The proposed investigation is designed to provide clinical and pharmacodynamic data to determine the efficacy and safety of the sequential administration of a DNA damaging agent (doxorubicin) followed by a vinca alkaloid (vinorelbine) in the treatment of breast cancer. The rationale for this study is based on the following laboratory investigations. The functional status of p53 affects the cellular response to a variety of injuries. Whereas wild-type p53 favors growth arrest or programmed cell death (apoptosis), mutant p53 favors continued cell-cycle progression. Recent studies indicate that p53 may affect the sensitivity to cancer chemotherapeutic drugs through the transcriptional regulation of Microtubule Associated Protein 4 (MAP4), a microtubule associated protein that regulates the polymerization state of microtubules. Our preclinical studies demonstrated that induction of wild-type p53 following DNA damage repressed MAP4, decreased polymerization of microtubules, and increased sensitivity to vinca alkaloids. Therefore, the overall goal of this proposal is to determine if these observations apply to patients, and thereby provide a rationale for optimal sequencing and selection of combination chemotherapy. There are phase II data supporting the concurrent use of doxorubicin and vinorelbine.
The specific aims of the proposed investigation are (1) To assess the safety and efficacy of the sequential use of a DNA damaging drug (doxorubicin) followed by a vinca alkaloid (vinorelbine) in the treatment of breast cancer. (2) To assess the feasibility of measuring the pharmacodynamic response to doxorubicin and vinorelbine administered in patients with breast cancer as follows: to determine the effect of DNA damaging agent, doxorubicin, on p53 and MAP4 expression by assaying the proteins in sequential tumor biopsies and peripheral blood mononuclear cells.
