Tomkinson Blake, Bendele Ray, Giles Francis J, Brown Eric, Gray Atherton, Hart Karen, LeRay Jeremy D, Meyer Denny, Pelanne Michelle, Emerson David L
OSI Pharmaceuticals, Inc, 2860 Wilderness Place, Boulder, CO 80301, USA.
Leuk Res. 2003 Nov;27(11):1039-50. doi: 10.1016/s0145-2126(03)00092-4.
OSI-211 (liposomal lurtotecan), was evaluated using several different dose schedules (1mg/kg, d1-5, 1.75 mg/kg d1, 3, 5 and 6 mg/kg d1, 8) in severe combined immunodeficient (SCID) mouse models of acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL) with early treatment (ET, days 6-8) or late treatment (LT, days 15-19), examining early and advanced disease, respectively. Due to the aggressive nature of the Molt-4 model, the ET and LT were accelerated to day 3 or 4 and day 8 post-implant, respectively. For each model, 2 x 10(7) (KBM-3B) or 1 x 10(7) (Molt-4, HL-60 and CEM) leukemia cells were injected intravenously into the tail vein. Each control and test group consisted of eight animals. All three schedules (1mg/kg qd1-5, 1.75 mg/kg d1, 3, 5 and 6 mg/kg d1, 8) increased the life span of OSI-211 treated animals in each model, with a tendency toward improved efficacy with the 6 mg/kg d1, 8 schedule. As a result, the activity of the 6 mg/kg d1, 8 schedule is detailed for each model. ET significantly (P<0.005) increased survival in the KBM-3B model with 86% long-term survivors (LTS). Using PRC analysis, human beta-globin gene sequences in one or several tissues were amplified in all but 3 LTS, suggesting minimal residual disease in 26 of the 29 LTS. LT also significantly (P<0.005) improved average life span in the KBM-3B model, with an average ILS=196+/-11% and one LTS. Treatment of HL-60 leukemia animals significantly (P<0.005) increased life span, with an ILS=213+/-9% and two LTS for ET, and with an ILS=219+/-4% and no LTS for LT. Treatment of Molt-4 animals, the most aggressive leukemia model tested, significantly (P<0.005) increased life span, with an average ILS=181+/-3% and no LTS for ET and an average ILS=172+/-1% with no LTS for LT. In the CEM model, ET resulted in a significantly (P<0.005) improved ILS=244+/-24% with one LTS. In comparison to OSI-211, treatment with DaunoXome, the liposomal formulation of daunorubicin, a drug with clinical efficacy in AML and ALL, had no effect on survival in the KBM-3B, nor Molt-4 A4 leukemia models when administered at its maximum or near maximum tolerated doses of 3mg/kg d1, 8. These data demonstrate that OSI-211 has potent antileukemia activity in preclinical SCID mouse AML and ALL leukemia models, supporting the clinical investigation of OSI-211 for hematological malignancies.
OSI - 211（脂质体鲁托替康）在严重联合免疫缺陷（SCID）小鼠急性髓性白血病（AML）和急性淋巴细胞白血病（ALL）模型中，采用几种不同的给药方案（1mg/kg，第1 - 5天；1.75mg/kg，第1、3、5天；6mg/kg，第1、8天）进行评估，分别在疾病早期（ET，第6 - 8天）或晚期（LT，第15 - 19天）给药，以研究早期和晚期疾病。由于Molt - 4模型具有侵袭性，ET和LT分别提前至植入后第3或4天以及第8天。对于每个模型，将2×10⁷（KBM - 3B）或1×10⁷（Molt - 4、HL - 60和CEM）白血病细胞经尾静脉注射到小鼠体内。每个对照组和试验组由8只动物组成。所有三种给药方案（1mg/kg每日1次共5天、1.75mg/kg第1、3、5天、6mg/kg第1、8天）均延长了OSI - 211治疗动物在每个模型中的生存期，其中6mg/kg第1、8天的给药方案有疗效改善的趋势。因此，详细阐述了6mg/kg第1、8天给药方案在每个模型中的活性。在KBM - 3B模型中，ET显著（P<0.005）提高了生存率，长期存活者（LTS）达86%。采用聚合酶链反应（PRC）分析，除3只LTS外，所有LTS的一个或多个组织中的人β - 珠蛋白基因序列均被扩增，表明29只LTS中有26只残留疾病极少。LT也显著（P<0.005）延长了KBM - 3B模型中的平均生存期，平均生存期延长率（ILS）=196±11%，有1只LTS。HL - 60白血病动物经治疗后生存期显著（P<0.005）延长，ET组的ILS = 213±9%，有2只LTS；LT组的ILS = 219±4%，无LTS。在测试的最具侵袭性的白血病模型Molt - 4动物中，治疗后生存期显著（P<0.005）延长，ET组的平均ILS = 181±3%，无LTS；LT组的平均ILS = 172±1%，无LTS。在CEM模型中，ET使ILS显著（P<0.005）提高至244±24%，有1只LTS。与OSI - 211相比，柔红霉素脂质体制剂DaunoXome在以其最大或接近最大耐受剂量3mg/kg第1、8天给药时，对KBM - 3B和Molt - 4 A4白血病模型的生存无影响，柔红霉素是一种对AML和ALL有临床疗效的药物。这些数据表明，OSI - 211在临床前SCID小鼠AML和ALL白血病模型中具有强大的抗白血病活性，支持对OSI - 211用于血液系统恶性肿瘤的临床研究。
