) Advanced prostate cancer is only temporarily controlled with androgen ablation therapy, which may be secondary to the development of tumor resistance mechanisms, such as p53 mutations and Bcl-2 overexpression. We developed a preclinical epithelial cell line model to dissect out p53 and bcl-2 mechanisms of resistance, derived from primary baby rat kidney cpitlielial cells (BIZK), which were transfected with genes encoding the murine temperature sensitive p53(vaII35) 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 irradiated resistance when combined with TAX including 13- cis retinoic acid and alpha interferon (CRAIIFN). In a pilot clinical trial using IFN/CRA alone in patients with prostate cancer, we demonstrated minimal activity, but gained important experience in obtaining biological correlates. Based on our initial observations using CRA/IFN in both the laboratory and the clinic, and the known importance of bcl-2 and p53 mechanisms of drug resistance in prostate cancer, we hypothesize that certain agents that overcome p53mt/+bcl-2 mediated resistance alter the function of bcl-2, and these agents when moved into the clinic will translate into improved therapeutic results against hormone refractory prostate cancer. To test this hypothesis, we will perform a clinical trial treating patients with advanced malignancy and hormone refractory prostate cancer in a phase I/U trial with CRA/IFN in combination with TAX and a detailed analysis of bcl-2 and p53 in clinical specimens.
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| Rafi, M M; Rosen, R T; Vassil, A et al. (2000) Modulation of bcl-2 and cytotoxicity by licochalcone-A, a novel estrogenic flavonoid. Anticancer Res 20:2653-8 |
| Chiang, P W; Schneider, A; Borgnat, S et al. (2000) Molecular analysis of urine sediment for follow-up of urinary tract cancers. J Natl Cancer Inst 92:1779-80 |
| DiPaola, R S; Rafi, M M; Vyas, V et al. (1999) Phase I clinical and pharmacologic study of 13-cis-retinoic acid, interferon alfa, and paclitaxel in patients with prostate cancer and other advanced malignancies. J Clin Oncol 17:2213-8 |
