Cisplatin chemotherapy plus adenoviral p53 gene therapy in EBV-positive and -negative nasopharyngeal carcinoma

Weinrib, L.; Li, Jianhua; Donovan, Jeffrey C. H.; Huang, Dolly P.; Liu, Fei‐Fei

doi:10.1038/sj.cgt.7700319

Cited by 26 publications

(18 citation statements)

References 36 publications

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“…Consistent with previous studies that show the gene transfer of wild-type p53 as effectively cytotoxic in NPC cells, 18,[21][22][23] our results demonstrated that Ad-p53/GM-CSF/B7-1 infection significantly inhibited cell growth and increased apoptosis of CNE-1 cells in vitro. HuPBL-NOD/SCID mice treated with Ad-p53/GM-CSF/B7-1 demonstrated a reduced tumor burden by 34%-71%, compared with NS groups (p Ͻ 0.05).…”

Section: Discussionsupporting

confidence: 92%

“…18,[21][22][23] The earliest study noted that a wildtype p53-transfected CNE-3 cell line demon-600 NOD/SCID, nonobese/diabetic severe combined immunodeficiency; NS, normal saline; GM-CSF, granulocyte-macrophage colony-stimulating factors. strated a delay in tumor growth.…”

Section: Discussionmentioning

confidence: 99%

“…Local tumors in Adp53/GM-CSF/B7-1 groups displayed diffuse necrosis, mainly caused by apoptosis, and much more human T-cells infiltrated into the tumor tissues, compared to those in the Ad-p53 and NS groups. Several studies also achieved highly significant results, which combined p53 gene transfer with radio-, 18 chemo-, 22 or hyperthermo-therapy 23 in a synergistic or additive manner.…”

Section: Discussionmentioning

confidence: 99%

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Gene Therapy for Human Nasopharyngeal Carcinoma by Adenovirus–Mediated Transfer of Human p53, GM-CSF, and B7-1 Genes in a Mouse Xenograft Tumor Model

Ren¹,

Wang²,

Wang³

et al. 2008

Cancer Biotherapy and Radiopharmaceuticals

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Incidence of nasopharyngeal carcinoma (NPC) remains high in endemic regions. Prevention of tumor recurrences and metastases is a crucial approach to improve therapeutic outcome in NPC patients. In this study, we investigated the effects of the cotransfer of the tumor suppressor gene, p53, in combination with the immunostimulatory genes, GM-CSF and B7-1, on tumor regression and subsequent tumor recurrence. We constructed a recombinant adenovirus carrying human wild-type p53, granulocyte-macrophage colony-stimulating factor (GM-CSF), and B7-1 genes (Ad-p53/GM-CSF/B7-1), which mediated high-level expression of these three genes in NPC CNE-1 cells. Ad-p53/GM-CSF/B7-1 infection inhibited the growth of CNE-1 cells and induced tumor-specific cytotoxic T-lymphocytes (CTLs) in vitro. In CNE-1 xenograft tumor models in huPBL-nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, an intratumoral injection of Ad-p53/GM-CSF/B7-1 resulted in a reduced tumor burden, compared to normal saline (NS) and Ad-p53 controls. Tumors in the Ad-p53/GM-CSF/B7-1 group displayed diffuse necrosis and infiltration of human T-cells. Further, the tumor occurrence of CNE-1 cell rechallenge largely decreased after the primary tumor was intratumorally injected with Ad-p53/GM-CSF/B7-1 in the HuPBL-NOD/SCID mice model. Only 2 of 8 (25%) animals in the Ad-p53/GM-CSF/B7-1 group had developed measurable tumors, which demonstrated extensive necrosis and much more human T-cell infiltration, compared to 5 of 7 (71%) in the NS and Ad-p53 groups. Therefore, the adenovirus-mediated introduction of p53, GM-CSF, and B7-1 genes could improve local control and prevent the recurrence or metastases of NPC tumors, which suggests a potential therapeutic value in NPC treatment.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Gene Therapy for Human Nasopharyngeal Carcinoma by Adenovirus–Mediated Transfer of Human p53, GM-CSF, and B7-1 Genes in a Mouse Xenograft Tumor Model

Ren¹,

Wang²,

Wang³

et al. 2008

Cancer Biotherapy and Radiopharmaceuticals

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“…C666-1 cells, an NPC line, were maintained in RPMI medium supplemented with 10% FBS and penicillinstreptomycin and were grown on plates treated with fibronectin (Sigma). C666-1 cells (a gift from Dolly Huang) contain a deletion at codon 249 of p53 (64). 293 cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% FBS and penicillin-streptomycin.…”

Section: Ebv Cell Linesmentioning

confidence: 99%

The Epstein-Barr Virus BRRF1 Protein, Na, Induces Lytic Infection in a TRAF2- and p53-Dependent Manner

Hagemeier

Barlow

Kleman

et al. 2011

J Virol

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The Epstein-Barr virus (EBV) BRRF1 lytic gene product (Na) is encoded within the same immediate-early region as the BZLF1 (Z) and BRLF1(R) gene products, but its role during EBV infection has not been well defined. We previously showed that Na cooperates with the R protein to induce lytic gene expression in latently infected EBV-positive 293 cells, and in some EBV-negative cell lines it can activate the Z promoter in reporter gene assays. Here we show that overexpression of Na alone is sufficient to induce lytic gene expression in several different latently infected epithelial cell lines (Hone-Akata, CNE2-Akata, and AGS-Akata), while knockdown of endogenous Na expression reduces lytic gene expression. Consistent with its ability to interact with tumor necrosis factor receptor-associated factor 2 (TRAF2) in a yeast two-hybrid assay, we demonstrate that Na interacts with TRAF2 in cells. Furthermore, we show that TRAF2 is required for Na induction of lytic gene expression, that Na induces Jun N-terminal protein kinase (JNK) activation in a TRAF2-dependent manner, and that a JNK inhibitor abolishes the ability of Na to disrupt viral latency. Additionally, we show that Na and the tumor suppressor protein p53 cooperate to induce lytic gene expression in epithelial cells (including the C666-1 nasopharyngeal carcinoma cell line), although Na does not appear to affect p53 function. Together these data suggest that Na plays an important role in regulating the switch between latent and lytic infection in epithelial cells and that this effect requires both the TRAF2 and p53 cellular proteins.

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“…Weinrib et al . [47] suggested that rAd-p53 and cisplatin interact in an additive manner to kill C666-1 and CNE-1 cells. Somatic cell DNA damage inflicted by chemotherapy does not increase the risk of adenovirus DNA integration into genome.…”

Section: Discussionmentioning

confidence: 99%

Selective intra-arterial infusion of rAd-p53 with chemotherapy for advanced oral cancer: a randomized clinical trial

Wang

et al. 2014

BMC Med

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BackgroundIn this study, a combination of recombinant adenoviral p53 (rAd-p53) gene therapy and intra-arterial delivery of chemotherapeutic agents for treatment of oral squamous cell carcinoma was evaluated.MethodsIn total, 99 patients with stage III or IV oral carcinoma who had refused or were ineligible for surgery were enrolled in a randomized, placebo-controlled, double-blind, phase III clinical trial. They were randomly assigned to group I (n = 35; intra-arterial infusion of rAd-p53 plus chemotherapy), group II (n = 33; intra-arterial infusion of rAd-p53 plus placebo chemotherapy), or group III (n = 31; intra-arterial infusion of placebo rAd-p53 plus chemotherapy).ResultsThe median length of follow-up was 36 months (range, 3 to 86 months). During follow-up, 16 patients in group I, 20 in group II, and 22 in group III died. Group I (48.5%) had a higher complete response rate than groups II (16.7%) and III (17.2%) (P = 0.006). The rate of non-responders in group I was significantly lower than that in groups II and III (P < 0.020). A log-rank test for survival rate indicated that group I had a significantly higher survival rate than group III (P = 0.019). The survival rate of patients with stage III but not stage IV oral cancer was significantly higher in group I than in group III (P = 0.015, P = 0.200, respectively). The survival rate of patients with stage IV did not differ significantly among the three groups. Or the 99 patients, 63 patients experienced adverse events of either transient flu-like symptoms or bone marrow suppression, while 13 patients had both these conditions together. No replication-deficient virus was detected in patient serum, urine, or sputum. rAd-p53 treatment increased Bax expression in the primary tumor of 80% of patients, as shown by immunohistochemical staining.ConclusionsIntra-arterial infusion of combined rAd-p53 and chemotherapy significantly increased the survival rate of patients with stage III but not stage IV oral cancer, compared with intra-arterial chemotherapy. Intra-arterial infusion of combined rAd-p53 and chemotherapy may represent a promising alternative treatment for oral squamous cell carcinoma.Trial registrationChiCTR-TRC-09000392 (Date of registration: 2009-05-18).

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Cisplatin chemotherapy plus adenoviral p53 gene therapy in EBV-positive and -negative nasopharyngeal carcinoma

Cited by 26 publications

References 36 publications

Gene Therapy for Human Nasopharyngeal Carcinoma by Adenovirus–Mediated Transfer of Human p53, GM-CSF, and B7-1 Genes in a Mouse Xenograft Tumor Model

Gene Therapy for Human Nasopharyngeal Carcinoma by Adenovirus–Mediated Transfer of Human p53, GM-CSF, and B7-1 Genes in a Mouse Xenograft Tumor Model

The Epstein-Barr Virus BRRF1 Protein, Na, Induces Lytic Infection in a TRAF2- and p53-Dependent Manner

Selective intra-arterial infusion of rAd-p53 with chemotherapy for advanced oral cancer: a randomized clinical trial

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