This proposal outlines plans for a phase II clinical evaluation of the potential activity of paclitaxel in the treatment of patients with hormone-refractory prostate cancer (HRPC), when given as a 96 hour continuous intravenous infusion of 120 mg/M2 every 3 weeks. Preclinical and early clinical data suggest that paclitaxel possesses substantial activity against HRPC, with an in vitro IC50 of 10 nM, a concentration well below the serum paclitaxel concentrations achieved during conventional 24 hour infusions of paclitaxel. The prolonged infusional schedule to be utilized in this protocol is anticipated to generate serum paclitaxel concentrations well above 10 nM, and yet prove pharmacologically advantageous when compared to the conventional 24 hour infusional schedule because of paclitaxel's cell cycle phase-specificity and the low growth fraction of most human tumors. The primary endpoint to be used in assessing paclitaxel's activity against this disease will be changes in the serum level of prostate specific antigen (PSA). Twenty patients will be initially accrued to this trial. If 8 or more patients fulfill the definition of response by PSA criteria, then this regimen will subsequently be tested in a standard phase II protocol that requires patients to have measurable disease. In addition to the primary objective of assessing paclitaxel's activity in HRPC when given by prolonged infusion, this proposal also requests support for studies whose purpose it is to determine whether paclitaxel acts as an inhibitor of isoprenylation of signal transducing proteins in vivo, as it does in vitro. Recent work in our laboratory has demonstrated that the cytotoxicity of paclitaxel in vitro against the human prostate cancer cell line, PC-3, can be partially antagonized by the addition of farnesyl-PP and geranylgeranyl-PP, and that the isoprenylation of both p21 ras and p21 rap 1 are reduced by exposure to paclitaxel. Our intention is to determine the state of isoprenylation of p21 rap 1 in peripheral blood mononuclear cells of patients, both before and upon completion of their first 96 hour treatment with paclitaxel. If it is possible to demonstrate that this phenomenon occurs in vivo, then subsequent studies of paclitaxel in combination with other inhibitors of isoprenylation will be proposed.
