Site Specific Alkylation of the HER2/neu Promoter
Site Specific Alkylation of the HER2/neu Promoter
批准号:
6469944
负责人:
SCOT W EBBINGHAUS
金额:
$33.21万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2002
资助国家:
美国
项目状态:
已结题
起止时间:
2002-04-01 至 2005-03-31
关键词:
Adenoviridae alkylation drug design /synthesis /production epidermal growth factor gene mutation genetic promoter element growth factor receptors neoplasm /cancer genetics neoplasm /cancer pharmacology nitrogen mustard nonsmall cell lung cancer oligonucleotides polymerase chain reaction protooncogene southern blotting tissue /cell culture transfection /expression vector
中文摘要
描述(由申请人提供):HER-2/新的癌基因似乎起作用
英文摘要
DESCRIPTION (PROVIDED BY APPLICANT): The HER-2/neu oncogene appears to play
an important role in the initiation and progression of many types of human cancer,
including approximately 25 percent of non-small cell lung cancer (NSCLC), the
leading cause of cancer death in both men and women in the U.S. The overall
goal of this project is to find novel ways to specifically inhibit HER-2/neu
expression by developing triplex forming oligonucleotide (TFO)-alkylator
conjugates what will bind in a site-specific manner to the HER-2/neu promoter
by triplex DNA formation and lead to covalent DNA modification at specific
guanine bases by the DNA alkylating agent. The specific aims of this proposal
are designed to address the major obstacles to the successful development of a
TFO-based DNA binding drug. Site-specific alkylation with TFOs conjugated to
nitrogen mustards will be demonstrated in the HER-2/neu promoter. These data
will be rationalized by molecular modeling, and these models will be used to
further refine the design of the TFO-alkylator conjugates (Specific Aim 1).
Much of this work has now been accomplished, and future work will focus on the
design of novel conjugates with a minor groove DNA binding agent and the
investigation of nuclease resistant oligonucleotide backbone modifications. The
ability of these compounds to inhibit transcription initiation will be studied
by triple helix formation in a reporter plasmid transiently transfected into
NSCLC cell lines, and the ability of NSCLC cells to recognize and repair
triplex directed DNA alkylation will be characterized after transfection
(Specific Aim 2). Our preliminary data demonstrates that a TFO conjugated to a
nitrogen mustard at both the 3' and 5' ends can direct two guanine adducts
adjacent to both ends of the triple helix to resist DNA repair and suppress
HER-2/neu promoter activity in NSCLC cells. An adenovirus based ODN delivery
system will be developed, and the ability of adenoviruses to mediate ODN uptake
and nuclear localization will be determined when adenovirus-ODN complexes are
formed by a semi-stable chemical linker (Specific Aim 3). The ability of
triplex forming ODNs to bind to the endogenous HER-2/neu gene and direct
site-specific DNA alkylation will be studied by Southern blot and ligation
mediated-PCR after the treatment of NSCLC cells with the TFO-alkylator
conjugates (Specific Aim 4). The therapeutic potential of these compounds to
inhibit HER-2/neu expression and alter the malignant and invasive phenotype of
NSCLC cells will be evaluated in tissue culture (Specific Aim 5). The
development of a HER-2/neu specific anti-gene compound will provide a great
deal of information about the role of the HER-2/neu gene in the initiation and
progression of NSCLC and may lead to novel treatment approaches for HER-2/neu
expressing cancers such as NSCLC.
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Site Specific Alkylation of the HER2/neu Promoter
-
批准号:6623724
-
项目类别:
-
资助金额:$31.92万
-
财政年份:2002
-
负责人:SCOT W EBBINGHAUS
-
依托单位:
Site Specific Alkylation of the HER2/neu Promoter
-
批准号:6729846
-
项目类别:
-
资助金额:$31.92万
-
财政年份:2002
-
负责人:SCOT W EBBINGHAUS
-
依托单位:
SPECIFIC INHIBITION OF HER2/NEU TRANSCRIPTION ELONGATION
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批准号:6311254
-
项目类别:
-
资助金额:$8.94万
-
财政年份:1998
-
负责人:SCOT W EBBINGHAUS
-
依托单位:
SPECIFIC INHIBITION OF HER2/NEU TRANSCRIPTION ELONGATION
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批准号:6489126
-
项目类别:
-
资助金额:$2.65万
-
财政年份:1998
-
负责人:SCOT W EBBINGHAUS
-
依托单位:
SPECIFIC INHIBITION OF HER2/NEU TRANSCRIPTION ELONGATION
-
批准号:6137647
-
项目类别:
-
资助金额:$1.58万
-
财政年份:1998
-
负责人:SCOT W EBBINGHAUS
-
依托单位:
SPECIFIC INHIBITION OF HER2/NEU TRANSCRIPTION ELONGATION
-
批准号:6342067
-
项目类别:
-
资助金额:$10.61万
-
财政年份:1998
-
负责人:SCOT W EBBINGHAUS
-
依托单位:
SPECIFIC INHIBITION OF HER2/NEU TRANSCRIPTION ELONGATION
-
批准号:2856489
-
项目类别:
-
资助金额:$10.08万
-
财政年份:1998
-
负责人:SCOT W EBBINGHAUS
-
依托单位:
SPECIFIC INHIBITION OF HER2/NEU TRANSCRIPTION ELONGATION
-
批准号:2465347
-
项目类别:
-
资助金额:$10.08万
-
财政年份:1998
-
负责人:SCOT W EBBINGHAUS
-
依托单位:
TRIPLEX BASED GENE THERAPY OF BREAST AND OVARIAN CANCER
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批准号:2114186
-
项目类别:
-
资助金额:$7.88万
-
财政年份:1996
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负责人:SCOT W EBBINGHAUS
-
依托单位:
TRIPLEX BASED GENE THERAPY OF BREAST AND OVARIAN CANCER
-
批准号:2769850
-
项目类别:
-
资助金额:$7.88万
-
财政年份:1996
-
负责人:SCOT W EBBINGHAUS
-
依托单位:
TRIPLEX BASED GENE THERAPY OF BREAST AND OVARIAN CANCER
-
批准号:2517708
-
项目类别:
-
资助金额:$7.88万
-
财政年份:1996
-
负责人:SCOT W EBBINGHAUS
-
依托单位:
海外基金