E1A is sufficient by itself to induce apoptosis independent of p53 and other adenoviral gene products

Pützer, B M; Stiewe, Thorsten; Parssanedjad, Keiarasch; Rega, S; Esche, Helmut

doi:10.1038/sj.cdd.4400618

Cited by 48 publications

(36 citation statements)

References 52 publications

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“…25 -27 The apoptotic function of E1A is accompanied by the processing of caspase-3 and cleavage of poly ( CADP -ribose ) polymerases. 28,29 The mechanism of the E1A -induced apoptosis in this tumor model is not clear at this time. However, based on our previous work, we hypothesize that the enhanced sensitivity to VP -16 is secondary to E1A's ability to up -regulate topoisomerase II expression.…”

Section: Discussionmentioning

confidence: 92%

Adenovirus-E1A gene therapy enhances the in vivo sensitivity of Ewing's sarcoma to VP-16

et al. 2002

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This study determined the effect of Ad -E1A gene therapy in vivo. TC71 cells ( 2Â10 6 ) injected subcutaneously into nude mice resulted in tumor development ( 1 -3 mm ) 6 days later. Animals were then treated with Ad -E1A or Ad --gal ( 5Â10 9 plaque -forming units ) by intratumoral injection twice weekly for 2 weeks. Animals received 8 mg / kg VP -16 given by intraperitoneal injection daily for 5 days following the first week of treatment with Ad -E1A or Ad --gal. Control animals received no therapy or VP -16 only after tumor cells were injected. When tumors exceeded 2Â2 cm, the mice were sacrificed and the tumors underwent histologic and immunohistochemical analysis. Tumors from mice treated with Ad -E1A plus VP -16 were 9.6 -fold smaller than those treated with VP -16 alone and 6.3 -fold smaller than those treated with Ad -E1A alone. HER2 / neu p185 protein expression decreased in all tumors that received Ad -E1A therapy. TUNEL fluorescence staining revealed more apoptosis in the tumors from animals treated with Ad -E1A plus VP -16 than in those from animals treated with Ad -E1A alone, Ad --gal plus VP -16, or VP -16 alone. These data demonstrated that Ad -E1A gene therapy down -regulated HER2 / neu expression, increased tumor cell apoptosis induced by VP -16, and enhanced tumor cell sensitivity to VP -16. Ad -E1A may have potential in the treatment of relapsed drug -resistant Ewing's sarcoma. Cancer Gene Therapy ( 2002 ) 9, 407 -413 DOI: 10.1038 / sj / cgt / 7700449Keywords: Ewing's sarcoma; Ad -E1A; gene therapy; VP -16 E wing's sarcoma is the second most common primary malignant bone tumor in children and young adults and has a high potential for metastasizing to the lungs, bones, and bone marrow. Most patients with Ewing's sarcoma die from lung and bone metastases. The overall 5-year survival rate is 41.2%. 1,2 Moreover, the prognosis is poor for patients who have had a relapse and for patients with large primary tumors or metastatic disease at presentation. Therefore, new strategies are needed to improve the survival rates. The HER2/neu oncogene encodes a 185 -kDa human epidermal growth factor receptor-2 transmembrane protein ( p185 ) with intrinsic tyrosine kinase activity. Overexpression of HER2 /neu was found in approximately 30% of human breast and ovarian cancers. 3,4 Enhanced expression of HER2 /neu increased the tumorigenicity and metastatic potential of human ovarian and lung cancer cells. Clinical studies indicated that overexpression of HER2/neu correlated with poor prognosis, shorter patient survival, and chemoresistance. 5,6 We previously demonstrated that TC71 human Ewing's sarcoma cells overexpress HER2/neu. Thus, HER2/ neu may also play a role in the poor disease-free survival rate associated with multiagent chemotherapy in this disease. The adenovirus type 5 early region 1A (E1A ) gene is a wellknown transcriptional factor. This gene inhibits HER2 /neu expression in both rodent and human breast cancer and ovarian cancer cells through the HER2 /neu promoter and with the involvement of the H...

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Section: Discussionmentioning

confidence: 92%

Adenovirus-E1A gene therapy enhances the in vivo sensitivity of Ewing's sarcoma to VP-16

et al. 2002

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“…Oncogenic signals such as the adenovirus E1A render primary cells sensitive to induction of apoptosis in a p53-dependent and independent manner by diverse stimuli, including many anticancer agents (Lowe et al, 1993;Pu¨tzer et al, 2000). Thus, we wished to determine whether oncogenic signals sensitize cells to induction of apoptosis by Nutlin-3.…”

Section: Resultsmentioning

confidence: 99%

E2F-1 transcriptional activity is a critical determinant of Mdm2 antagonist-induced apoptosis in human tumor cell lines

et al. 2008

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“…In Enhanced paclitaxel efficacy by systemic delivery of the E1A gene Y Liao et al the literature, previous studies on E1A-mediated sensitization to drug-induced apoptosis in different cell systems or cell-free systems have identified a few other molecules that are also linked to E1A-mediated chemosensitization other than downregulation of Her-2/neu, such as the proapoptotic protein Bax, Apaf-1, p19ARF, procaspase-2, -3, -7, -8, and -9, cell cycle inhibitor p21 Cip1/WafÀ1 , or as yet unidentified inhibitor that ordinarily provides protection against cell death. 23,32,[34][35][36][37][38][39][40][41] Whether one of these molecules or other unknown molecules could be used as a surrogate marker to monitor the therapeutic effect of this combination therapy in tumors with low Her-2/neu expression needs further assessment. It is worthwhile mentioning the important clinical implications of the concentration of paclitaxel that we tested in the in vitro study because the paclitaxel concentration that can kill cancer cells in vitro, in the presence of E1A, is clinically relevant.…”

Section: Discussionmentioning

confidence: 99%

Enhanced paclitaxel cytotoxicity and prolonged animal survival rate by a nonviral-mediated systemic delivery of E1A gene in orthotopic xenograft human breast cancer

et al. 2004

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Paclitaxel (Taxol) is a promising frontline chemotherapeutic agent for the treatment of human breast and ovarian cancers. The adenoviral type 5 E1A gene has been tested in multiple clinical trials for its anticancer activity. E1A has also been shown to sensitize paclitaxel-induced killing in E1A-expressing cells. Here, we show that E1A can sensitize paclitaxel-induced apoptosis in breast cancer cells in a gene therapy setting by an orthotopic mammary tumor model. We first showed that expression of E1A enhanced in vitro paclitaxel cytotoxicity, as compared to the control cells. We then compared the therapeutic efficacy of paclitaxel between orthotopic tumor models established with vector-transfected MDA-MB-231 (231-Vect) versus 231-E1A stable cells, using tumor weight and apoptotic index (TUNEL assay) as the parameters. We found paclitaxel was more effective in shrinking tumors and inducing apoptosis in tumor models established with stable 231-E1A cells than the control 231-Vect cells. We also tested whether E1A could directly enhance paclitaxel-induced killing in nude mice, by using a nonviral, surface-protected cationic liposome to deliver E1A gene via the mouse tail vein. We compared the therapeutic effects of E1A gene therapy with or without Taxol chemotherapy in the established orthotopic tumor model of animals inoculated with MDA-MB-231 cells, and found that a combination of systemic E1A gene therapy and paclitaxel chemotherapy significantly enhanced the therapeutic efficacy and dramatically repressed tumor growth (Po.01). In addition, survival rates were significantly higher in animals treated with combination therapy than in the therapeutic control groups (both Po.0001). Thus, the E1A gene therapy indeed enhances the sensitivity of tumor cells to chemotherapy in a gene therapy setting and, the current study provides preclinical data to support combination therapy between E1A gene and chemotherapy for future clinical trials.

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E1A is sufficient by itself to induce apoptosis independent of p53 and other adenoviral gene products

Cited by 48 publications

References 52 publications

Adenovirus-E1A gene therapy enhances the in vivo sensitivity of Ewing's sarcoma to VP-16

Adenovirus-E1A gene therapy enhances the in vivo sensitivity of Ewing's sarcoma to VP-16

E2F-1 transcriptional activity is a critical determinant of Mdm2 antagonist-induced apoptosis in human tumor cell lines

Enhanced paclitaxel cytotoxicity and prolonged animal survival rate by a nonviral-mediated systemic delivery of E1A gene in orthotopic xenograft human breast cancer

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