UNIQUE SYNERGISM OR ANTAGONISM OF COMBINATIONS OF CHEMOTHERAPEUTIC AND HORMONAL AGENTS IN HUMAN PROSTATE-CANCER CELL-LINES

Objective To evaluate combinations of anti-tumour agents in tissue cul tures using three established cell lines derived from patients with pr ostate cancer to obtain potential candidates for therapeutic testing i n patients with prostate cancer. Materials and methods Seventeen anti- tumour agents were tested for synergism or antagonism in combination s tudies in DU 145, PC 3 and LnCaP cell lines. After determining the dos e required for 50% inhibition of growth in each, combinations were scr eened using the median-effect plot and combination-index isobolograms. Results Estramustine (the primary product of dephosphorylation of est ramustine phosphate) showed strong synergism in all three cell lines w ith hydroxyflutamide, the non-immunosuppressive cyclosporin analogue P SC 833, and Liarozole(R). In the hormone-sensitive cell line LnCaP alo ne, synergism was also observed with vinblastine, paclitaxel, docetaxe l, bicalutamide, ketoconazole and all-trans-retinoic acid. Other syner gistic combinations of two agents were: Liarozole plus docetaxel in Ln CaP, PSC 833 plus bicalutamide in DU 145 and PC 3, dexamethasone plus docetaxel in LnCaP, and finasteride plus hydroxyflutamide. Synergistic combinations of three agents were: estramustine plus PSC 833 and Liar ozole and schedule-dependent combinations of estramustine, PSC 833, an d all-trans-retinoic acid. Conclusion Some of the synergistic combinat ions have shown clinical effects in patients with hormone-refractory p rostate cancer, Based on these findings, new combinations, e.g. estram ustine with either PSC 833 or Liarozole, need to be clinically evaluat ed.