Cationic Liposome-Mediated<i>E1A</i>Gene Transfer to Human Breast and Ovarian Cancer Cells and Its Biologic Effects: A Phase I Clinical Trial

Hortobágyi, Gabriel N.; Ueno, Naoto T.; Xia, Wei; Zhang, Shaozeng; Wolf, Judith K.; Putnam, Joe B.; Pl, Weiden; Willey, Jie; Carey, M.; Branham, Donna; Payne, J. Y.; Tucker, Stephen B.; Bartholomeusz, Chandra; Kilbourn, Robert G.; Jager, Robert L. De; Sneige, Nour; Katz, Ruth L.; Anklesaria, Pervin; Ibrahim, Nuhad K.; Murray, James L.; Theriault, Richard L.; Valero, Vicente; Gershenson, David M.; Bevers, Michael W.; Huang, Lee Wen; López-Berestein, Gabriel; Hung, Mien‐Chie

doi:10.1200/jco.2001.19.14.3422

Cited by 198 publications

(94 citation statements)

References 20 publications

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“…One such strategy is based on the finding that the HER2 gene can be repressed by the adenovirus E1A gene (41,42). A phase I clinical trial of E1A therapy showed that intracavitary injection of the E1A gene complexed with DC-Chol cationic liposome (DCC-E1A; Targeted Genetics Corp., Seattle, WA, USA) was accompanied by HER2 down-regulation, increased apoptosis, and reduced proliferation in patients with breast cancer (43).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological blockade of Fatty Acid Synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin™) by transcriptionally inhibiting ‘HER2 super-expression’ occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells

Vázquez-Martín

Colomer²,

Brunet³

et al. 2007

Int J Oncol

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Abstract. Elucidating the mechanisms underlying resistance to the human epidermal growth factor receptor 2 (HER2)-targeted antibody trastuzumab (Tzb; Herceptin™) is a major challenge that is beginning to be addressed. This dilemma is becoming increasingly important as recent studies strongly support a role for Tzb in the adjuvant setting for HER2-overexpressing early-stage breast cancers. We previously reported that pharmacological and RNA interference-induced inhibition of tumor-associated fatty acid synthase (FASN; Oncogenic antigen-519), a key metabolic enzyme catalyzing the synthesis of long-chain saturated fatty acids, drastically down-regulates HER2 expression in human breast cancer cells bearing HER2 gene amplification. Given that FASN blockade was found to suppress HER2 overexpression by attenuating the promoter activity of the HER2 gene, we here envisioned that this mechanism of action may represent a valuable strategy in breast cancers that have progressed while under Tzb. We created a preclinical model of Tzb resistance by continuously growing HER2-overexpressing SKBR3 breast cancer cells in the presence of clinically relevant concentrations of Tzb (20-185 μg/ml Tzb). This pool of Tzb-conditioned SKBR3 cells, which optimally grows now in the presence of 100 μg/ml trastuzumab (SKBR3/Tzb100 cells), exhibited HER2 levels notably higher (~2-fold) than those found in SKBR3 parental cells. Real-time polymerase chain reaction studies showed that up-regulation of HER2 mRNA levels closely correlated with HER2 protein up-regulation in SKBR3/ Tzb100 cells, thus suggesting that 'HER2 super-expression' upon acquisition of autoresistance to Tzb resulted, at least in part, from up-regulatory effects in the transcriptional rate of the HER2 gene. SKBR3/Tzb100 cells did not exhibit crossresistance to C75, a small-compound specifically inhibiting FASN activity. On the contrary, SKBR3/Tzb100 cells showed a remarkably increased sensitivity (~3-fold) to the cytotoxic effects occurring upon C75-induced inhibition of FASN enzymatic activity. Both HER2 mRNA and HER2 protein 'super-expression', which have not been reported in earlier Tzb-resistant breast cancer models, were entirely suppressed following pharmacological blockade of FASN activity. Moreover, while Tzb was still able to reduce HER2 protein expression by ~20% in SKBR/Tzb100 cells, C75 and Tzb coexposure synergistically down-regulated HER2 protein levels by >85%. The nature of the interaction between Tzb and C75 in Tzb-resistant SKBR3/Tzb100 cells was also found to be strongly synergistic when analyzing the extent of apoptotic cell death using ELISA-based detection of histone-associated DNA fragments. In summary, a) the molecular mechanism(s) contributing to Tzb resistance in our SKBR3/Tzb100 model appear to be clearly different to those previously reported as we found important transcriptional up-regulatory transcriptional changes in HER2 gene expression levels relative to parental cells; b) since FASN inhibition acts on HER2 gene expression via reduction of its tr...

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Section: Discussionmentioning

confidence: 99%

Pharmacological blockade of Fatty Acid Synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin™) by transcriptionally inhibiting ‘HER2 super-expression’ occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells

Vázquez-Martín

Colomer²,

Brunet³

et al. 2007

Int J Oncol

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“…Thus, the adenovirus type 5 E1A is not a transforming protein and is distinct from the adenovirus type 12 E1A which alone can transform established cell lines (Lamberti and Williams, 1990). As a matter of fact, the adenovirus type 5 E1A has been reviewed as a tumor suppressor (Chinnadurai, 1992;Mymryk, 1996;Frisch, 2001) and used in the clinical trial (Hortobagyi et al, 2001). Unless otherwise speci®ed, the E1A referred in this article is the type 5 E1A.…”

Section: Introductionmentioning

confidence: 99%

Akt is required for Axl-Gas6 signaling to protect cells from E1A-mediated apoptosis

et al. 2002

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“…5,10 Therefore, based on its ability to suppress both tumorigenicity and metastasis, E1A has been considered as a tumor suppressor gene 5,[11][12][13] and translated into multiple clinical trials. [14][15][16] In addition to the tumor suppressor activities, expression of the E1A gene in stably transfected normal fibroblast and human cancer cells has also been shown to increase sensitivity to the in vitro cytotoxicity of several anticancer drugs, such as etoposide and cisplatin in normal fibroblasts and sarcoma cells, Adriamycin in colon and hepatocellular carcinoma cells, Gemcitabine in hepatocellular and breast cancer cells, and paclitaxel in breast and ovarian cancers. [17][18][19][20][21][22][23][24][25][26][27] Our previous studies demonstrated that E1A can sensitize paclitaxel-induced cell killing in Her-2/neu-overexpressing cancer cells.…”

mentioning

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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Cationic Liposome-MediatedE1AGene Transfer to Human Breast and Ovarian Cancer Cells and Its Biologic Effects: A Phase I Clinical Trial

Abstract: These results argue for the feasibility of intracavitary DCC-E1A administration, provide a clear proof of preclinical concept, and warrant phase II trials to determine the antitumor activity of the E1A gene.

Cited by 198 publications

References 20 publications

Pharmacological blockade of Fatty Acid Synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin™) by transcriptionally inhibiting ‘HER2 super-expression’ occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells

Pharmacological blockade of Fatty Acid Synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin™) by transcriptionally inhibiting ‘HER2 super-expression’ occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells

Akt is required for Axl-Gas6 signaling to protect cells from E1A-mediated apoptosis

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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