana Adams
- Mary Crowley Cancer Research Centers, Dallas, Texas, USA
| | - Esther H Chang
- Department of Oncology, Experimental Therapeutics Division, Georgetown University Medical Center, Washington, District of Columbia, USA.,SynerGene Therapeutics, Potomac, Maryland, USA
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Li Y, Li B, Li CJ, Li LJ. Key points of basic theories and clinical practice in rAd-p53 ( Gendicine ™) gene therapy for solid malignant tumors. Expert Opin Biol Ther 2014; 15:437-54. [PMID: 25496374 DOI: 10.1517/14712598.2015.990882] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Wild-type p53 gene is an essential cancer suppressor gene which plays an important role in carcinogenesis and malignant progressions. The p53 gene family participates in almost all the key procedures of cancer biology, such as programmed cell death, angiogenesis, metabolism and epithelial-mesenchymal transition. The mutation or functional defects of the p53 gene family are detected in most of the solid malignant tumors, and the restoration of the p53 gene by adenovirus-mediated gene therapy becomes a promising treatment for cancer patients now. AREAS COVERED In the present review, the potential therapeutic effects of recombinant adenovirus p53 rAd-p53 ( Gendicine ™) were reviewed to explore the biological mechanism underlying the adenovirus-mediated p53 gene therapy. Then, the key points of the drug administration were discussed, including the routes of administration, dosage calculation and treatment cycles, based on findings of the preclinical and clinical trials in order to establish a standard treatment for the p53 gene therapy. EXPERT OPINION As an important part of the combined therapy for the cancer patients, the adenovirus-mediated p53 gene therapy was blossomed to be a promising treatment strategy. A new evaluation criteria and guideline for the gene therapy is urgently needed for the further clinical practice.
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Affiliation(s)
- Yi Li
- Sichuan University, West China Hospital of Stomatology, State Key Laboratory of Oral Disease , Chengdu, 610041 , China
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19
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Shilpa PS, Kaul R, Bhat S, Sultana N, Pandeshwar P. Oncolytic viruses in head and neck cancer: a new ray of hope in the management protocol. Ann Med Health Sci Res 2014; 4:S178-84. [PMID: 25364586 PMCID: PMC4212374 DOI: 10.4103/2141-9248.141953] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
This paper intends to highlight the different types of oncolytic viruses (OVs), mechanism of tumor specificity, its safety, and various obstacles in the design of treatment and combination therapy utilizing oncotherapy. Search was conducted using the internet-based search engines and scholarly bibliographic databases with key words such as OVs, head and neck cancer, viruses, oral squamous cell carcinoma, and gene therapy. Revolutionary technologies in the field of cancer treatment have gone through a series changes leading to the development of innovative therapeutic strategies. Oncolytic virotherapy is one such therapeutic approach that has awaited phase III clinical trial validation. OVs are self-replicating, tumor selective and lyse cancer cells following viral infection. By modifying the viral genome, it is possible to direct their toxicity toward cancer cells. Viruses that are used for treatment of head and neck cancer are either naturally occurring or genetically modified. OVs are tumor selective and potential anticancer agents. Virotherapy may become the standard of care and part of combination therapy in the management of head and neck cancer in the future.
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Affiliation(s)
- PS Shilpa
- Department of Oral Medicine and Radiology, Vydehi Institute of Dental Sciences and Research Center, Bengaluru, Karnataka, India
| | - R Kaul
- Department of Oral Medicine and Radiology, Vydehi Institute of Dental Sciences and Research Center, Bengaluru, Karnataka, India
| | - S Bhat
- Department of Oral Medicine and Radiology, Vydehi Institute of Dental Sciences and Research Center, Bengaluru, Karnataka, India
| | - N Sultana
- Department of Oral Medicine and Radiology, Vydehi Institute of Dental Sciences and Research Center, Bengaluru, Karnataka, India
| | - P Pandeshwar
- Department of Oral Medicine and Radiology, Vydehi Institute of Dental Sciences and Research Center, Bengaluru, Karnataka, India
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Ramzan Z, Nassri AB, Huerta S. Genotypic characteristics of resistant tumors to pre-operative ionizing radiation in rectal cancer. World J Gastrointest Oncol 2014; 6:194-210. [PMID: 25024812 PMCID: PMC4092337 DOI: 10.4251/wjgo.v6.i7.194] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 03/19/2014] [Accepted: 05/08/2014] [Indexed: 02/05/2023] Open
Abstract
Due to a wide range of clinical response in patients undergoing neo-adjuvant chemoradiation for rectal cancer it is essential to understand molecular factors that lead to the broad response observed in patients receiving the same form of treatment. Despite extensive research in this field, the exact mechanisms still remain elusive. Data raging from DNA-repair to specific molecules leading to cell survival as well as resistance to apoptosis have been investigated. Individually, or in combination, there is no single pathway that has become clinically applicable to date. In the following review, we describe the current status of various pathways that might lead to resistance to the therapeutic applications of ionizing radiation in rectal cancer.
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Targeting tumors using nanoparticle platforms: a phase I study of a systemically administered gene therapy system. Mol Ther 2014; 21:922-3. [PMID: 23636291 DOI: 10.1038/mt.2013.76] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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Phase I study of a systemically delivered p53 nanoparticle in advanced solid tumors. Mol Ther 2013; 21:1096-103. [PMID: 23609015 DOI: 10.1038/mt.2013.32] [Citation(s) in RCA: 185] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Selective delivery of therapeutic molecules to primary and metastatic tumors is optimal for effective cancer therapy. A liposomal nanodelivery complex (scL) for systemic, tumor-targeting delivery of anticancer therapeutics has been developed. scL employs an anti-transferrin receptor (TfR), scFv as the targeting molecule. Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, is present in most human cancers. Rather than being transiently permissive for tumor initiation, persistence of p53 dysfunction is a continuing requirement for maintaining tumor growth. Herein, we report results of a first-in-man Phase I clinical trial of restoration of the normal human tumor suppressor gene p53 using the scL nanocomplex (SGT-53). Minimal side effects were observed in this trial in patients with advanced solid tumors. Furthermore, the majority of patients demonstrated stable disease. One patient with adenoid cystic carcinoma had his status changed from unresectable to resectable after one treatment cycle. More significantly, we observed an accumulation of the transgene in metastatic tumors, but not in normal skin tissue, in a dose-related manner. These results show not only that systemically delivered SGT-53 is well tolerated and exhibits anticancer activity, but also supply evidence of targeted tumor delivery of SGT-53 to metastatic lesions.
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LU HONGYANG, WANG XIAOJIA, MAO WEIMIN. Targeted therapies in small cell lung cancer. Oncol Lett 2013; 5:3-11. [PMID: 23255884 PMCID: PMC3525471 DOI: 10.3892/ol.2012.791] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2012] [Accepted: 06/29/2012] [Indexed: 12/29/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related mortality. Small cell lung cancer (SCLC) accounted for 12.95% of all lung cancer histological types in 2002. Despite trends toward modest improvement in survival, the outcome remains extremely poor. Chemotherapy is the cornerstone of treatment in SCLC. More than two-thirds of patients who succumb to lung cancer in the United States are over 65 years old. Elderly patients tolerate chemotherapy poorly and need novel therapeutic agents. Targeted drugs have less toxicity than chemotherapy drugs, but no targeted agents have been approved for use in the treatment of SCLC patients to date. Certain new targeted agents, including gefitinib, bevacizumab and Bcl-2 inhibitors, offer a promise of improved outcomes, however negative results are more commonly reported than positive. This review focuses on targeted therapies in SCLC.
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Affiliation(s)
- HONG-YANG LU
- Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022,
P.R. China
| | - XIAO-JIA WANG
- Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022,
P.R. China
| | - WEI-MIN MAO
- Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022,
P.R. China
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Kast K, Krause M, Schuler M, Friedrich K, Thamm B, Bier A, Distler W, Krüger S. Late onset Li-Fraumeni Syndrome with bilateral breast cancer and other malignancies: case report and review of the literature. BMC Cancer 2012; 12:217. [PMID: 22672556 PMCID: PMC3487792 DOI: 10.1186/1471-2407-12-217] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2011] [Accepted: 06/06/2012] [Indexed: 11/28/2022] Open
Abstract
Background Li-Fraumeni-Syndrome (LFS) is an autosomal-dominant, inherited tumour predisposition syndrome associated with heterozygous germline mutations in the TP53 gene. Patients with LFS are at a high risk to develop early-onset breast cancer and multiple malignancies, among which sarcomas are the most common. A high incidence of childhood tumours and close to 100% penetrance has been described. Knowledge of the genetic status of the TP53 gene in these patients is critical not only due to the increased risk of malignancies, but also because of the therapeutic implications, since a higher rate of radiation-induced secondary tumours in these patients has been observed. Case report We report a patient with LFS harbouring heterozygous, pathogenic TP53 germline mutation, who was affected by four synchronous malignancies at the age of 40: a myxofibrosarcoma of the right upper arm, bilateral breast cancer and a periadrenal liposarcoma. Radiological treatments and a surveillance program were adjusted according to recommendations for LFS patients. Conclusion Management of tumour treatment of patients with LFS is different to the general population because of their risk for secondary cancers in the radiation field. Screening procedures should take a possibly elevated risk for radiation induced cancer into account.
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Affiliation(s)
- Karin Kast
- Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Carl Gustav Carus, Fetscherstr, 74, 01307, Dresden, Germany.
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Safa M, Kazemi A, Zaker F, Razmkhah F. Cyclic AMP-induced p53 destabilization is independent of EPAC in pre-B acute lymphoblastic leukemia cells in vitro. J Recept Signal Transduct Res 2011; 31:256-63. [PMID: 21619452 DOI: 10.3109/10799893.2011.578140] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
CONTEXT Activation of the tumor suppressor protein p53 facilitates the cellular response to genotoxic stress. Thus, releasing the wild-type p53 from indirect suppression would be crucial to successful killing of cancer cells by DNA-damaging therapeutic agents. OBJECTIVE The aim of this study was to investigate the inhibitory role of cyclic adenosine monophosphate (cAMP) levels on p53 protein in acute lymphoblastic leukemia (ALL) cells. More importantly, we were interested to show through which receptor cAMP acts to promote p53 degradation. MATERIALS AND METHODS In cell cultures, we investigated the effects of forskolin/3-isobutyl-1-methylxanthine (IBMX) on stimulated p53 of ALL cell lines. Western blotting analysis was performed to detect the expression of p53, phospho-p53, acetylated-p53, phospho-cAMP response element-binding protein (CREB), and Mdm2 proteins. Flow cytometry was applied to analyze apoptosis. The gene expression of p53 and its target genes was examined by real-time polymerase chain reaction. RESULTS We show that elevation of cAMP levels in ALL cells exposed to DNA damage attenuates p53 accumulation. Inhibition of proteosome function with MG-132 reversed the inhibitory effect of cAMP on p53. However, targeting the p53-Mdm2 interaction did not rescue accumulated p53 from the destabilizing signal of cAMP. The specific agonist of the cAMP receptor exchange protein activated by cAMP had no effect on p53 expression in doxorubicin-treated NALM-6 cells, whereas PKA activators decreased p53 accumulation. DISCUSSION AND CONCLUSION Our studies demonstrate that cAMP-PKA pathway regulates the sensitivity toward DNA-damaging agents via inhibition of a p53-dependent pathway in B-cell precursor ALL (BCP-ALL) cells.
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Affiliation(s)
- Majid Safa
- Department of Hematology, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran.
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Reim D, Gertler R, Novotny A, Becker K, zum Büschenfelde CM, Ebert M, Dobritz M, Langer R, Hoefler H, Friess H, Schumacher C. Adenocarcinomas of the esophagogastric junction are more likely to respond to preoperative chemotherapy than distal gastric cancer. Ann Surg Oncol 2011; 19:2108-18. [PMID: 22130620 DOI: 10.1245/s10434-011-2147-8] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND Preoperative chemotherapy has been shown to improve outcome of patients with adenocarcinoma of the esophagogastric junction (AEG) and gastric cancer (GC), and histopathologic response has been identified as an independent prognostic parameter in these patients. A recent meta-analysis has identified patients with AEG as benefiting more from preoperative chemotherapy than patients with GC. The aim of this retrospective analysis was to prove these findings in an experienced single-center large patient cohort because there are currently no recruiting prospective clinical trials. METHODS In a single center, 551 patients underwent preoperative platin-based chemotherapy followed by oncologic surgery for locally advanced AEG and GC. Pretherapeutic clinical parameters were correlated with histopathologic response to preoperative chemotherapy. RESULTS Histopathologic response (<10% of residual tumor) was found in 130 patients (24%) and was significantly correlated with overall survival (P<0.0001). Tumor localization at the esophagogastric junction (GE junction), lower baseline cT stage, and baseline cN0 stage were significantly associated with histopathologic response (P=0.034, P=0.015, and P=0.002, respectively). In subgroup analyses, the latter two predictive parameters were confirmed only for AEG (n=378) but not for other GC (n=173). AEG patients who were pretherapeutically staged as having cT3/4, cN0 disease (n=73) were identified as the subgroup with the highest rate of histopathologic response (48%). CONCLUSIONS AEG is more likely to respond to preoperative chemotherapy than GC, a finding that might help identify patients who would benefit from preoperative chemotherapy.
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Affiliation(s)
- Daniel Reim
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
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Messina RL, Sanfilippo M, Vella V, Pandini G, Vigneri P, Nicolosi ML, Gianì F, Vigneri R, Frasca F. Reactivation of p53 mutants by prima-1 [corrected] in thyroid cancer cells. Int J Cancer 2011; 130:2259-70. [PMID: 21647879 DOI: 10.1002/ijc.26228] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2010] [Accepted: 05/20/2011] [Indexed: 12/12/2022]
Abstract
Most undifferentiated thyroid carcinomas express p53 mutants and thereafter, are very resistant to chemotherapy. p53 reactivation and induction of massive apoptosis (Prima-1) is a compound restoring the tumor-suppressor activity of p53 mutants. We tested the effect of Prima-1 in thyroid cancer cells harboring p53 mutations. Increasing doses of Prima-1 reduced viability of thyroid cancer cells at a variable extent (range 20-80%). Prima-1 up-regulated p53 target genes (p21(WAF1) , BCL2-associated X protein (Bax), and murine double minute 2 (MDM2)), in BC-PAP and Hth-74 cells (expressing D259Y/K286E and K286E p53 mutants) but had no effect in SW1736 (p53 null) and TPC-1 (expressing wild-type p53) thyroid cancer cells. Prima-1 also increased the cytotoxic effects of either doxorubicin or cisplatin in thyroid cancer cells, including the chemo-resistant 8305C, Hth-74 and BC-PAP cells. Moreover, real-time PCR and Western blot indicated that Prima-1 increases the mRNA of thyroid-specific differentiation markers in thyroid cancer cells. Fluorescence-activated cell sorting analysis revealed that Prima-1 effect on thyroid cancer cells occurs via the enhancement of both cell cycle arrest and apoptosis. Small interfering RNA experiments indicated that Prima-1 effect is mediated by p53 mutants but not by the p53 paralog p73. Moreover, in C-643 thyroid cancer cells, forced to ectopically express wild-type p53, Prima-1 prevented the dominant negative effect of double K248Q/K286E p53 mutant. Finally, co-IP experiments indicated that in Hth-74 cells Prima-1 prevents the ability of p53 mutants to sequestrate the p53 paralog TAp73. These in vitro studies imply that p53 mutant reactivation by small compounds may become a novel anticancer therapy in undifferentiated thyroid carcinomas.
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Affiliation(s)
- Rosa Linda Messina
- Department of Clinical and Molecular Biomedicine, University of Catania, Catania, Italy
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Targeting p53 for Novel Anticancer Therapy. Transl Oncol 2011; 3:1-12. [PMID: 20165689 DOI: 10.1593/tlo.09250] [Citation(s) in RCA: 184] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2009] [Revised: 08/26/2009] [Accepted: 09/21/2009] [Indexed: 12/23/2022] Open
Abstract
Carcinogenesis is a multistage process, involving oncogene activation and tumor suppressor gene inactivation as well as complex interactions between tumor and host tissues, leading ultimately to an aggressive metastatic phenotype. Among many genetic lesions, mutational inactivation of p53 tumor suppressor, the "guardian of the genome," is the most frequent event found in 50% of human cancers. p53 plays a critical role in tumor suppression mainly by inducing growth arrest, apoptosis, and senescence, as well as by blocking angiogenesis. In addition, p53 generally confers the cancer cell sensitivity to chemoradiation. Thus, p53 becomes the most appealing target for mechanism-driven anticancer drug discovery. This review will focus on the approaches currently undertaken to target p53 and its regulators with an overall goal either to activate p53 in cancer cells for killing or to inactivate p53 temporarily in normal cells for chemoradiation protection. The compounds that activate wild type (wt) p53 would have an application for the treatment of wt p53-containing human cancer. Likewise, the compounds that change p53 conformation from mutant to wt p53 (p53 reactivation) or that kill the cancer cells with mutant p53 using a synthetic lethal mechanism can be used to selectively treat human cancer harboring a mutant p53. The inhibitors of wt p53 can be used on a temporary basis to reduce the normal cell toxicity derived from p53 activation. Thus, successful development of these three classes of p53 modulators, to be used alone or in combination with chemoradiation, will revolutionize current anticancer therapies and benefit cancer patients.
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Bioinformatic analyses identifies novel protein-coding pharmacogenomic markers associated with paclitaxel sensitivity in NCI60 cancer cell lines. BMC Med Genomics 2011; 4:18. [PMID: 21314952 PMCID: PMC3050680 DOI: 10.1186/1755-8794-4-18] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2010] [Accepted: 02/11/2011] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Paclitaxel is a microtubule-stabilizing drug that has been commonly used in treating cancer. Due to genetic heterogeneity within patient populations, therapeutic response rates often vary. Here we used the NCI60 panel to identify SNPs associated with paclitaxel sensitivity. Using the panel's GI50 response data available from Developmental Therapeutics Program, cell lines were categorized as either sensitive or resistant. PLINK software was used to perform a genome-wide association analysis of the cellular response to paclitaxel with the panel's SNP-genotype data on the Affymetrix 125 k SNP array. FastSNP software helped predict each SNP's potential impact on their gene product. mRNA expression differences between sensitive and resistant cell lines was examined using data from BioGPS. Using Haploview software, we investigated for haplotypes that were more strongly associated with the cellular response to paclitaxel. Ingenuity Pathway Analysis software helped us understand how our identified genes may alter the cellular response to paclitaxel. RESULTS 43 SNPs were found significantly associated (FDR<0.005) with paclitaxel response, with 10 belonging to protein-coding genes (CFTR, ROBO1, PTPRD, BTBD12, DCT, SNTG1, SGCD, LPHN2, GRIK1, ZNF607). SNPs in GRIK1, DCT, SGCD and CFTR were predicted to be intronic enhancers, altering gene expression, while SNPs in ZNF607 and BTBD12 cause conservative missense mutations. mRNA expression analysis supported these findings as GRIK1, DCT, SNTG1, SGCD and CFTR showed significantly (p<0.05) increased expression among sensitive cell lines. Haplotypes found in GRIK1, SGCD, ROBO1, LPHN2, and PTPRD were more strongly associated with response than their individual SNPs. CONCLUSIONS Our study has taken advantage of available genotypic data and its integration with drug response data obtained from the NCI60 panel. We identified 10 SNPs located within protein-coding genes that were not previously shown to be associated with paclitaxel response. As only five genes showed differential mRNA expression, the remainder would not have been detected solely based on expression data. The identified haplotypes highlight the role of utilizing SNP combinations within genomic loci of interest to improve the risk determination associated with drug response. These genetic variants represent promising biomarkers for predicting paclitaxel response and may play a significant role in the cellular response to paclitaxel.
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Huerta S, Hrom J, Gao X, Saha D, Anthony T, Reinhart H, Kapur P. Tissue microarray constructs to predict a response to chemoradiation in rectal cancer. Dig Liver Dis 2010; 42:679-84. [PMID: 20227932 DOI: 10.1016/j.dld.2010.02.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2009] [Revised: 01/26/2010] [Accepted: 02/02/2010] [Indexed: 12/11/2022]
Abstract
PURPOSE To identify, using tissue microarray (TMA), an immunohistochemical panel predictive of response to ionizing radiation (IR) in rectal cancer. METHODS TMA constructs were prepared from archived stage II/III rectal tumors and matching adjacent mucosa (n=38) from patients treated with pre-operative chemoradiation. Immunohistochemistry (IHC) was performed for MIB, Cyclin E, p21, p27, p53, survivin, Bcl-2, and BAX. Immunoreactivity along with clinical variables was subjected to univariate and forward stepwise logistic regression analyses. RESULTS Pathological complete response (pCR) was 23.9%. The number of positive lymph nodes obtained in the resected specimen was associated with pCR. Immunoreactivity for MIB (Sn 15%, Sp 65%, OR 0.33), p53 (Sn 3%, Sp 84%, OR 0.16), Bcl-2 (Sn 11%, Sp 74%, OR 0.35), and BAX (Sn 92%, Sp 80%, OR 46) was associated with pathological response (all p's<0.001). Forward stepwise logistic regression analysis demonstrated that MIB was an independent predictor of a response to chemoradiation (p=0.001). CONCLUSIONS A combined panel of mediators of apoptosis alone or combined with clinical factors is a feasible approach that can be applied to rectal tumor biopsies to predict a response to chemoradiation. The most sensitive factor was BAX; while MIB independently predicted a response to chemoradiation.
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Affiliation(s)
- Sergio Huerta
- Department of Surgery, University of Texas Southwestern Medical Center, United States.
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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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Huerta S, Gao X, Saha D. Mechanisms of resistance to ionizing radiation in rectal cancer. Expert Rev Mol Diagn 2009; 9:469-80. [PMID: 19580431 DOI: 10.1586/erm.09.26] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
While patients with breast cancers are not subjected to the adverse side effects of tamoxifen or trastuzumab if their tumors are negative for estrogen, progesterone or Her-2/Neu, neoadjuvant ionizing radiation with concurrent chemotherapeutic agents is administered almost universally to patients with stage II/III rectal cancers. There is, however, a tremendously wide range of response to this preoperative modality from complete pathological response to continuous tumor growth in patients receiving the same form of treatment. The specific phenotype of the tumor plays a major role in rendering tumor cells survival advantage to the cytotoxic effects of chemoradiation. Pathways such as proliferation, cell cycle, apoptosis and hypoxia have been investigated under a variety of conditions in preirradiated tissues and postirradiated tumors. This article reviews the current evidence available to identify a molecular profile predictive of the best response to ionizing radiation.
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Affiliation(s)
- Sergio Huerta
- Department of Surgery, University of Texas Southwestern Medical Center/Dallas VA Medical Center, 4500 Lancaster Road, Dallas, TX 75216, USA.
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Huang PI, Chang JF, Kirn DH, Liu TC. Targeted genetic and viral therapy for advanced head and neck cancers. Drug Discov Today 2009; 14:570-8. [PMID: 19508919 DOI: 10.1016/j.drudis.2009.03.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2008] [Revised: 03/07/2009] [Accepted: 03/11/2009] [Indexed: 11/24/2022]
Abstract
Head and neck cancers usually present with advanced disease and novel therapies are urgently needed. Genetic therapy aims at restoring malfunctioned tumor suppressor gene(s) or introducing proapoptotic genes. Oncolytic virotherapeutics induce multiple cycles of cancer-specific virus replication, followed by oncolysis, virus spreading and infection of adjacent cancer cells. Oncolytic viruses can also be armed to express therapeutic transgene(s). Recent advances in preclinical and clinical studies are revealing the potential of both therapeutic classes for advanced head and neck cancers, including the approval of two products (Gendicine and H101) by a governmental agency. This review summarizes the available clinical data to date and discusses the challenges and future directions.
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Affiliation(s)
- Pin-I Huang
- Cancer Center, Taipei Veterans General Hospital, School of Medicine, National Yang-Ming University, Taipei, Taiwan
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Nemunaitis JM, Nemunaitis J. Potential of Advexin: a p53 gene-replacement therapy in Li-Fraumeni syndrome. Future Oncol 2009; 4:759-68. [PMID: 19086841 DOI: 10.2217/14796694.4.6.759] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Li-Fraumeni syndrome is a rare autosomal dominant cancer predisposition syndrome. The majority of families fulfilling definition of Li-Fraumeni syndrome demonstrate inherited abnormalities involving the p53 gene. Cells with dysfunctional p53 are predisposed to the development of cancer phenotype. Advexin (Introgen Therapeutics Inc., TX, USA) is an adenoviral-based experimental therapeutic that provides delivery of wild-type p53 to cancer cells and demonstrates anticancer activity following adequate expression of p53. Theoretically, correction of p53 function in cancer developing in patients with Li-Fraumeni syndrome through treatment with Advexin will provide anti-tumor activity. One patient with Li-Fraumeni syndrome has been reported to have responded to Advexin. This review will summarize background knowledge of Li-Fraumeni syndrome, mechanisms of Advexin and clinical response of cancer to Advexin with a focus on Li-Fraumeni syndrome.
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Affiliation(s)
- Jackie M Nemunaitis
- Mary Crowley Cancer Research Centers, 1700 Pacific Avenue, Ste 110, Dallas, TX 75201, USA.
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Ryu SY, Kim K, Lee WS, Kwon HC, Lee KH, Kim CM, Kang SB. Synergistic growth inhibition by combination of adenovirus mediated p53 transfer and cisplatin in ovarian cancer cell lines. J Gynecol Oncol 2009; 20:48-54. [PMID: 19471670 PMCID: PMC2676500 DOI: 10.3802/jgo.2009.20.1.48] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2008] [Revised: 12/12/2008] [Accepted: 12/13/2008] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE This study was to investigate the synergistic growth inhibitory effect by combination of adenovirus mediated p53 gene transfer and cisplatin in ovarian cancer cell lines with different p53 gene mutation patterns. METHODS Three ovarian cancer cell lines, p53 deleted SKOV3, p53 mutated OVCAR-3, and PA-1 with wild-type p53 were transduced with human adenovirus vectors carrying p53 gene (Ad-p53) and treated with a sublethal concentration of cisplatin before and after Ad-p53. The cell number was counted daily for 5 days after Ad-p53 transduction. Western blotting was used to identify p53 and p21 protein expressions, and flow cytometric analysis was performed to investigate any change of DNA ploidy after Ad-p53 transfer. RESULTS Ad-p53 transduced cells successfully expressed p53 and p21 proteins after 48 hours of Ad-p53 transduction. Synergistic growth inhibition by combination of Ad-p53 and cisplatin was detected only in SKOV3 and OVCAR-3 cells, but not in PA-1 cells. In p53 deleted SKOV3 cells, cisplatin treatment after Ad-p53 showed higher growth inhibition than the treatment before Ad-p53 transduction, and reverse relationship was observed in p53 mutated OVCAR-3 cells. In SKOV3 cells, the fraction of cells at G2/M phase increased after cisplatin treatment, however, it decreased dramatically with Ad-p53 transduction. CONCLUSION The synergistic growth inhibition by combination of Ad-p53 and cisplatin may depend on the p53 status and the temporal sequence of cisplatin treatment, suggesting judicious selective application of this strategy in clinical trials.
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Affiliation(s)
- Sang Young Ryu
- Department of Obstetrics and Gynecology, Korea Cancer Center Hospital, Seoul, Korea
| | - Kidong Kim
- Department of Obstetrics and Gynecology, Korea Cancer Center Hospital, Seoul, Korea
| | - Woo Sik Lee
- Department of Laboratory of Molecular Biology, Korea Cancer Center Hospital, Seoul, Korea
| | - Hee Chung Kwon
- Department of Laboratory of Molecular Biology, Korea Cancer Center Hospital, Seoul, Korea
| | - Kee Ho Lee
- Department of Laboratory of Molecular Biology, Korea Cancer Center Hospital, Seoul, Korea
| | - Chang Min Kim
- Department of Internal Medicine, National Cancer Center, Goyang, Korea
| | - Soon-Beom Kang
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
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Lu Y, Zhang X, Beheshti B, Zhang J. Adenoviral-mediated pHyde gene transfer and cisplatin additively inhibit human prostate cancer growth by enhancing apoptosis. Prostate 2009; 69:234-48. [PMID: 19016247 PMCID: PMC2936923 DOI: 10.1002/pros.20867] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND A novel gene, rat pHyde, has been cloned by us recently. The rat pHyde was shown by the same group to have growth inhibitory effects on human prostate cancer through the induction of apoptosis. METHODS In this report, a human homologue, hpHyde of the rat pHyde, was cloned by cDNA libraries screening. The database search and in situ hybridization were used to map the genomic loci of hpHyde in human chromosome. The anti-prostate cancer effects of pHyde in conjunction with chemotherapy agent were analyzed by in vitro and in vivo assays using adenoviral vector expressing pHyde (AdRSVpHyde) in combination with DNA damaging chemotherapeutic agent, cisplatin, and docetaxel, respectively. RESULTS Database search and FISH analysis consistently indicated that hpHyde gene localizes at human chromosome 2q14. Protein sequence analysis suggests that hpHyde may be a plasma membrane protein. hpHyde is differentially expressed in various normal human tissues and organs, suggesting that hpHyde may play roles in development and differentiation. Growth suppression and induction of apoptosis were additively greater in DU145 human prostate cancer cells treated with AdRSVpHyde and cisplatin than either agent alone both in vitro and in vivo. Moreover, AdRSVpHyde and docetaxel also have a similar additively inhibitory effect on DU145 cell growth. CONCLUSIONS A novel gene hpHyde, the human homologue of rat pHyde, has been cloned and its genomic location in the human chromosome has been identified. Our results support the potential use of pHyde for prostate cancer gene therapy coupled with chemotherapy to improve therapeutic index.
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Affiliation(s)
- Yi Lu
- Department of Pathology and Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
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Rossi A, Maione P, Palazzolo G, Sacco PC, Ferrara ML, Falanga M, Gridelli C. New Targeted Therapies and Small-Cell Lung Cancer. Clin Lung Cancer 2008; 9:271-9. [DOI: 10.3816/clc.2008.n.042] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Kamoshida S, Suzuki M, Shimomura R, Sakurai Y, Komori Y, Uyama I, Tsutsumi Y. Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer. Br J Cancer 2007; 96:277-83. [PMID: 17211470 PMCID: PMC2360001 DOI: 10.1038/sj.bjc.6603546] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
High expression of thymidylate synthase (TS) and inactivation of p53 are allegedly associated with chemoresistance. The authors evaluated TS and p53 expression in gastric cancer treated with neoadjuvant S-1/cisplatin chemotherapy. Paraffin sections of pretreatment biopsy and surgical specimens from 41 gastric cancers were immunostained for TS and p53 protein after appropriate antigen retrieval. Fifty-one cases without neoadjuvant chemotherapy were also studied. In the pretreatment biopsies, high expression of TS was seen in 8% of the histologic responders, in 28% of the nonresponders and in 31% of the controls. High expression of p53 was observed in 56% of the nonresponders, but in 8% of the responders and in 29% of the controls (P<0.01 and P<0.05, respectively). The TS- and/or p53-high phenotype was seen in 76% of the nonresponders and in 54% of the controls, but in 8% of the responders (P<0.0001 and P<0.005, respectively). The data of the surgical specimens were consistent with those of the pretreatment biopsies. These results suggest that immunostaining for TS and p53 protein is useful for pretreatment selection of gastric cancer patients unresponsive to S-1/cisplatin chemotherapy.
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Affiliation(s)
- S Kamoshida
- Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.
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Abstract
To date, dysfunctional tumour suppressor genes are the most common genetic lesions identified in human cancers. Functional copies of tumour suppressor genes can be introduced into cancer cells by gene transfer using adenoviral vectors. This approach has been extensively studied in the clinic with intratumoural injection of a replication-defective adenovirus that expresses p53 (Ad-p53). Overexpression of p53 in cancer cells induces growth arrest and apoptosis. Ad-p53 injections have an excellent safety profile, and have mediated tumour regression and growth arrest as monotherapy, or have overcome resistance or increased the effectiveness of radiation therapy and chemotherapy. Expression of the p53 transgene has occurred at high levels and is associated with the activation of other genes in the p53 pathway. These studies indicate proof-of-principle for tumour suppressor gene therapy and represent a new paradigm in targeted therapy.
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Affiliation(s)
- Jack A Roth
- Department of Thoracic and Cardiovascular Surgery, UT M. D. Anderson Cancer Center, P.O. Box 301402, Houston, TX 77230-1402, USA.
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Wu X, Wan M, Li G, Xu Z, Chen C, Liu F, Li J. Growth hormone receptor overexpression predicts response of rectal cancers to pre-operative radiotherapy. Eur J Cancer 2006; 42:888-94. [PMID: 16516462 DOI: 10.1016/j.ejca.2005.12.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2005] [Revised: 11/30/2005] [Accepted: 12/02/2005] [Indexed: 01/30/2023]
Abstract
In this study, we evaluated the possible role of Growth Hormone Receptor (GHR) expression pattern in determining rectal cancer radiosensitivity. We examined GHR expression in pre-treatment biopsy materials and post-operative specimens from 98 patients by immunohistochemistry (IHC) and reverse transcription-polymerase chain reaction (RT-PCR). GHR expression was evaluated for association with tumour radiosensitivity, which was defined according to Rectal Cancer Regression Grade (RCRG). IHC results demonstrated that GHR overexpression was significantly associated with a poor response to radiotherapy (P < 0.001, r(s) = 0.399); RT-PCR detection of GHR expression on pre-radiation biopsy specimens also showed that GHR mRNA negative group had a higher radiation sensitivity (P < 0.001, r(s) = 0.398). Compared with the pre-radiation biopsy specimens, the paired post-operative specimens showed a significantly up-regulated GHR expression in the reliquus cancer cells (P < 0.001). In conclusion, GHR expression levels may be an indicator for rectal cancer radiosensitivity before pre-operative irradiation. The administration of GHR antagonist may have the potential to increase rectal cancer radiosensitivity.
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Affiliation(s)
- Xiaoyu Wu
- Nanjing University School of Medicine, Department of General Surgery of Jinling Hospital, 305 Zhong-shan-dong Road, Nanjing 210002, JS, PR China.
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Kelley ST, Coppola D, Yeatman T, Marcet J. Tumor response to neoadjuvant chemoradiation therapy for rectal adenocarcinoma is mediated by p53-dependent and caspase 8-dependent apoptotic pathways. Clin Colorectal Cancer 2006; 5:114-8. [PMID: 16098252 DOI: 10.3816/ccc.2005.n.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND We tested the hypothesis that rectal tumors are most responsive to neoadjuvant therapy if they possess p53 and/or caspase 8 activity. PATIENTS AND METHODS Fifty patients diagnosed with biopsy-proven rectal cancer underwent neoadjuvant chemoradiation therapy consisting of 5-fluorouracil (300 mg/m(2) daily) and radiation (4,500 cGy). Endorectal ultrasonography was performed before and after neoadjuvant therapy along with digital rectal examination and/or sigmoidoscopy for staging purposes and to evaluate response to therapy. All patients underwent resection with specimens submitted for gross and microscopic review. Pretreatment biopsy specimens were subjected to immunohistochemical staining for mutated p53 and caspase 8 bioactivity. RESULTS The study population consisted of 32 men and 18 women. There were 17 complete responses (CRs; 34%), 17 partial responses (PRs; 34%), and 16 cases of no response (NR; 32%). There were 10 stage I tumors (20%), 22 stage II tumors (44%), and 18 stage III tumors (36%) in the cohort at the time of initial diagnosis. p53 protein staining (ie, mutated p53) was positive in 31 tumors (62%; CR, n = 8; PR, n = 11; NR, n = 12); caspase 8 positivity was apparent in 30 specimens (60%; CR, n = 13; PR, n = 13; NR, n = 4). In terms of pretreatment predictions, we scored 3 separate levels of response (CR, 3; PR, 2; NR, 1) and compared them with the expected responses (ie, p53 positivity and caspase 8 negativity should yield NR, whereas all other combinations should yield responses). Wilcoxon 2-sample tests yielded a 1-sided P value of 0.007. CONCLUSION The present study highlights a possible mechanism for tumor response to neoadjuvant manipulation, namely that dual mechanisms for apoptotic cell death are working in concert to cause tumor regression; one is p53 transcription-dependent, and the other is p53 transcription-independent.
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Affiliation(s)
- Scott T Kelley
- H. Lee Moffitt Cancer Center and Department of Surgery , Tampa, FL, USA
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Lu-Hesselmann J, van Beuningen D, Meineke V, Franke E. Influences of TP53 expression on cellular radiation response and its relevance to diagnostic biodosimetry for mission environmental monitoring. RADIATION PROTECTION DOSIMETRY 2006; 122:237-43. [PMID: 17164278 DOI: 10.1093/rpd/ncl459] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
TP53 is a transcriptional activator and regulates genomic instability and cellular responses to DNA damage in response to ionising radiation. The molecular mechanism behind p53-mediated responses, such as, apoptosis and genomic instability remains unclear. An in vitro model of biological effects to irradiation was established. In order to elucidate the functional role of TP53 under different stress-reaction pathways and identify possible biological indicators, p53 was stably transfected into HL-60 cells, which provides a p53 minus background. Significantly enhanced radiosensitivity and growth suppression were observed. G(2) accumulation was obtained. Radiation-induced apoptosis of HL-60 cells was significantly inhibited by TP53, indicating that, in the event of DNA damage, TP53 is able to prevent cell death of HL-60 leukaemia cells by sustaining an arrest of the cell cycle at G(2) phase. Further evidence will be presented to identify specific radiation-targeted genes or signals as possible biomarkers for early diagnosis of radiation damage as well as mission environmental monitoring.
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Affiliation(s)
- J Lu-Hesselmann
- Bundeswehr Institute of Medical Occupational and Environmental Safety, Scharnhorststrasse 13, 10115 Berlin, Germany.
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Sunada F, Itabashi M, Ohkura H, Okumura T. p53 negativity, CDC25B positivity, and metallothionein negativity are predictors of a response of esophageal squamous cell carcinoma to chemoradiotherapy. World J Gastroenterol 2005; 11:5696-700. [PMID: 16237768 PMCID: PMC4481491 DOI: 10.3748/wjg.v11.i36.5696] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Esophageal squamous cell carcinoma is generally sensitive to chemoradiotherapy (CRT), but some cases are not. Using a retrospective analysis, we aimed to identify the predictors of the response by esophageal squamous cell carcinoma to definitive CRT.
METHODS: The intensities of expression of p53, Ki67, Bcl-2, Bax, cyclin D1, VEGF, CDC25B, and metallothionein (MT) were evaluated immunohistochemically in the biopsy specimens obtained before CRT, and the intensities of their expression were tested for correlations with the clinical effects of CRT.
RESULTS: The esophageal squamous cell carcinomas with negative p53, positive CDC25B, and negative MT expression were found to be significantly more sensitive to CRT. In addition, p53 positivity and CDC25B positivity respond well to CRT.
CONCLUSION: Esophageal squamous cell carcinomas with negative p53,positive CDC25B, and negative MT expressions respond well to CRT. Even with p53 positivity, if with CDC25B positivity, CRT can be expected.
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Affiliation(s)
- Fumiko Sunada
- Department of Internal Medicine, Jichi Medical School Hospital, Yakushiji 3311, Minamikawachi-machi, Kawachi-gun, Japan.
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D'Amico TA. Molecular Staging and the Selection of Therapy for Non-Small Cell Lung Cancer. Semin Thorac Cardiovasc Surg 2005; 17:180-5. [PMID: 16253819 DOI: 10.1053/j.semtcvs.2005.06.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2005] [Indexed: 11/11/2022]
Abstract
The stage-specific selection of therapy is the standard for patients with non-small cell lung cancer. Investigation of the molecular biology of lung cancer has provided pathways and targets that may be used to improve the efficacy of therapy and improve the survival for patients with lung cancer.
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Affiliation(s)
- Thomas A D'Amico
- Division of Thoracic Surgery, Duke University Medical Center, Durham, NC 27710, USA.
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Büyükçelik A, Onur H, Akbulut H, Bülent Y, Ensari A, Utkan G, Onal BS, Içli F. Expression of P53 Protein and Dna Flow Cytometry in Gastric Adenocarcinoma: Implications in Patients Treated with Adjuvant Etoposide, Adriamycin and Cisplatin. TUMORI JOURNAL 2005; 91:302-8. [PMID: 16277093 DOI: 10.1177/030089160509100403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Aims and background We evaluated the prognostic value of p53 protein, DNA content and S-phase fraction in patients with adenocarcinoma of the stomach or the gastroesophageal junction treated with adjuvant etoposide, doxorubicin and cisplatin. Methods and study design Thirty-five consecutive patients with stage II or III gastric or gastroesophagial junction adenocarcinoma treated with at least two cycles of adjuvant etoposide, doxorubicin and cisplatin after curative gastric resection were included. The expression of p53 protein was determined by immunohistochemistry and DNA content by flow cytometry. The presence of p53 expression and DNA content was compared with clinicopathological features. Results Median age was 54 years (range, 31–71). P53 expression was detected in 42.9% (15 of 35) of gastric cancer tissues of the patients. Aneuploidy was observed in 31.4% of patients, and S-phase fraction was more than 10% in 22.9%. P53 immunoreactivity (33.3% vs 47.8%) was more common in advanced disease. There was no association among p53 immunoreactivity, DNA content and S-phase fraction. We also found no significant relationship between p53 immunoreactivity, DNA content, S-phase fraction or other clinicopathological parameters. In univariate analysis, the involvement of lymph nodes was a significant predictor of a poor outcome (P = 0.001). Also, p53-positive patients had a poor survival close to the level of significance (P = 0.051). Likewise, p53 immunoreactivity (P = 0.0071), in addition to lymph node involvement (P = 0.0016), were the independent prognostic factors in multivariate analysis. Conclusions This trial supports the results of previous reports that p53 immunoreactivity is a prognostic factor for patients with adenocarcinoma of stomach or gastroesophageal junction treated with adjuvant chemotherapy.
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Affiliation(s)
- Abdullah Büyükçelik
- Department of Medical Oncology, Ankara University School of Medicine, Ibni Sina Hospital, Turkey.
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Díez M, Pollán M, Ramos P, Villeta R, Ratia T, Hernández P, Lozano O, Noguerales F, Granell J. [Variation in the prognostic value of p53 protein in relation to tumoral stage in patients with colorectal adenocarcinoma]. Cir Esp 2005; 77:213-220. [PMID: 16420920 DOI: 10.1016/s0009-739x(05)70840-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To analyze the prognostic value of p53 protein as a marker of recurrence risk in each tumoral stage. PATIENTS AND METHOD A prospective study of a cohort of 288 patients who underwent surgery for colorectal adenocarcinoma was performed. Stage 1 of the tumor-node-metastasis (TNM) classification was found in 42 patients (14.6%), stage II in 144 (50%) and stage III in 102 (35.4%). Histopathological variables were examined in tumor samples fixed in formol and embedded in paraffin and p53 (DO7 antibody) and proliferative cell nuclear antigen (PC-10 antibody) proteins were determined using immunohistochemistry. The results of p53 were analyzed in each of the categories of clinical and histopathological variables. Recurrence-free survival was calculated using the Kaplan-Meier method. The value of each variable as a predictive marker for tumoral recurrence was analyzed using Cox regression analysis. Hazard ratios and 95% confidence intervals were calculated as indicators of relative risk. The analysis was applied to the whole cohort and was subsequently repeated in each TNM tumoral stage separately. RESULTS Tumors with p53 protein overexpression more frequently recurred and showed lower recurrence-free survival at 5 years. However, the association between p53 expression and postoperative outcome was statistically significant in stage III tumors only. In this subgroup of patients, recurrence-free survival at 60 months was 60% in p53-negative tumors and was 26% in p53-positive tumors (p=0.010). In the multivariate analysis, p53 was an independent prognostic factor associated with a high risk of recurrence in stage III tumors (hazard ratio=2.76; 95% CI, 1.29-5.9; p=0.009). Overexpression of p53 showed prognostic value as a marker of high risk of recurrence in the form of metastases (hazard ratio=2.23; 95% CI, 1.04-4.75), but not as a prognostic marker of locoregional recurrence. No relationship was found between the state of p53 protein and the effect of postoperative adjuvant therapy. CONCLUSION The p53 protein does not have the same prognostic value in all tumoral stages. This protein is only predictive of high recurrence risk in the subgroup of patients with stage III tumors.
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Affiliation(s)
- Manuel Díez
- Departamento de Cirugía, Universidad de Alcalá, Hospital Príncipe de Asturias, Madrid, Spain.
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Marshall BJ, Windsor HM. The relation of Helicobacter pylori to gastric adenocarcinoma and lymphoma: pathophysiology, epidemiology, screening, clinical presentation, treatment, and prevention. Med Clin North Am 2005; 89:313-44, viii. [PMID: 15656929 DOI: 10.1016/j.mcna.2004.09.001] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Helicobacter pylori infection may be the most common chronic bacterial infection worldwide; however, the prevalence varies between countries and is usually linked to socioeconomic conditions. Gastric cancer is one of the most frequent cancers in developing countries and usually about the seventh most common in developed countries. This article explores the relation of H. pylori to gastric adenocarcinoma and lymphoma. The pathophysiology, epidemiology, screening, clinical presentation, treatment, and prevention are discussed.
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Affiliation(s)
- Barry J Marshall
- Department of Microbiology, University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia.
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Freytag SO, Kim JH, Brown SL, Barton K, Lu M, Chung M. Gene therapy strategies to improve the effectiveness of cancer radiotherapy. Expert Opin Biol Ther 2005; 4:1757-70. [PMID: 15500404 DOI: 10.1517/14712598.4.11.1757] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Having the ability to alter the genetic makeup of a cancer cell by gene transfer is a potentially powerful strategy for treating human cancer. However, a low efficiency of gene delivery in vivo and poor tumour specificity has prevented the widespread implementation of this technology in the clinic. Despite these formidable obstacles, the first successful application of gene therapy in the treatment of cancer may occur when it is combined with local modalities such as radiation therapy. A small number of gene therapy strategies have been evaluated in clinical trials in combination with external beam radiation therapy. The combined therapy has been well-tolerated and has not exacerbated the side effects of radiation therapy. Gene transfer and tumour cell destruction has been demonstrated in vivo. Although the results await confirmation in larger, prospective Phase III trials, there is suggestive evidence that the combined therapies may be demonstrating better than expected antitumour activity. Our vast knowledge of the molecular defects that drive the cancer process, coupled with our expanding understanding of the genes responsible for tumour cell radioresistance, have spawned the development of rational, targeted gene therapies designed to increase tumour cell radiosensitivity. Here, the results of the clinical trials conducted so far will be reviewed, followed by a description of new approaches under development at present.
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Affiliation(s)
- Svend O Freytag
- Department of Radiation Oncology, Henry Ford Health System, Detroit, MI 48202-3405, USA.
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50
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Rossi A, Maione P, Colantuoni G, Guerriero C, Gridelli C. The role of new targeted therapies in small-cell lung cancer. Crit Rev Oncol Hematol 2005; 51:45-53. [PMID: 15207253 DOI: 10.1016/j.critrevonc.2004.02.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2004] [Indexed: 01/02/2023] Open
Abstract
Lung cancer is the leading world-wide cause of cancer death. Small-cell lung cancer (SCLC) accounts for 20-25% of lung carcinomas. Chemotherapy is the cornerstone of treatment of SCLC. In limited disease, median survival is about 12-16 months with 4-5% of long-term survivors, in extensive disease median survival is 7-11 months. Improving the survival rate of patients with SCLC requires a better understanding of tumour biology and the subsequent development of novel therapeutic strategies. Several targeted agents have been introduced into clinical trials in SCLC and some phase III studies have already produced definitive results. Currently, the minority of these new agents offers a promise of improved outcomes, and negative results are more commonly reported than positive ones. To date, no targeted therapy has been approved for use in the treatment of patients with SCLC. This review will focus on the main novel biologic agents investigated in the treatment of SCLC.
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MESH Headings
- Antineoplastic Agents/therapeutic use
- Cancer Vaccines/therapeutic use
- Carcinoma, Small Cell/blood supply
- Carcinoma, Small Cell/genetics
- Carcinoma, Small Cell/metabolism
- Carcinoma, Small Cell/mortality
- Carcinoma, Small Cell/pathology
- Carcinoma, Small Cell/therapy
- Clinical Trials, Phase III as Topic
- Drug Delivery Systems
- Humans
- Immunotherapy, Active
- Lung Neoplasms/blood supply
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/mortality
- Lung Neoplasms/pathology
- Lung Neoplasms/therapy
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/therapy
- Oligoribonucleotides, Antisense/therapeutic use
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Affiliation(s)
- A Rossi
- Unità Operativa di Oncologia Medica, Azienda Ospedaliera S.G. Moscati, Via Circumvallazione 68, 83100-Avellino, Italy
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