) 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.
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