Combination therapy of Ad-mda7 and trastuzumab increases cell death in Her-2/neu–overexpressing breast cancer cells

McKenzie, Tamra; Liu, Yanna; Fanale, Michelle A.; Swisher, Stephen G.; Chada, Sunil; Hunt, Kelly K.

doi:10.1016/j.surg.2004.05.022

Cited by 50 publications

(44 citation statements)

References 14 publications

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“…Differences in tumor size were analyzed for significance by the Student's t-test. Enhanced in vitro growth inhibitory and cytotoxic activity of Ad-mda7 and Herceptin in Her-2 þ breast cancer cells The antiproliferative effects of Ad-mda7 in various cancer cell types have been demonstrated in previous studies; [16][17][18][19][20][21][22][24][25][26][27][28][29][30][31][32][33][34]36 and the relevance of these findings to the clinical setting is supported by in vivo lung and breast xenograft models. 17,21 To corroborate that the Her-2 receptors expressed by the breast cancer cells are functional, we evaluated cell death in MDA-MB-453 and MCF-7 lines treated with increasing amounts of Herceptin (0-100 mg/ ml).…”

Section: Discussionmentioning

confidence: 81%

“…29 Briefly, estrogen pellets were injected in the posterior cervical region, and 2 days later, MCF-7-Her-18 cells were injected into the thoracic mammary fat pad (5 Â 10 6 cells/mouse). When tumors reached a volume of 100 mm 3 , the mice were divided into six treatment groups: vehicle, Ad-luc, Ad-mda7 Herceptin or a combination of these; viral vectors were injected intratumorally (2 Â 10 10 vp/weekly, for a total of 3 weeks).…”

Section: Animal Studiesmentioning

confidence: 99%

“…[18][19][20][21][22][23]38 It is now known that mda-7 activates various signaling pathways in a cell-type-specific manner, and that these pathways ultimately converge on mitochondrial destruction and induction of apoptosis. 21,22,[24][25][26][27][28][29][30] However, in spite of its clear tumor-suppressive effects, the mechanisms by which Ad-mda7 induces cytotoxicity have not been fully characterized. Our group has previously demonstrated that Ad-mda7, as a single agent therapy, induces apoptosis and inhibits growth in pancreatic, lung and breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

et al. 2006

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The melanoma differentiation-associated gene-7 (mda-7) is a member of the interleukin-10 cytokine family and a novel tumor suppressor gene. Adenoviral-mediated mda-7 (Ad-mda7) gene transfer has tumor-specific growth inhibitory and proapoptotic effects in a broad spectrum of cancer cells. In breast cancer cells, adenoviral-induced mda-7 expression triggers antiproliferative effects by downregulation of survival signals, such as Bcl-2 and Akt. The anti-human epidermal growth factor receptor-2 (Her-2) monoclonal antibody, Trastuzumab (Herceptin), increases the sensitivity of Her-2/neu-overexpressing breast cancer cells to chemotherapeutic agents and radiotherapy. In this study, we evaluate the effects of treatment with Ad-mda7 and Herceptin combination therapy in a panel of Her-2/neu-overexpressing cell lines, and in established tumors in nude mice. Compared to individual treatments, the combination of Ad-mda7 and Herceptin elicits supra-additive antitumor activity in Her-2/neuoverexpressing tumor cell lines: increased cell death, cell cycle block and apoptosis. The Ad-mda7 and Herceptin interaction was shown to be synergistic by isobologram analysis. Ad-mda7 does not alter cell surface Her-2/neu levels, but the combination of Ad-mda7 þ Herceptin results in increased expression of cell surface E-cadherin with concomitant translocation of b-catenin from the nucleus to the cell membrane. In vivo, the combination of Ad-mda7 and Herceptin showed significantly increased antitumor activity (Po0.003) against Her-2/neu-overexpressing tumors. These data suggest that the combination of Ad-mda7 with Herceptin may be a novel therapy for breast cancer patients whose tumors overexpress Her-2/neu. The observed synergistic effect may improve treatment options for otherwise poorly responsive, Her-2-positive, breast cancer patients. Cancer Gene Therapy (2006) 13, 958-968.

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Section: Discussionmentioning

confidence: 81%

Section: Animal Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

et al. 2006

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“…27,37,38,[81][82][83][84][85][86] McKenzie et al 81 investigated the combinatorial effects of Ad.mda-7 and Herceptin (Trastuzumab), an anti-p185ErbB2 murine monoclonal antibody (4D5) on Her-2/ neu-overexpressing breast cancer cells. This combination treatment resulted in decreased levels of β-catenin, Akt and phosphorylated Akt as compared with a single treatment with Ad.mda-7 or Herceptin.…”

Section: Combinatorial Effects Of Mda-7/il-24: Overcoming Chemo-resismentioning

confidence: 99%

Historical perspective and recent insights into our understanding of the molecular and biochemical basis of the antitumor properties of mda-7/IL-24

Emdad

Lebedeva

et al. 2009

Cancer Biology & Therapy

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A subtraction hybridization approach combined with a differentiation therapy model of human melanoma identified melanoma differentiation associated gene-7 (mda-7) as a gene upregulated during induction of terminal differentiation. Based on conserved structure, chromosomal location and cytokine-like properties, mda-7, has now been classified as a member of the expanding interleukin (IL)-10 gene family and designated as mda-7/IL-24. Extensive in vitro and in vivo human tumor xenograft studies confirm that mda-7/IL-24 induces apoptosis specifically in tumor cells without harming normal cells. Unique properties of mda-7/IL-24 action also include potent "bystander antitumor" activity, an ability to exert anti-angiogenic effects, immune modulating ability and a capacity to enhance the sensitivity of tumor cells to radiotherapy, chemotherapy and monoclonal antibody therapy. Very recent studies from our groups further reveal autocrine regulation and chemoprevention facilitating properties of mda-7/IL-24. Based on these remarkable antitumor attributes, mda-7/IL-24 was evaluated by intratumoral injection with a replication incompetent adenovirus expressing this gene (Ad.mda-7; INGN 241) in a phase I clinical trial in patients with metastatic melanomas and other advanced solid cancers. mda-7/IL-24 was well tolerated with significant clinical activity. This review highlights our current understanding of the molecular and biochemical basis of mda-7/IL-24 antitumor properties and highlights its potential as a viable gene-based therapy for a wide spectrum of primary and advanced cancers.

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“…Hence, TSGs can induce apoptosis or suppress tumor cell growth; most often gatekeeper genes have been the most attractive targets for developing gene replacement strategies so far. Several TSGs have already been shown to induce apoptosis or cause cell cycle arrest when introduced to breast cancer cells, including Rb, 28,29 p16, 30,31 p27, 32 p21, 33 p53, 29 mda7, 34,35 BRCA-1, 36 BRCA-2, 37 Maspin, 38 and Testin. 39 Most clinical trials to date involve replacement of the TSG most commonly altered in cancer, p53.…”

Section: Mutation Compensationmentioning

confidence: 99%

Gene therapy for carcinoma of the breast

2006

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Combination therapy of Ad-mda7 and trastuzumab increases cell death in Her-2/neu–overexpressing breast cancer cells

Cited by 50 publications

References 14 publications

Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

Historical perspective and recent insights into our understanding of the molecular and biochemical basis of the antitumor properties of mda-7/IL-24

Gene therapy for carcinoma of the breast

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