The bcl-2 gene is highly expressed in various human malignancies where it promotes tumor formation and contributes to drug-resistance by preventing tumor cells from undergoing programmed death. A growing body of research evidence indicates that preventing bcl-2 expression either kills tumor cells outright or sensitizes them to radiation and/or chemotherapeutic agents. We therefore intend to develop compounds, suitable for human use, that repress bcl-2 gene expression by selectively activating genomic imprinting mechanisms. Our ultimate objective is to develop a new class of pharmacotherapeutic agents for the treatment of solid tumors and hematological cancers. In the Phase I grant period, we will employ proprietary gene inactivation technology to prepare a series of chemical compounds which will then be tested in cell-based assays to determine their capacity to (1) repress bcl-2 gene transcription and reduce intracellular Bcl-2 protein levels, (2) inhibit tumor cell growth, and (3) potentiate the antitumor actions of conventional chemotherapeutic agents. Our overall goal in the Phase I grant period is to identify lead compounds for pre-IND safety and efficacy testing.
Thesaurus Terms: BCL2 gene /protein, antineoplastic, drug design /synthesis /production, gene induction /repression, neoplasm /cancer chemotherapy, neoplastic growth DNA methylation, antisense nucleic acid, genetic promoter element, genetic transcription, genetic translation, insulinlike growth factor, messenger RNA, neoplasm /cancer genetics, oligonucleotide MCF7 cell
