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1808
Downregulation of HER2, Induction of Apoptosis,
and Increase in TNF-? Level After E1A Gene Therapy in Patients with
Advanced Breast/Ovarian Cancers. Naoto T Ueno, Weiya Xia, Su
Zhang, Chandra Bartholomeusz, Judith K Wolf, David M. D. Andeson
Cancer Center Gershenson, Leaf Huang, Gabriel Lopez-Berestein,
Gabriel Naoto Hortobagyi, Pervin Anklesaria, Mien-Chie Hung, M D
Andeson Cancer Ctr, Houston, TX; Univ of Pittsburgh, Pittsburgh, PA;
Targeted Genetics Corp, Seattle, WA.
E1A is recognized as a tumor suppressor gene by its repression of
HER2 transcription, its repression of metastatic potential and
induction of apoptosis in malignant cells, and its ability to
prolong DFS in nude mice bearing HER2-overexpressing breast/ovarian
cancers. We evaluated the molecular effect of an E1A-cationic
liposome (DC-Chol) complex injected weekly into the thoracic or
peritoneal cavities of pts with recurrent breast (n=6) or ovarian
(n=6) cancers. In several pts, treatment resulted in stable disease
(SD). Twelve tumor overexpressed HER2. We subjected tissue samples
from 6 HER2-overexpressing pts' tumor to molecular analysis. In all
6 cases, this revealed E1A gene expression in both cancer and
non-cancer cells and downregulation of HER2 expression via IHC (as
confirmed by imaging analysis). In 5 of 6 cases, apoptosis was
strongly induced (TUNEL assay). Because TNF-a induces apoptosis of E1A-transduced cells in
vitro, TNF-a levels in intracavitary fluid
were examined after E1A/DC-Chol injection, and a similar correlation
was found. The precise mechanism behind these E1A's antitumor
activities will be further evaluated in an upcoming Phase II trial
of E1A gene therapy for ovarian cancer.
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