title: Successful treatment of human chronic lymphocytic leukemia xenografts with combination biological agents auristatin PE and bryostatin 1.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, Michigan 48201, USA. Mohammad@oncgate.roc.wayne.edu
authors.forename: R M
authors.initials: RM
authors.lastname: Mohammad
authors.forename: M L
authors.initials: ML
authors.lastname: Varterasian
authors.forename: V P
authors.initials: VP
authors.lastname: Almatchy
authors.forename: G N
authors.initials: GN
authors.lastname: Hannoudi
authors.forename: G R
authors.initials: GR
authors.lastname: Pettit
authors.forename: A
authors.initials: A
authors.lastname: Al-Katib
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D054713:Bryostatins; D002452:Cell Count / Q000187:drug effects; D047630:Depsipeptides; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007783:Lactones / Q000008:administration & dosage; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality; D018942:Macrolides; D051379:Mice; D016513:Mice, SCID; D008938:Mitosis / Q000187:drug effects; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D013370:Subrenal Capsule Assay; D016019:Survival Analysis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D054713:Bryostatins; D047630:Depsipeptides; D007783:Lactones; D018942:Macrolides; D009842:Oligopeptides; C046785:bryostatin 1; C105791:soblidotin; C064570:dolastatin 10