Disruption of microtubule structure by antimicrotubule drugs results in induction of tumor suppressor gene p53 and inhibitor of cyclin-dependent kinases, p21WAF1/CIP1 (p21), and activation/inactivation of several protein kinases including Ras/Raf, PKC/PKA I/II, MAP kinases, and p34cdc2. These protein kinases are associated directly or indirectly with phosphorylation of bcl-2. Phosphorylation of bcl-2 and the elevations of p53 and p21 lead to apoptosis. New pathways of antitumor agents could be directed at this p53, p21 and bcl-2/bax function, and may enhance the effect of existing agents.

EP given continuously with every three-week docetaxel at a dose of 70 mg/m2 is tolerable with evidence of antitumor activity based upon significant declines in PSA in the majority of patients and improvement of lung metastasis in one patient. Larger phase II studies of this combination in a homogenous population are warranted.

Objective To evaluate combinations of anti-tumour vinblastine, paclitaxel, docetaxel, bicalutamide, ketoconazole and all-trans-retinoic acid. Other synergistic agents in tissue cultures using three established cell lines derived from patients with prostate cancer to combinations of two agents were: Liarozole plus docetaxel in LnCaP, PSC 833 plus bicalutamide in DU 145 obtain potential candidates for therapeutic testing in patients with prostate cancer.and PC 3, dexamethasone plus docetaxel in LnCaP, and finasteride plus hydroxyflutamide. Synergistic Materials and methods Seventeen anti-tumour agents were tested for synergism or antagonism in combicombinations of three agents were: estramustine plus PSC 833 and Liarozole and schedule-dependent nation studies in DU 145, PC 3 and LnCaP cell lines. After determining the dose required for 50% inhibition combinations of estramustine, PSC 833, and all-transretinoic acid. of growth in each, combinations were screened using the median-effect plot and combination-index Conclusion Some of the synergistic combinations have shown clinical effects in patients with hormoneisobolograms. Results Estramustine (the primary product of dephosrefractory prostate cancer. Based on these findings, new combinations, e.g. estramustine with either PSC phorylation of estramustine phosphate) showed strong synergism in all three cell lines with hydroxyflutamide, 833 or Liarozole, need to be clinically evaluated. Keywords Prostate cancer cell lines, anti-tumour agents, the non-immunosuppressive cyclosporin analogue PSC 833, and LiarozoleA . In the hormone-sensitive cell combinations, synergism, antagonism line LnCaP alone, synergism was also observed with potential lack of correlation between the plasma concen-

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