Mohammad R M, Varterasian M L, Almatchy V P, Hannoudi G N, Pettit G R, Al-Katib A
Department of Internal Medicine, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, Michigan 48201, USA.
Clin Cancer Res. 1998 May;4(5):1337-43.
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.
我们测试了多拉司他汀10（一种从无壳海洋软体动物——海兔耳海牛Dolabella auricularia中提取的天然产物）及其结构修饰物奥瑞他汀PE单独使用以及与苔藓抑素1（一种从海洋苔藓虫类动物红苔藓虫Bugula neritina中提取的蛋白激酶C激活剂）联合使用时，对人B细胞慢性淋巴细胞白血病细胞系（WSU-CLL）以及携带该细胞系的重症联合免疫缺陷（SCID）小鼠异种移植模型的作用。WSU-CLL细胞在RPMI 1640培养基中，以2×10⁵/ml的浓度接种于24孔板进行培养。将药物加入一式三份的孔中，在37℃孵育24小时后评估细胞计数、活力、有丝分裂和凋亡情况。结果显示，多拉司他汀10在浓度低于500 pg/ml时对细胞生长无明显抑制作用。另一方面，奥瑞他汀PE在低至50 pg/ml的浓度时就显示出显著的生长抑制作用。在此浓度下，经奥瑞他汀PE处理的培养物分别表现出27% 的有丝分裂和4.5% 的凋亡。相同浓度下，多拉司他汀10未产生任何作用，与对照培养物相当。在WSU-CLL-SCID小鼠异种移植模型中，评估了这些药物单独使用以及与苔藓抑素1联合使用的疗效。多拉司他汀10、奥瑞他汀PE和苔藓抑素1的肿瘤生长抑制率（T/C）、肿瘤生长延迟时间（T-C）和对数杀灭值分别为14%、25天和1.98；2%、25天和1.98；19%、13天和1.03。奥瑞他汀PE使五只小鼠中的三只治愈，而多拉司他汀10显示出活性但未治愈。联合使用时，经奥瑞他汀PE + 苔藓抑素1处理的动物在150天内均无肿瘤（五只中的五只），被认为已治愈。经多拉司他汀10 + 苔藓抑素1处理的动物在五只小鼠中仅两只治愈。我们得出以下结论：（a）在该模型中，奥瑞他汀PE比多拉司他汀10更有效；（b）奥瑞他汀PE的给药浓度可比多拉司他汀10高10倍；（c）这些药物与苔藓抑素1之间存在协同作用，在苔藓抑素1 + 奥瑞他汀PE组合中更为明显。应在临床上探索这些药物在慢性淋巴细胞白血病治疗中的应用。
