PROTEIN KINASE C--A NOVEL TARGET FOR CANCER THERAPY

描述：(申请人描述)我们的长期目标是 通过开发一种新的治疗策略来改善临床癌症治疗 以蛋白激酶C(PKC)为靶点治疗人类恶性肿瘤 增强化疗诱导肿瘤细胞凋亡的靶点。 最近的研究表明，诱导细胞凋亡之间存在联系 (细胞程序性死亡)和P53的表达。表达野生型的细胞 P53在暴露于普通细胞后能够发生细胞凋亡 化疗药物；而p53突变或缺失的细胞 耐化疗，避免细胞凋亡，继续复制。一个 癌症化疗的主要障碍是如何克服这种形式的药物 抵抗。已有研究表明，许多化合物的抗肿瘤活性 化疗药物(如顺铂和依托泊苷)是 它们能诱导细胞凋亡。最近对以下因素的调查 调节细胞凋亡为平衡的存在提供了证据 在决定最终选择的促凋亡和抗凋亡信号之间。 我们的假设是，基于临床前研究，PKC的激活 抑制化疗诱导的细胞凋亡，这可以 可通过联合使用PKC抑制剂和化疗来克服。 我们的临床开发的具体和长期目标是：1)开发 使用PKC抑制剂(例如赛芬戈、UCN-01、 黄烷醇和Bryostatin)与化疗联合使用 实验室相关性(PKC活性、CDK2活性和终端 肿瘤组织和白细胞中脱氧核苷酸转移酶(TDT)活性) 作为假定的替代活动终点；2)进行体外研究 使用PKC抑制剂和化疗，这将定义最佳 最大程度的细胞凋亡的条件和组合 并利用这些研究来确定 细胞周期调节的改变(如CDK2活性增加)；3) 确定特定的PKC异构体是否可能是 检测PKC在化疗诱导细胞凋亡中的药物开发 实验室模型中特定异构体的反义。

DESCRIPTION: (Applicant's Description) Our long term objective is to improve clinical cancer therapy by developing a new therapeutic strategy in the treatment of human malignancies which utilizes protein kinase C (PKC) as a target for enhancing chemotherapy induced apoptosis in tumor cells. Recent studies have indicated a link between the induction of apoptosis (programmed cell death) and p53 expression. Cells which express wild-type p53 are capable of undergoing apoptosis after exposure to common chemotherapeutic agents; whereas cell with mutated or deleted p53 are resistant to chemotherapy, avoid apoptosis and continue to replicate. A major hurdle for cancer chemotherapy is how to overcome this form of drug resistance. It has been suggested that the antitumor activity of many chemotherapeutic agents (e.g., cisplatin and etoposide) is a consequence of their induction of apoptosis. Recent investigations into the elements that regulate apoptosis have provided evidence for the existence of a balance between pro- and anti-apoptotic signaling that determines the final choice. Our hypothesis, based on pre-clinical studies, is that the activation of PKC inhibits the induction of chemotherapy induced apoptosis and that this can be overcome by utilizing PKC inhibitors in conjunction with chemotherapy. Our specific and long term aims for clinical development are: 1) To develop an integrated clinical program with PKC inhibitors (e.g. safingol, UCN-01, flavopiridol, and bryostatin) in combination with chemotherapy that uses laboratory correlates (PKC activity, cdk2 activity, and terminal deoxynucleotidyl transferase (TdT) activity in tumor tissues and leukocytes) as putative surrogate end-points of activity; 2) To perform in vitro studies with PKC inhibitors and chemotherapy which will define the optimal conditions and combinations under which the greatest degree of apoptosis can be achieved and to use these studies to define the mechanisms by which there are alterations in cell-cycle regulation (e.g increase in cdk2 activity); 3) To determine whether a specific PKC isofrom may be a critical target for drug development in induction of apoptosis with chemotherapy by testing PKC antisense for specific isoforms in a laboratory model.