) Advanced breast cancer is only temporarily controlled with chemotherapy, which may be secondary to the development of tumor resistance mechanisms, such as bcl-2 overexpression. We used a pre-clinical epithelial cell line model to dissect out bcl-2 mechanisms of resistance derived from primary baby rat kidney epithelial cells (BRK), which were transfected with genes encoding the murine temperature sensitive p53(va1135) and a bcl-2 expression vector. We found that cells with p53 mutation and overexpression of bcl-2 were resistant to paclitaxel (TAX). In an attempt to sensitize these cells to TAX, we found several active agents capable of overcoming p53 and bcl-2 mediated resistance when combined with TAX including 13-cis retinoic acid and alpha interferon (CRA/IFN). We found that CRA/IFN also enhanced the effect of TAX on breast tumor cells (MCF-7) and prostate tumor cells (PC-3), both of which overexpress bcl-2. Additionally, we found that the effect of CRA/IFN on these cell lines correlated to reduction in expression of bcl-2. Based on these data, we hypothesized that agents that modulate the expression of bcl-2 and sensitize tumor cells to chemotherapy in the laboratory will translate into improved clinical results. To test this hypothesis, we completed a phase I clinical trial using CRA/IFN and TAX in patients with advanced malignancy and plan to treat patients with advanced breast cancer in a phase II trial with CRA/IFN in combination with TAX (using the dose established in our phase I trial) along with and a detailed analysis of bcl-2 in clinical specimens.
