Effect of TRA-8 Anti-Death Receptor 5 Antibody in Combination With Chemotherapy in an Ex Vivo Human Ovarian Cancer Model

Frederick, Peter J.; Kendrick, James E.; Straughn, J. Michael; Manna, Debbie L. Della; Oliver, Patsy G.; Lin, Hui‐Yi; Grizzle, William E.; Stockard, Cecil R.; Alvarez, Ronald D.; Zhou, Tong; LoBuglio, Albert F.; Buchsbaum, Donald J.

doi:10.1111/igc.0b013e3181a2a003

Cited by 17 publications

(11 citation statements)

References 19 publications

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“…Sensitivity to D269H/E195R was observed in two of the four tumours. An analogous observation was made with the anti-DR5 antibody TRA-8 that effectively induced apoptosis in most tumours tested using a similar ex vivo model of ovarian cancer ( Estes et al , 2007 ; Frederick et al , 2009 ). Several in vitro studies have reported that ovarian cancer cell lines are intrinsically resistant to rhTRAIL (for review, refer to the study by Khaider et al , 2012 ).…”

Section: Discussionsupporting

confidence: 59%

Nutlin-3 preferentially sensitises wild-type p53-expressing cancer cells to DR5-selective TRAIL over rhTRAIL

et al. 2013

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Section: Discussionsupporting

confidence: 59%

Nutlin-3 preferentially sensitises wild-type p53-expressing cancer cells to DR5-selective TRAIL over rhTRAIL

et al. 2013

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“…Primarily, tumor tissue slices have been used to determine drug responses including responses to cytotoxic chemotherapeutics, small molecule inhibitors, and other drugs [135–138, 141, 142, 144, 146, 147, 150–154]. Cellular responses were assessed on different levels ranging from drug uptake, proliferation and induction of cell death to changes in protein levels, and gene expression.…”

Section: Tumor Tissue Slices: Culture System Preserving the Individmentioning

confidence: 99%

“…3). Different slicing procedures with slicers such as Krumdieck [135, 138, 146, 151, 157, 163], manual choppers [153, 154], and vibratomes [140, 153, 154, 163] as well as different culture conditions including floating [135, 136, 138, 142, 152], filter‐supported [140, 148, 153, 154], and rotating [149] systems have been published. However, to date no systematic analysis or comparison of the different preparation and culture conditions is available.…”

Section: Tumor Tissue Slices: Culture System Preserving the Individmentioning

confidence: 99%

Three‐dimensional models of cancer for pharmacology and cancer cell biology: Capturing tumor complexity in vitro/ex vivo

Hickman¹,

Graeser²,

Hoogt³

et al. 2014

Biotechnology Journal

344

276

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Cancers are complex and heterogeneous pathological "organs" in a dynamic interplay with their host. Models of human cancer in vitro, used in cancer biology and drug discovery, are generally highly reductionist. These cancer models do not incorporate complexity or heterogeneity. This raises the question as to whether the cancer models' biochemical circuitry (not their genome) represents, with sufficient fidelity, a tumor in situ. Around 95% of new anticancer drugs eventually fail in clinical trial, despite robust indications of activity in existing in vitro pre-clinical models. Innovative models are required that better capture tumor biology. An important feature of all tissues, and tumors, is that cells grow in three dimensions. Advances in generating and characterizing simple and complex (with added stromal components) three-dimensional in vitro models (3D models) are reviewed in this article. The application of stirred bioreactors to permit both scale-up/scale-down of these cancer models and, importantly, methods to permit controlled changes in environment (pH, nutrients, and oxygen) are also described. The challenges of generating thin tumor slices, their utility, and potential advantages and disadvantages are discussed. These in vitro/ex vivo models represent a distinct move to capture the realities of tumor biology in situ, but significant characterization work still remains to be done in order to show that their biochemical circuitry accurately reflects that of a tumor.

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“…Taxol, as a DNA-damaging agent, just like cisplatin and doxorubicin, is one of the most active cancer chemotherapeutic agents and is effective against several human tumors including ovarian, breast, non-small cell lung tumors, and head and neck carcinomas (16)(17)(18). It is evident that Taxolininduced apoptosis is primarily through caspase-8 and -10 activation, which indicated that Taxol could prevent c-FLIP expression to facilitate caspase-8 activation and apoptosis signaling (19,20).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of c-FLIP expression by miR-512-3p contributes to Taxol-induced apoptosis in hepatocellular carcinoma cells

Chen

2010

Oncol Rep

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Abstract. Dysregulation of the antiapoptotic protein cellular FLICE-like inhibitory protein (c-FLIP) has been proven to be associated with tumorigenesis and progress of most human cancers. However, its aberrant expression is poorly elucidated. MicroRNAs (miRNAs) are small non-coding RNAs that are involved in tumorigenesis through negatively regulating gene expression. Our study disclosed that c-FLIP was overexpressed in HepG2 hepatocellular carcinoma cells and downregulation of c-FLIP enhanced Taxol-induced apoptosis. Taxol induction significantly decreased the protein level of c-FLIP. While no decrease in c-FLIP mRNA level was observed, indicating Taxol decreased c-FLIP expression through a posttranscriptional mechanism. miR-512-3p was a predicted suppressor of c-FLIP and exhibited an opposite expression manner to c-FLIP before and after Taxol induction. Luciferase report assay demonstrated miR-512-3p negatively regulated c-FLIP expression via a conserved miRNA-binding site in 3' untranslated region (3'UTR) of c-FLIP. The decrease of c-FLIP protein due to transfection of miR-512-3p further validated the inhibitory effect of miR-512-3p on c-FLIP. Additional transfection of miR-512-3p remarkably promoted Taxol-induced apoptosis, confirming its involvement in apoptosis. In summary, our study disclosed a novel regulatory mechanism that down-regulation of c-FLIP by miR-512-3p contributed to Taxol-induced apoptosis. Importantly, the pivotal role of miR-512-3p in determining c-FLIP abundance helps to broaden the implications for cancer therapy by developing small molecules to directly target c-FLIP at mRNA level.

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Effect of TRA-8 Anti-Death Receptor 5 Antibody in Combination With Chemotherapy in an Ex Vivo Human Ovarian Cancer Model

Abstract: This study demonstrates the efficacy of the death receptor monoclonal antibody TRA-8 in combination with conventional chemotherapy in an ex vivo human ovarian cancer model. This model can be used to assess cytotoxicity of novel agents in combination with chemotherapy in ovarian cancer.

Cited by 17 publications

References 19 publications

Nutlin-3 preferentially sensitises wild-type p53-expressing cancer cells to DR5-selective TRAIL over rhTRAIL

Nutlin-3 preferentially sensitises wild-type p53-expressing cancer cells to DR5-selective TRAIL over rhTRAIL

Three‐dimensional models of cancer for pharmacology and cancer cell biology: Capturing tumor complexity in vitro/ex vivo

Inhibition of c-FLIP expression by miR-512-3p contributes to Taxol-induced apoptosis in hepatocellular carcinoma cells

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