During Phase I research, two palytoxin-derived prodrugs were prepared. The prodrugs were up to 1000-fold less cytotoxic to cells in culture than palytoxin. In the presence of activating enzyme, full conversion of the prodrug to palytoxin was demonstrated. Anti-tumor monoclonal antibody conjugates of the activating enzyme conferred antigen-selective cytotoxicity to the prodrugs of up to 100-fold, against cells in culture. In mixed populations of antigen-positive and -negative cells, a potent """"""""bystander-cell"""""""" killing effect was observed. This is the first marine toxin derivative used as a prodrug. The Phase II research effort will further optimize synthetic, purification, and analytical methodology for palytoxin-derived prodrugs. Additional congeners of the palytoxin derivatives will be prepared and evaluated against cells in culture. Preclinical antitumor activity will be investigated under a collaborative research agreement.
| Lau, C O; Tan, C H; Khoo, H E et al. (1995) Lophozozymus pictor toxin: a fluorescent structural isomer of palytoxin. Toxicon 33:1373-7 |
