CHEMOSENSITIZATION OF HUMAN PROSTATE CARCINOMA CELL-LINES TO ANTI-FAS-MEDIATED CYTOTOXICITY AND APOPTOSIS

Androgen ablation has been an effective treatment in patients with adv anced prostate cancer, However, most treated patients develop hormonal ly resistant disease and do not respond to conventional chemotherapy. Immunotherapy against prostate cancer is an alternative approach in ov ercoming hormonal/drug-resistant prostate cancer, Cytotoxic immune lym phocytes kill target cells via the perforin/granzyme and the Fas-ligan d (Fas-L) pathways, We hypothesize that tumor cells respond poorly to immunotherapy by developing resistance to killing by the Fas-L, mechan ism, This study investigated whether prostate tumor cells are sensitiv e to Fas-mediated killing, The human prostate carcinoma cell lines DU1 45, PC-3, and LnCAP were examined for their sensitivity to killing and apoptosis by the Fas-L agonist anti-Fas antibody and CTLs, All three lines moderately expressed the Fas antigen on the cell surface; howeve r, all three lines were relatively resistant to cytotoxicity mediated by anti-Fas (CH-11) antibody, Pretreatment of DU145 and PC-3 with subt oxic concentrations of drugs followed by anti-Fas antibody resulted in synergistic cytotoxicity and apoptosis, whereas only an additive effe ct was obtained with LnCAP, Chemosensitization with drugs and anti-Fas was completely blocked by the addition of neutralizing anti-Pas antib ody, The murine CTL hybridoma, PMMI, which kills only via the Fas-L pa thway, was able to kill chemosensitized PC-3 and DU145 but not LnCAP c ells, Furthermore, this cytotoxicity was blocked by anti-Fas neutraliz ing antibody, Chemosensitization of PC-3 and DU145 prostate tumor cell s was not due to up-regulation of Fas-receptor antigen expression, Tre atment of tumor cells with cisplatin did not down-regulate the antiapo ptotic genes bcl-2, FAP-1, and c-myc, Further, there was no induction by cisplatin of Pas-L, on the tumor cells, thus ruling out Fas/Fas-L-m ediated autologous killing, These findings demonstrate that pretreatme nt of drug-resistant/CTL-resistant prostate DU145 and PC-3 tumor cells with subtoxic concentrations of certain chemotherapeutic drugs sensit izes the tumor cells to Fas-mediated cytotoxicity, These findings sugg est that chemosensitization of tumor cells should optimize the respons e to immunotherapeutic interventions in the treatment of hormone-resis tant/drug-resistant prostate cancer.