Gap Junctions and Cancer Drug Therapy

间隙连接和癌症药物治疗

• 批准号: 6994921
• 负责人: RANDALL J RUCH
• 金额: $ 4.99万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6994921
• 关键词: cell cell interaction; clone cells; cytotoxicity; drug interactions; enzyme inhibitors; flow cytometry; fluorescent dye /probe; gap junctions; gene therapy; high performance liquid chromatography; hydroxyurea; leukocytes; mixed tissue /cell culture; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; pharmacokinetics; postdoctoral investigator; ribonucleotide reductase; southern blotting; transfection; western blottings

DESCRIPTION (provided by applicant): Gap junctions (GJs) connect the interiors of neighboring cells and permit the passive cell-to-cell flux of molecules and ions less than approximately 1 kDa. GJs have the potential to modify conventional and non-conventional cancer therapies in several ways, but this has seen little investigation. I propose to investigate how GJs alter the cytotoxicity of chemotherapeutic agents known as ribonucleotide reductase (RR) inhibitors. These agents induce nucleotide imbalances in cells, and I hypothesize nucleotide buffering via GJs will impact RR toxicity. I have proposed two Specific Aims to address the hypothesis: Aim 1: Isolate clones of GJ-competent and GJ-incompetent WB cells that are sensitive and resistant to the RR inhibitor, hydroxyurea (HU). We will use WB-F344 (GJ+) and WB-aB1 (GJ-) cells for this purpose and will characterize HU cytotoxic dose response, nucleotide pools, and RR activity and expression. Aim 2: Quantify the effects of GJs on cytotoxic response and nucleotide buffering in co-cultures of HU-sensitive and resistant cells. HU-sensitive and resistant, GJ+ or GJ- cells will be co-cultured and treated with HU, then cytotoxicity and nucleotides will be quantified in each type of cell. These studies may lead to new cancer therapy paradigms and treatments.

描述（由申请人提供）：间隙连接（GJ）连接相邻细胞的内部，并允许分子和离子的被动细胞间通量小于约1 kDa。GJ有可能以多种方式改变常规和非常规癌症疗法，但这方面的研究很少。我建议研究GJs如何改变称为核糖核苷酸还原酶（RR）抑制剂的化疗药物的细胞毒性。这些药物诱导细胞中的核苷酸失衡，我假设通过GJ的核苷酸缓冲将影响RR毒性。我已经提出了两个具体的目标来解决这个假设：目标1：分离对RR抑制剂羟基脲（HU）敏感和耐药的GJ感受态和GJ不感受态WB细胞的克隆。我们将使用WB-F344（GJ+）和WB-aB 1（GJ-）细胞用于此目的，并将表征HU细胞毒性剂量反应、核苷酸池以及RR活性和表达。目的2：定量GJ对HU敏感细胞和抗性细胞的共培养物中的细胞毒性反应和核苷酸缓冲的影响。将HU敏感性和抗性、GJ+或GJ-细胞共培养并用HU处理，然后在每种类型的细胞中定量细胞毒性和核苷酸。这些研究可能会导致新的癌症治疗模式和治疗方法。