PROTEIN KINASE C AND GLIAL TUMOR GROWTH

蛋白激酶 C 和神经胶质瘤生长

• 批准号: 2891368
• 负责人: Ian F. Pollack
• 金额: $ 9.45万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2891368
• 关键词: antineoplastics; antisense nucleic acid; astrocytes; astrocytoma; athymic mouse; cell cycle; cell growth regulation; disease /disorder model; drug resistance; enzyme activity; enzyme inhibitors; gene expression; glioma; human tissue; immunocytochemistry; isozymes; messenger RNA; neoplasm /cancer genetics; neoplasm /cancer pharmacology; neoplasm /cancer surgery; neoplastic cell; neoplastic growth; protein kinase C; tissue /cell culture; western blottings

Astrocytomas are the most common central nervous system tumors in both children and adults and are also the group most poorly controlled with conventional therapies. Recent studies have indicated that overexpression and excessive activation of protein kinase C (PKC) may play a significant role in mediating the growth of these tumors and, conversely, that inhibition of this second messenger may provide a novel strategy for blocking astrocytoma proliferation. The goals of the present study are to characterize the patterns of PKC isoenzyme expression in neoplastic and non-neoplastic astrocytes in order to determine whether one or more isoforms are differentially overexpressed in astrocytoma cells; these data will then form the basis for developing and examining the efficacy of therapeutic strategies directed at inhibiting PKC as a means for blocking astrocytoma growth in vitro and in vivo. The hypotheses to be evaluated in this study are that astrocytic tumor cells demonstrate overexpression of specific PKC isoforms in comparison to non-neoplastic astrocytes, that such isoforms play a role in mediating the growth of these tumors, and that the proliferation of astrocytic tumors may be inhibited by blocking PKC-mediated pathways. The experimental strategy is designed to identify which PKC isoenzymes are overexpressed in neoplastic astrocytes in comparison to non-neoplastic astrocytes using immunohistochemical and Western blotting studies on a series of established and low-passage astrocytoma and non-neoplastic astrocyte cell lines, and surgical tumor and nonneoplastic brain specimens. Antisense-mediated inhibition of the expression of such isoenzymes will then be employed to determine whether a selective decrease in the levels of individual isoforms inhibits basal and/or mitogen- stimulated cell proliferation in vitro. In addition, a series of well characterized PKC-selective inhibitors, which have been well tolerated in animal model studies of non-glial tumors, will be used to determine whether a more generalized inhibition of PKC activity is effective in blocking basal and mitogen-stimulated cell proliferation in vitro. Since excessive activation of PKC has been associated with resistance to a variety of conventional chemotherapeutic agents in non-glial tumor model systems, and this resistance may be reversed by inhibition of PKC, attention will also be focused on determining whether PKC inhibition potentiates the efficacy of conventional chemotherapeutic agents in gliomas, which characteristically show poor responsiveness to such agents. Based on the results of the in vitro experiments, subsequent studies will examine the efficacy of PKC inhibition both alone and in conjunction with conventional chemotherapeutic agents as a therapeutic strategy in a nude mouse glioma model. Taken together, these studies will provide fundamental information on the biology astrocytomas and would form the basis for future clinical application of PKC inhibition in the treatment of astrocytic neoplasms.

星形胶质细胞瘤是两者中最常见的中枢神经系统肿瘤 儿童和成人，也是最不良控制的小组 常规疗法。 最近的研究表明过表达 蛋白激酶C（PKC）的过度激活可能会显着 在介导这些肿瘤的生长中的作用，相反 抑制此第二使者可能会为 阻断星形细胞瘤增殖。 本研究的目标是 表征PKC同工酶表达在肿瘤和 非塑性星形胶质细胞以确定一个或多个 在星形细胞瘤细胞中，同工型差异表达。这些数据 然后将构成开发和检查功效的基础 针对抑制PKC作为阻止的手段的治疗策略 体外和体内星形胶质细胞瘤的生长。 要评估的假设 在这项研究中，星形细胞肿瘤细胞表现出过表达 与非塑性星形胶质细胞相比，特定的PKC同工型 这种同工型在介导这些肿瘤的生长中起作用，以及 通过阻塞可以抑制星形细胞肿瘤的增殖 PKC介导的途径。 实验策略旨在确定哪些PKC同工酶是 与非神经塑性相比，肿瘤星形胶质细胞过表达 使用免疫组织化学和蛋白质印迹研究的星形胶质细胞 一系列已建立和低通量的星形胶质细胞瘤和非塑性瘤 星形胶质细胞系，手术肿瘤和非肿瘤大脑 标本。 反义介导的这种表达抑制 然后将使用同工酶来确定选择性减少 在单个同工型的水平中，抑制基础和/或有丝分裂原 - 体外刺激细胞增殖。 此外，一系列井 PKC选择性抑制剂的表征，在 非腹膜肿瘤的动物模型研究将用于确定 PKC活性的更普遍的抑制是否有效 在体外阻断基础和有丝分裂原刺激的细胞增殖。 自从 PKC的过度激活与对A的抗性有关 非粘膜肿瘤模型中的常规化学治疗剂的种类 系统，这种抗性可能会因抑制PKC而逆转， 注意还将集中于确定PKC是否抑制 增强常规化学治疗剂在 神经胶质瘤，其特征在于对此类药物的反应性不佳。 根据体外实验的结果，随后的研究将 检查PKC抑制的功效，并与 常规化学治疗剂作为裸体的治疗策略 小鼠胶质瘤模型。 两者一起，这些研究将提供 有关生物学星形胶质细胞瘤的基本信息，并将形成 PKC抑制在治疗中的未来临床应用的基础 星形细胞肿瘤。

项目成果

The relationship between TP53 mutations and overexpression of p53 and prognosis in malignant gliomas of childhood.

TP53突变和p53过表达与儿童恶性胶质瘤预后的关系。

• 发表时间: 1997
• 期刊: Cancer research.
• 作者: Pollack,IF;Hamilton,RL;Finkelstein,SD;Campbell,JW;Martinez,AJ;Sherwin,RN;Bozik,ME;Gollin,SM
• 通讯作者: Gollin,SM

Surgical management of spinal cord compression from plexiform neurofibromas in patients with neurofibromatosis 1.

神经纤维瘤病患者丛状神经纤维瘤压迫脊髓的手术治疗 1.

• DOI: 10.1097/00006123-199808000-00038
• 发表时间: 1998
• 期刊: Neurosurgery
• 影响因子: 4.8
• 作者: Pollack,IF;Colak,A;Fitz,C;Wiener,E;Moreland,M;Mulvihill,JJ
• 通讯作者: Mulvihill,JJ

Pediatric brain tumors.

小儿脑肿瘤。

• DOI: 10.1002/(sici)1098-2388(199903)16:2
• 发表时间: 1999
• 期刊: Seminars in surgical oncology.
• 作者: Pollack,IF

Posterior fossa syndrome.

后颅窝综合征。

• DOI: 10.1016/s0074-7742(08)60362-1
• 发表时间: 1997
• 期刊: International review of neurobiology.
• 作者: Pollack,IF

An intrasylvian "fibroma" in a child with cystic fibrosis: case report.

囊性纤维化儿童的外侧裂内“纤维瘤”：病例报告。

• DOI: 10.1097/00006123-200003000-00043
• 发表时间: 2000
• 期刊: Neurosurgery
• 影响因子: 4.8
• 作者: Pollack,LF;Hamilton,RL;Fitz,C;Orenstein,DM
• 通讯作者: Orenstein,DM