Successful treatment of chronic lymphocytic leukemia (CLL) xenografts with marine animal products

We have previously demonstrated that bryostatin I (bryo), a protein kinase C activator derived from the marine animal Broyzoa neritina, has antitumor activity against the chronic lymphocytic leukemia model, WSU-CLL (Mohammad et al. Leukemia, 10: BO137,1996). In this study, we tested the activity of dolastatin 10, derived front the marine shell-less mollusk, and its structural modification, auristatin PE, alone or in combination with bryo in the same CLL model. WSU-CLL cells were cultured in RPMI-1640 at a concentration of 2xl05/ml using 24-well plate. Agents were added to duplicate wells and cell count, viability, mitosis and apoptosis were assessed after 24h of incubation at 37C. At a concentration of 0.05 ng/ml, auristatin PE exhibited more pronounced mitotic arrest and apoptosis compared with dolastatin 10 at the same concentration. Using WSU-CLL-SCID mouse xenograft model, the efficacy of these agents alone or with bryo was evaluated. Tumor growth inhibition (T/C), tumor growth delay (T-C), and log,0 kill for bryo (75 ug/ kg.ip), dollO (0.2 mg/kg,iv) and auriPE(2.0mg/kg,iv) respectively were 19%, 13 days, and 1.03; 14%, 25d and 1.98; 2%, 25d, and 1.98.When given in combination, bryo+auriPE-treated animals were all free of tumors (5/5) for 150 d and were considered cured. However, bryo+ dollO produced cure in 2/5 animals. Of interest, auriPE alone produced cure in 3/5 animals whereas dollO did not result in any cures. We conclude that:l) Both dollO and auriPE are effective agents against WSU-CLL model, 2) AuriPE is more effective in this model than dollO, 3) There is synergetic effect between these agents arid byo which is more apparent in auriPE/bryo combination, 4) The use of these agents should be explored clinically in the treatment of CLL.