Effects of TPA on Leukemia and Solid Tumors

TPA 对白血病和实体瘤的影响

• 批准号: 7068103
• 负责人: ALLAN H CONNEY
• 金额: $ 27.03万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7068103
• 关键词: antineoplastics; athymic mouse; blood /lymphatic neoplasm; butyrates; cell differentiation; cell growth regulation; cholecalciferol; combination chemotherapy; cytotoxicity; drug interactions; drug resistance; drug screening /evaluation; gene expression; isozymes; kinase inhibitor; messenger RNA; myelogenous leukemia; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nuclear factor kappa beta; phorbols; prostate neoplasms; protein kinase C; retinoate; tissue /cell culture

DESCRIPTION (provided by applicant): The present proposal for preclinical studies with 12-O-tetradecanoylphorbol-13-acetate (TPA) will: 1. Identify and characterize combinations of TPA and other potential therapeutic agents that may enhance differentiation and therapeutic efficacy and overcome potential resistance to TPA-induced differentiation in the treatment of myeloid malignancies. 2. Examine the hypothesis that the effects of TPA, all-trans retinoic acid (ATRA), 1 alpha,25-dihydroxyvitamin D3 or butyrate alone or as synergistic combinations are mediated through changes in the levels and translocation of PKC alpha, PKC beta and PKC delta, and on the expression of mRNAs for PKC alpha, PKC beta and PKC delta in TPA-sensitive HL-60 and TPA-resistant HL-525 cells. We will also determine the effects of selective inhibitors of PKC beta and PKC delta as well as the expression of dominant negative PKC isoforms in HL-60 cells on the differentiation response of these cells to TPA alone or together with potential synergistic agents. The effects of overexpression of constitutive PKC isoforms on the action of TPA alone to cause differentiation in TPA-resistant HL-525 cells will also be determined. 3. Study the hypothesis that TPA may have therapeutic efficacy for inducing cytotoxicity in human prostate cancer cells. Specifically, we will determine the effects of TPA alone or in combination with (a) differentiating agents (ATRA, 1alpha, 25-dihydroxyvitamin D3, and butyrate), (b) inhibitors of NF-kappaB (BAY 11-7082) or (c) cytotoxic drugs (taxol, taxotere, mitoxantrone and estramustine) on proliferation and apoptosis of cultured human prostate cancer cell lines. We will test the hypothesis that levels of constitutive NF-kappaB activity determine sensitivity of these cells to TPA-induced cytotoxicity. The effects of TPA alone or in combination with synergizers on the levels and translocation of PKC alpha PKC beta and PKC delta and on the expression of these genes in prostate cancer cells will be evaluated. 4. Determine the in vivo effects of TPA alone, or in combination with other agents that are synergistic, on the growth of human prostate tumors in immunodeficient mice. Blood levels of TPA that are associated with inhibition of tumor growth will be determined. The effect of inhibitors of tumor growth on proliferation and apoptosis in the tumors will be determined.

描述（由申请人提供）： 目前关于12-O-十四烷酰基佛波醇-13-乙酸酯（TPA）的临床前研究提案将： 1.识别和表征TPA和其他潜在治疗药物的组合，这些药物可以增强分化和治疗功效，并克服骨髓恶性肿瘤治疗中对TPA诱导分化的潜在耐药性。2.检查TPA、全反式维甲酸（ATRA）、1 α，25-二羟基维生素D3或丁酸盐单独或协同组合的作用是通过改变PKC α、PKC β和PKC δ的水平和易位以及对TPA敏感性HL-60和TPA耐药HL-525细胞中PKC α、PKC β和PKC δ mRNA表达的影响来介导的假设。我们还将确定PKC β和PKC δ的选择性抑制剂以及HL-60细胞中显性阴性PKC亚型的表达对这些细胞对TPA单独或与潜在协同剂一起的分化反应的影响。还将确定组成型PKC同种型的过表达对TPA单独引起TPA抗性HL-525细胞分化的作用的影响。3.研究TPA可能对诱导人前列腺癌细胞的细胞毒性具有治疗效果的假设。具体而言，我们将确定TPA单独或与（a）分化剂（ATRA，1 α，25-二羟基维生素D3和丁酸盐），（b）NF-κ B抑制剂（BAY 11-7082）或（c）细胞毒性药物（紫杉醇，泰索帝，米托蒽醌和雌莫司汀）对培养的人前列腺癌细胞系增殖和凋亡的影响。我们将测试的假设，组成型NF-κ B活性水平决定这些细胞TPA诱导的细胞毒性的敏感性。将评估TPA单独或与协同剂组合对前列腺癌细胞中PKC α、PKC β和PKC δ的水平和易位以及对这些基因表达的影响。4.确定TPA单独或与其他具有协同作用的药物组合对免疫缺陷小鼠中人前列腺肿瘤生长的体内作用。将测定与肿瘤生长抑制相关的TPA血液水平。将确定肿瘤生长抑制剂对肿瘤中增殖和凋亡的影响。

项目成果

Inhibitory effect of voluntary running wheel exercise on the growth of human pancreatic Panc-1 and prostate PC-3 xenograft tumors in immunodeficient mice.

• DOI: 10.3892/or.19.6.1583
• 发表时间: 2008-06
• 期刊: Oncology reports
• 影响因子: 4.2
• 作者: Xi Zheng;X. Cui;Mou-tuan Huang;Yue Liu;W. Shih;Y. Lin;Yaoping Lu;G. C. Wagner;A. Conney

Inhibition of NF-kappaB by (E)3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile (BAY11-7082; BAY) is associated with enhanced 12-O-tetradecanoylphorbol-13-acetate-induced growth suppression and apoptosis in human prostate cancer PC-3 cells.

• 发表时间: 2008
• 期刊: International journal of oncology
• 影响因子: 5.2
• 作者: Xi Zheng;R. Chang;X. Cui;Gina E. Avila;Mou-tuan Huang;Yue Liu;A. Kong;A. Rabson;A. Conney