p53 performs both positive and negative roles in cancer in that it 1) acts faithfully over time as a tumor suppressor by causing apoptosis and cell growth arrest in response to genotoxic stresses and 2) is responsible for the severe toxicity to normal tissues during cancer treatments. Roughly 50% of human tumors lack functional p53 and recent work has shown that an inhibitor of p53 has the potential in these cases to ameliorate the side-effects of both chemotherapy and radiation therapy by sparing normal tissues from p53 induced cell death. In an effort to expand this new technology to the other 50% of human tumors that do contain functional p53 we propose prodrugs of p53 inhibitors that localize in the skeletal system (bone) and release active p53 inhibitors over time to the nearby bone marrow. In this way we propose to deliver a protective effect selectively to hematopoietic tissue which often suffers dose-limiting side effects during chemotherapy and radiation treatment of cancer. By concentrating in the bone/marrow and not being accessible to the tumor, such an approach could allow for higher tolerated doses of anticancer drugs in therapeutic modalities where the marrow toxicity was dose limiting.
The proposed work is aimed at delivering prodrug forms of p53 inhibitors to bone such that under physiological conditions therapeutically useful quantities of biologically active p53 inhibitors are released at the bone surface. This targeted delivery of p53 inhibitors has commercial application as a marrow protecting adjuvant in chemotherapy and radiation treatment of tumors that do not reside in the bone or marrow.
