Growth Suppression and Therapy Sensitization of Breast Cancer
Final rept. 1 Jul 1996-30 Jun 2001
SIDNEY KIMMEL CANCER CENTER SAN DIEGO CA
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The goal of this project is to provide a rationale and pre-clinical evaluation of p53-based approaches to growth suppression and therapy sensitization of breast cancer, including combination approaches in which p53 gene therapy is combined with traditional chemotherapy or with inhibitors of DNA repair. We have observed that restoration of p53 activity in tumor cells sensitizes them to a variety of DNA damaging treatments, including doxorubicin, a standard breast cancer therapeutic. An important determinant of p53-mediated apoptosis is the level of endogenous DNA damage, and this is increased by treatment of cells with inhibitors of DNA repair. We have also observed that disruption of the Jun Kinase pathway inhibits DNA repair, increases the sensitivity of tumor cells to DNA damage and to p53-mediated apoptosis through the bax pathway. Intratumoral administration of a replication-impaired adenovirus encoding wild-type p53 Adp53 suppresses the growth of established subcutaneous tumors of human breast cancer cells in nude mice, and this suppression is enhanced in the presence of doxorubicin. Systemic administration of Adp53 in combination with doxorubicin results in a significant reduction in the incidence of lung metastases, using an orthotopic model in nude mice of human metastatic breast cancer.
- Medicine and Medical Research