PROTEIN KINASE C--A NOVEL TARGET FOR CANCER THERAPY

描述：（申请人的描述）我们的长期目标是 通过开发新的治疗策略来改善临床癌症治疗 利用蛋白激酶C（PKC）治疗人类恶性肿瘤 用于增强化疗诱导的肿瘤细胞凋亡的靶点。 最近的研究表明，诱导细胞凋亡 （程序性细胞死亡）和p53表达。 表达野生型 p53能够在暴露于常见的 化疗药物;而具有突变或缺失的p53的细胞， 耐化疗，避免细胞凋亡并继续复制。 一 癌症化疗的主要障碍是如何克服这种形式的药物 阻力 据认为，许多化合物的抗肿瘤活性 化疗剂（例如，顺铂和依托泊苷）是 它们诱导细胞凋亡。 最近对这些因素的调查， 调节细胞凋亡提供了证据， 决定最终选择的促凋亡信号和抗凋亡信号之间的联系。 基于临床前研究，我们的假设是， 抑制化疗诱导的细胞凋亡的诱导，并且这可以 通过使用PKC抑制剂与化疗联合来克服。 我们临床开发的具体和长期目标是：1）开发 使用PKC抑制剂（例如沙芬戈，UCN-01， flavopiridol和bryostatin）与化疗联合使用， 实验室相关因素（PKC活性、cdk 2活性和终末 肿瘤组织和白细胞中的脱氧核苷酸转移酶（TdT）活性） 作为活性的推定替代终点; 2）进行体外研究 与PKC抑制剂和化疗，这将确定最佳的 在这些条件和组合下，最大程度的凋亡可以 并利用这些研究来确定 是细胞周期调节的改变（例如CDK 2活性的增加）; 3） 为了确定一个特定的PKC亚型是否可能是一个关键的目标， 通过检测PKC在化疗中诱导细胞凋亡的药物开发 在实验室模型中针对特定同种型的反义。

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.