SYNERGISTIC INTERACTION OF SELECTED MARINE ANIMAL ANTICANCER DRUGS AGAINST HUMAN DIFFUSE LARGE-CELL LYMPHOMA

We studied the antitumor effects of dolastatin 10, its structural modi fication, auristatin PE (TZT-1027), and vincristine alone and in combi nation with bryostatin 1 on a human diffuse large cell lymphoma line ( WSU-DLCL2) in vitro and in vivo. WSU-DLCL2 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 an d apoptosis were assessed. Dolastatin 10 showed no apparent inhibition of cell growth at concentrations less than 500 pg/ml. Auristatin PE s howed significant growth inhibition at concentrations as low as 10 pg/ ml, while vincristine had a minimal effect at 50 pg/ml. Dolastatin 10, auristatin PE and vincristine-treated cultures, at 50 pg/ml, exhibite d 11, 1.7; 45, 11.8%; and 39, 25% mitosis and apoptosis, respectively. In the WSU-DLCL2 SCID mouse xenograft model, the efficacy of these ag ents alone or in combination with bryostatin 1 was evaluated. Tumor gr owth inhibition (T/C), tumor growth delay (T-C) and log(10) kill for d olastatin 10, auristatin PE, vincristine and bryostatin 1 were 30%, 14 days and 1.4; 0.0%, 55 days and 5.5; 29.6%, 16 days and 1.6; and 39%, 7 days and 0.7, respectively. When given in combination, two out of f ive mice treated wit auristatin PE + bryostatin 1 were free of tumors for 150 days and were considered cured. Dolastatin 10 + bryostatin 1 a nd vincristine + bryostatin 1 combinations were highly active but no c ure was observed. We conclude that: (i) auristatin PE is more effectiv e in this model than dolastatin 10, vincristine or bryostatin 1, (ii) auristatin PE can be administered at a concentration 10 times greater than dolastatin 10, and (iii) there is a synergistic effect between th ese agents and bryostatin 1, which is more apparent in the bryostatin 1 + auristatin PE combination. The use of these agents should be furth er explored clinically in the treatment of lymphoma. [(C) 1998 Rapid S cience Ltd.].