Taurolidine: Cytotoxic and mechanistic evaluation of a novel antineoplastic agent

Bis-(I,1-dioxoperhydro-1,2,4-thiadiazinyl-4)methane (taurolidine) is a synt hetic broad-spectrum antibiotic that reacts with bacterial cell membrane co mponents to prevent adhesion to epithelial cell surfaces. Reflecting the ke y role of adhesion in the growth and development of human solid tumors, stu dies were initiated to assess the antiproliferative activity of this agent in selected human and marine tumor cell lines. A 3-day exposure to Taurolid ine inhibited the growth of all of the cell lines evaluated with IC(50)s ra nging from 9.6-34.2 muM. Studies to identify the mechanism responsible for this effect were conducted in NIH-3T3 marine fibroblasts and the PA-I and S KOV-3 human ovarian tumor cells. These studies revealed that a 48-h exposur e to taurolidine had little effect on cell cycle distribution in PA-I and S KOV-3 cells but significantly increased the appearance of DNA debris in the sub-G(0)/G(1) region, an effect consistent with an induction or apoptosis. In contrast, in NIH-3T3 cells, taurolidine exposure did not increase DNA d ebris in the sub-G(0)/G(1) region. Additional studies assessed phosphotidyl serine externalization after a 24-h exposure to taurolidine using annexin-V binding as a cell surface marker. These studies revealed that taurolidine increased the percentage of annexin-V-positive cells by 4-fold and 3-fold i n PA-1 and SKOV-3 cells, respectively. In NIH-3T3 cells, taurolidine exposu re slightly increased (similar to5%) annexin-V binding. Parallel studies re vealed that exposure to taurolidine also resulted in poly(ADP-ribose) polym erase cleavage in both ovarian tumor cell lines but not in NIH-3T3 cells. F inally, murine-based studies were conducted to assess the antineoplastic ac tivity of three consecutive daily i.p. bolus injections of taurolidine at d oses ranging from 5-mg injection/mouse to 30-mg injection/mouse. The 20-mg injection dose produced similar to 10% mortality and was identified as the maximally tolerated dose in this model. Administration of this regimen to n ude mice bearing i.p. human ovarian tumor xenografts significantly inhibite d both tumor formation and growth. These findings are discussed in light of their clinical implications.