Abstract A9: Potent preclinical impact of metronomic low-dose oral topotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer
Authors: Hashimoto Kae , Man Shan , Xu Ping , Cruz-Munoz William , Tang Terence , Mutsaers Anthony , Kumar Rakesh , Kerbel Robert S. 
Published: June 2012

Abstract
Low dose metronomic (LDM) chemotherapy has shown promising activity in many preclinical as well as some phase II clinical studies involving various tumor types. It involves chronic but close, regular administration of chemotherapeutic drugs without prolonged breaks. Combination of LDM chemotherapy with targeted biologic agents such as antiangiogenic drugs can sometimes induce striking anti-tumor effects in preclinical models, with minimal toxicity. The most encouraging clinical results thus far involve patients with metastatic breast cancer and recurrent metastatic ovarian cancer. Regarding the ovarian cancer trials, all have involved daily low-dose oral cyclophosphamide using a fixed dose of 50mg, combined with bevacizumab. However, there may be much more effective chemotherapy drugs for LDM chemotherapy-based treatments of ovarian cancer. Here we evaluated the impact of optimal biologic doses (OBDs) of LDM oral topotecan, a topo-isomerase-1 inhibitor already approved for refractory ovarian cancer, in combination with oral pazopanib, a receptor tyrosine kinase inhibitor which targets VEGF and PDGF receptors. 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 immune deficient SCID mice, and a highly aggressive clone, SKOV-3-13, was selected for further study. Treatments were initiated 14 days after injection of 3×106 cells when evidence of carcinomatosis-like disease in the peritoneum was established as assessed by imaging analysis. The drug concentrations were 1mg/kg for oral topotecan by daily gavage, 150mg/kg pazopanib daily gavage or 25mg/kg twice/day, and combinations of oral topotecan+pazopanib. These doses were based on suppressive effects on circulating endothelial progenitor cells, a method we have used previously to determine the OBD for other LDM chemotherapy regimens. Metronomic oral topotecan showed excellent anti-tumor activity, the extent of which was significantly enhanced by concurrent pazopanib, which itself had modest activity. The median survival value of mice in the control group was 34 days after start of treatment compared with 73 days for MTD topotecan, 41 days for 25mg/kg pazopanib, 41 days for 150mg/kg pazopanib, 90 days for oral topotecan, whereas all of the mice in the two oral topotecan/pazopanib combination treatment groups were still alive 150 days after initiation of treatment. Overt toxic side effect was not observed throughout the treatment period. Metronomic topotecan in combination with an antiangiogenic VEGF-pathway targeting drug, such as pazopanib should be considered for evaluation in clinical trials involving patients with advanced, recurrent epithelial ovarian cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A9.