We tested the activity of
dolastatin 10 (a
natural product derived from the shell-less marine mollusk, Dolabella auricularia, a sea hare) and its structural modification,
auristatin PE, alone and in combination with
bryostatin 1 (a
protein kinase C activator derived from the marine bryozoan Bugula neritina) on a human
B-cell chronic lymphocytic leukemia cell line (WSU-CLL) and in a severe combined immune deficient (SCID) mouse xenograft model bearing this cell line. WSU-CLL cells were cultured in RPMI 1640 at a concentration of 2 x 10(5)/ml using a 24-well plate. Agents were added to triplicate wells, and cell count, viability, mitosis, and apoptosis were assessed after 24 h of incubation at 37 degrees C. Results showed that
dolastatin 10 had no apparent inhibition of cell growth at concentrations less than 500 pg/ml.
Auristatin PE, on the other hand, showed significant growth inhibition at concentrations as low as 50 pg/ml.
Auristatin PE-treated cultures, at this concentration, exhibited 27 and 4.5% mitosis and apoptosis, respectively.
Dolastatin 10, at the same concentration, did not exert any effect and was comparable with that of control cultures. In the WSU-CLL-SCID mouse xenograft model, the efficacy of these agents alone and in combination with
bryostatin 1 was evaluated.
Tumor growth inhibition (T/C),
tumor growth delay (T-C), and log10 kill for
dolastatin 10,
auristatin PE, and
bryostatin 1 were 14%, 25 days, and 1.98; 2%, 25 days, and 1.98; 19%, 13 days, and 1.03, respectively.
Auristatin-PE produced cure in three of five mice, whereas
dolastatin 10 showed activity but no cures. When given in combination,
auristatin PE +
bryostatin 1-treated animals were all free of
tumors (five of five) for 150 days and were considered cured.
Dolastatin 10 +
bryostatin 1-treated animals produced cure in only two of five mice. We conclude that: (a)
auristatin-PE is more effective in this model than
dolastatin 10; (b)
auristatin PE can be administered at a concentration 10 times greater than
dolastatin 10; (c) there is a synergetic effect between these agents and
bryostatin 1, which is more apparent in the
bryostatin 1 +
auristatin PE combination. The use of these agents should be explored clinically in the treatment of CLL.