Potent preclinical impact of metronomic low-dose oral topotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer.
Potent preclinical impact of metronomic low-dose oral topotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer.
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DOI：
10.1158/1535-7163.mct-09-0960
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发表时间：
2010-04
影响因子：
5.7
通讯作者：
Kerbel RS
中科院分区：
文献类型：
--
作者：
Hashimoto K;Man S;Xu P;Cruz-Munoz W;Tang T;Kumar R;Kerbel RS
低剂量节律(LDM)化疗在许多临床前和一些涉及不同肿瘤类型的II期临床试验中显示出良好的活性。为了评估LDM化疗对卵巢癌的潜在治疗效果，我们建立了一个晚期疾病的临床前模型，并测试了各种LDM化疗方案单独或同时与抗血管生成药物帕佐帕尼联合使用。建立了表达人绒毛膜促性腺激素分泌型β亚单位(β-hCG)蛋白和萤火虫荧光素酶的人卵巢癌细胞系SKOV-3的克隆，并对其进行了原位(腹膜)注射后的生长评价；小鼠在注射细胞后10-14天开始治疗，当通过成像分析确定腹膜有癌病样疾病的证据时。初步试验的化疗药物包括口服环磷酰胺、单独注射伊立替康或紫杉醇或与环磷酰胺合用，结果表明LDM环磷酰胺没有抗肿瘤活性，而LDM伊立替康有较强的抗肿瘤活性。因此，我们测试了口服拓扑异构酶-1抑制剂，口服拓扑替康的最佳生物剂量为1毫克/公斤/天。LDM口服拓扑替康显示出良好的抗肿瘤活性，同时帕佐帕尼本身只有适度的活性，其抗肿瘤活性的程度显著增强，连续治疗6个月后，联合用药的存活率为100%。总之，口服拓扑替康可能是卵巢癌节律化疗临床试验评估的理想药物，特别是当与抗血管生成血管生成血管内皮生长因子通路靶向药物，如帕佐帕尼联合使用时。
Low dose metronomic (LDM) chemotherapy has shown promising activity in many preclinical and some phase II clinical trials involving various tumor types. To evaluate the potential therapeutic impact of LDM chemotherapy for ovarian cancer, we developed a preclinical model of advanced disease and tested various LDM chemotherapy regimens alone or in concurrent combination with an antiangiogenic drug, pazopanib. Clones of the SKOV-3 human ovarian carcinoma cell line expressing secretable β-subunit of human choriogonadotropic (β-hCG) protein and firefly luciferase were generated, and evaluated for growth after orthotopic (intraperitoneal) injection into SCID mice; a highly aggressive clone, SKOV-3-13, was selected for further study. Mice were treated beginning 10–14 days after injection of cells when evidence of carcinomatosis-like disease in the peritoneum was established as assessed by imaging analysis. Chemotherapy drugs tested for initial experiments included oral cyclophosphamide, injected irinotecan or paclitaxel alone or in doublet combinations with cyclophosphamide; the results indicated that LDM cyclophosphamide had no anti-tumor activity whereas LDM irinotecan had potent activity. We therefore tested an oral topoisomerase-1 inhibitor, oral topotecan at optimal biologic dose of 1mg/kg/daily. LDM oral topotecan showed excellent anti-tumor activity, the extent of which was significantly enhanced by concurrent pazopanib, which itself had only modest activity, with 100% survival values of the drug combination after six months of continuous therapy. In conclusion, oral topotecan may be an ideal agent to consider for clinical trial assessment of metronomic chemotherapy for ovarian cancer, especially when combined with an antiangiogenic VEGF-pathway targeting drug, such as pazopanib.