Lu Ze, Wientjes Trini S-S, Au Jessie L-S
College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210, USA.
Pharm Res. 2005 Jul;22(7):1069-78. doi: 10.1007/s11095-005-6038-1. Epub 2005 Jul 22.
We reported that nontoxic suramin treatments enhance the activity of chemotherapy in preclinical models, a finding supported by the results of subsequent phase I/II trials in chemotherapy-naive non-small cell lung cancer (NSCLC) patients who received/carboplatin (P/C) combination therapy. The present study evaluated whether suramin enhances the activity of docetaxel in human NSCLC xenografts.
The in vitro effect of suramin on docetaxel activity was evaluated using 3-D histocultures of chemotherapy-naive A549 tumors. For in vivo activity evaluation, we first established the P/C pretreatment schedule that produced tumor growth inhibition, but not tumor eradication, and established the maximally tolerated docetaxel/suramin regimens. In the second study, P/C-treated animals received physiological saline, single-agent suramin (10 mg/kg), docetaxel (10 mg/kg), or the combination twice weekly for 3 weeks.
The in vitro results showed that 20 microM suramin, which had no activity as single agent, enhanced the docetaxel activity (measured as 50% inhibition of DNA synthesis) by more than 10-fold. The in vivo studies showed reduced tumor growth by P/C (30% growth in 14 days vs. 75% in control). In contrast, docetaxel produced tumor regression (15% reduction) in P/C-treated animals, significantly reduced, on a cellular level, the viable cell density and the proliferating fraction (40% reduction for both measurements), and enhanced the apoptotic fraction 4-fold (p < 0.05 for all effects). Suramin had no activity or toxicity (measured as body weight loss) but significantly enhanced the docetaxel activity. Compared to docetaxel alone, the combination showed earlier onset of tumor size reduction, greater extent of tumor regression (31 vs. 15%), greater reduction of viable cell density and proliferating fraction (additional 15-25% reduction), and greater apoptotic fraction (additional 2.5-fold increase) (p < 0.05 for all parameters).
Results of the present study indicate that nontoxic suramin treatments enhanced the activity of docetaxel in P/C-pretreated A549 xenograft tumors in mice without enhancing host toxicity. These encouraging results provided the basis for phase I/II trials of docetaxel plus low-dose suramin in patients with NSCLC in second-/third-line settings.
我们曾报道，在临床前模型中，无毒的苏拉明治疗可增强化疗活性，后续针对未接受过化疗的非小细胞肺癌（NSCLC）患者进行的铂类/卡铂（P/C）联合治疗的I/II期试验结果支持了这一发现。本研究评估了苏拉明是否能增强多西他赛在人NSCLC异种移植瘤中的活性。
使用未接受过化疗的A549肿瘤的三维组织培养评估苏拉明对多西他赛活性的体外作用。为了评估体内活性，我们首先确定了能产生肿瘤生长抑制但不能根除肿瘤的P/C预处理方案，并确定了多西他赛/苏拉明的最大耐受方案。在第二项研究中，接受P/C治疗的动物每周两次接受生理盐水、单药苏拉明（10mg/kg）、多西他赛（10mg/kg）或联合用药，共3周。
体外实验结果显示，作为单药无活性的20μM苏拉明可使多西他赛活性（以DNA合成抑制50%衡量）增强10倍以上。体内研究显示，P/C可使肿瘤生长减缓（14天内生长30%，而对照组为75%）。相比之下，多西他赛使接受P/C治疗的动物肿瘤消退（减少15%），在细胞水平上显著降低了活细胞密度和增殖分数（两项测量均减少40%），并使凋亡分数增加4倍（所有效应p<0.05）。苏拉明无活性或毒性（以体重减轻衡量），但显著增强了多西他赛的活性。与单用多西他赛相比，联合用药显示肿瘤大小减小的起效更早，肿瘤消退程度更大（31%对15%），活细胞密度和增殖分数降低更多（额外降低15 - 25%），凋亡分数更高（额外增加2.5倍）（所有参数p<0.05）。
本研究结果表明，无毒的苏拉明治疗可增强多西他赛在经P/C预处理的小鼠A549异种移植瘤中的活性，且不增加宿主毒性。这些令人鼓舞的结果为在二线/三线NSCLC患者中进行多西他赛加低剂量苏拉明的I/II期试验提供了依据。
