BDNF INDUCED DRUG RESISTANCE IN NEUROBLASTOMA

BDNF 诱导神经母细胞瘤耐药

• 批准号: 6173227
• 负责人: DAVID S MIDDLEMAS
• 金额: $ 10.71万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6173227
• 关键词: apoptosis; biological signal transduction; cis platinum compound; cyclophosphamide; cytotoxicity; doxorubicin; drug resistance; enzyme inhibitors; etoposide; growth factor receptors; laboratory mouse; necrosis; neoplasm /cancer pharmacology; neoplastic cell; neuroblastoma; neurotrophic factors; phosphatidylinositol 3 kinase; phospholipase C; phosphorylation; receptor binding; receptor expression; retinoate; site directed mutagenesis; tissue /cell culture; vincristine

DESCRIPTION: There is increasing evidence that growth factors may have multiple effects. In addition to stimulating mitogenesis, growth factors may promote differentiation or act as survival factors during development, or as survival factors to cells undergoing stress due to changed in trophic support or damage due to anticancer drug treatments. In neuroblastoma (NB) expression of TRK, the receptor for nerve growth factor (NGF), has been correlated with a good prognosis. In contrast, data presented in this application demonstrates that expression of TRKB, the receptor for BDNF, is associated with resistance to cisplatin. This application proposes to test the hypothesis that brain derived growth factor (BDNF), which is a ligand for TRKB, induces resistance to cisplatin in a human neuroblastoma (NB) cell line and that this resistance is mediated through one of three potential pathways. Three specific aims have been presented. Specific Aim 1 proposes to determine whether NGF or BDNF protect NB cells from cytotoxic drugs or serum withdrawal. This specific aim will also test compounds etoposide, vincristine, cyclophosphamide and doxorubicin. It will also test whether these compounds cause cell death by apoptosis or necrosis. Additional cell lines will also be tested for these receptors and ligands to determine how relevant these findings are to NB. Specific Aim 2 will define the signaling pathways involved in TRK and TRKB mediated protection of cells from either cytotoxic agents or serum starvation. Three potential pathways of signal transduction have been proposed to investigate: 1) RAS, phosphatidyl inositol-3 kinase, 2) P13K pathway, and 3) phospholipase C-g1(PLC-g1). They also propose to use site specific mutagenesis of the tyrosines in the kinase domain of TRKB which form the binding site for the SHC, P13K or PLC-g1. Additional studies will include specific inhibitors of the TRK and TRKB ,P13K, RAS and PLC-g1, and dominant negative constructs against RAS. In Specific Aim 3 they propose to determine if TRKB or TRK increases drug resistance in vivo using mouse xenograft models.

描述：有越来越多的证据表明，生长因子可能有

项目成果

Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models.

• 发表时间: 2000-10
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: P. Houghton;C. Stewart;P. Cheshire;L. Richmond;M. Kirstein;C. Poquette;M. Tan;H. Friedman;T. Brent

Biochemical correlates of temozolomide sensitivity in pediatric solid tumor xenograft models.

• 发表时间: 2000-03
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: D. Middlemas;C. Stewart;M. Kirstein;C. Poquette;H. Friedman;Peter J. Houghton;T. Brent