Genz-644282, a novel non-camptothecin topoisomerase I inhibitor for cancer treatment.

人类骨髓CFU-GM对Top1抑制剂的敏感性高于小鼠骨髓CFU-GM。小鼠与人类IC(90)值的比率对于喜树碱类化合物超过10，而对于Genz-644282则小于10。无论是集落形成还是72小时增殖实验中，Genz-644282 显示出比喜树碱类化合物更强的细胞毒性。Genz-644282在人类肿瘤异种移植物中的抗肿瘤活性优于或等同于标准对照药物[1]。

在体内，Genz-644282在其最大耐受剂量(MTD) 4 mg/kg时，在6/6个可评估的实体瘤模型中诱导了持续的完全反应(MCR)。在2 mg/kg剂量下，Genz-644282在3/3相对对topotecan不敏感的肿瘤模型中诱导出CR或MCR，但在1 mg/kg时没有观察到客观反应。进一步在2mg/kg的测试显示，Genz-644282在17个模型中的7个(占41%)中诱导了客观性退缩。基于Affymetrix U133Plus2基线肿瘤表达轮廓的预测反应评分与观察到的对Genz-644282的体内响应之间存在显著相关性[2]。

Colony-forming assays were conducted with mouse and human bone marrow and eight human tumor cell lines. In addition, 29 human tumor cell lines representing a range of histology and potential resistance mechanisms were assayed for sensitivity to Genz-644282 in a 72-hour exposure assay. The efficacy of Genz-644282 was compared with standard anticancer drugs (i.e., irinotecan, docetaxel, and dacarbazine) in human tumor xenografts of colon cancer, renal cell carcinoma, non-small cell lung cancer, and melanoma[1].

Genz-644282 was tested against the PPTP in vitro panel (0.1 nM to 1 μM), and in vivo using three times per week × 2 schedule repeated at day 21 at its maximum tolerated dose (MTD) of 4 mg/kg. Subsequently Genz-644282 was tested at 4, 3, 2, and 1 mg/kg in 3 models to assess the dose-response relationship. mRNA gene signatures predictive for Genz-644282 response in vitro were applied to select 15 tumor models that were evaluated prospectively[2].