Mohammad R M, Pettit G R, Almatchy V P, Wall N, Varterasian M, Al-Katib A
Department of Internal Medicine, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI 48201, USA.
Anticancer Drugs. 1998 Feb;9(2):149-56. doi: 10.1097/00001813-199802000-00006.
We studied the antitumor effects of dolastatin 10, its structural modification, auristatin PE (TZT-1027), and vincristine alone and in combination 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 and apoptosis were assessed. Dolastatin 10 showed no apparent inhibition of cell growth at concentrations less than 500 pg/ ml. Auristatin PE showed 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, exhibited 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 agents alone or 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, 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 five mice treated with auristatin PE + bryostatin 1 were free of tumors for 150 days and were considered cured. Dolastatin 10 + bryostatin 1 and vincristine + bryostatin 1 combinations were highly active but no cure was observed. We conclude that: (i) auristatin PE is more effective 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 these agents and bryostatin 1, which is more apparent in the bryostatin 1 + auristatin PE combination. The use of these agents should be further explored clinically in the treatment of lymphoma.
我们研究了多拉司他汀10、其结构修饰物奥瑞他汀PE（TZT-1027）、长春新碱单独及与苔藓抑素1联合对人弥漫性大细胞淋巴瘤细胞系（WSU-DLCL2）的体内外抗肿瘤作用。WSU-DLCL2细胞在RPMI 1640培养基中以2×10⁵/ml的浓度接种于24孔板中培养。将药物加入一式三份的孔中，评估细胞计数、活力、有丝分裂和凋亡情况。多拉司他汀10在浓度低于500 pg/ml时未显示出明显的细胞生长抑制作用。奥瑞他汀PE在低至10 pg/ml的浓度时即显示出显著的生长抑制作用，而长春新碱在50 pg/ml时作用最小。多拉司他汀10、奥瑞他汀PE和长春新碱在50 pg/ml浓度处理的培养物中，有丝分裂率和凋亡率分别为11%、1.7%；45%、11.8%；39%、25%。在WSU-DLCL2 SCID小鼠异种移植模型中，评估了这些药物单独或与苔藓抑素1联合使用的疗效。多拉司他汀10、奥瑞他汀PE、长春新碱和苔藓抑素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30%、14天和1.4；0.0%、55天和5.5；29.6%、16天和1.6；39%、7天和0.7。联合用药时，五分之二接受奥瑞他汀PE + 苔藓抑素1治疗的小鼠150天内无肿瘤，被认为治愈。多拉司他汀10 + 苔藓抑素1和长春新碱 + 苔藓抑素1联合用药活性很高，但未观察到治愈情况。我们得出以下结论：（i）在该模型中，奥瑞他汀PE比多拉司他汀10、长春新碱或苔藓抑素1更有效；（ii）奥瑞他汀PE的给药浓度可比多拉司他汀10高10倍；（iii）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联合用药中更明显。这些药物在淋巴瘤治疗中的临床应用应进一步探索。
