Potent Preclinical Impact of Metronomic Low-Dose Oral Topotecan Combined with the Antiangiogenic Drug Pazopanib for the Treatment of Ovarian Cancer

Abstract

Low-dose metronomic chemotherapy has shown promising activity in many preclinical and some phase II clinical studies involving various tumor types. To evaluate further the potential therapeutic impact of metronomic chemotherapy for ovarian cancer, we developed a preclinical model of advanced human ovarian cancer and tested various low-dose metronomic chemotherapy regimens alone or in concurrent combination with an antiangiogenic drug, pazopanib. Clones of the SKOV-3 human ovarian carcinoma cell line expressing a secretable β-subunit of human choriogonadotropic (β-hCG) protein and firefly luciferase were generated and evaluated for growth after orthotopic (i.p.) injection into severe combined immunodeficient mice; a highly aggressive clone, SKOV-3-13, was selected for further study. Mice were treated beginning 10 to 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 metronomic cyclophosphamide had no antitumor activity whereas metronomic irinotecan had potent activity. We therefore tested an oral topoisomerase-1 inhibitor, oral topotecan, at optimal biological dose of 1 mg/kg/d. Metronomic oral topotecan showed excellent antitumor 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 drug targeting the vascular endothelial growth factor pathway, such as pazopanib. Mol Cancer Ther; 9(4); 996-1006. ©2010 AACR.

Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

“…The association of CLM3 with SN-38, the active metabolite of irinotecan, showed a marked synergistic effect on endothelial and cancer cells, placing our compound on the same level as those currently being tested for combination chemotherapy regimens, such as vandetanib [48], pazopanib [49] and axitinib [39]. In order to improve the antineoplastic activity of CLM3, we presently investigated the effects of CLM3 in combination with SN-38 in EGFR and VEGFR-2 expressing human endothelial cell line HMVEC-d and in EGFR and RET expressing human thyroid cancer cell 8305C [50].…”

“…irinotecan and topotecan) and tyrosine kinase inhibitors (TKIs; i.e. pazopanib, axitinib and sunitinib) appears not only possible but very promising based on the involved pharmacodynamic mechanisms of their synergism [39,49]. Even though it is still premature to predict the clinical perspective for the new compound CLM3, the possible immediate clinical significance of our results is the development of a rational strategy for irinotecan/TKIs combination.…”

Combined Antitumor Therapy with Metronomic Topotecan and Hypoxia-Activated Prodrug, Evofosfamide, in Neuroblastoma and Rhabdomyosarcoma Preclinical Models

“…LDM chemotherapy has lower acute toxicity due to lower exposure of the cytotoxic agents. It has been shown active in diverse tumor types, including metastatic disease, especially when combined with antiangiogenic drugs (27)(28)(29)(30). The availability of the oral topotecan, along with our previous studies combining metronomic topotecan with pazopanib in neuroblastoma preclinical models (23), suggest that oral metronomic topotecan may be an ideal candidate for pediatric solid tumors.…”

Chapter 8. Polymeric Nanoparticles and Cancer: Lessons Learnt from CRLX101

“…They demonstrated that combining pazopanib (Votrient s ; GlaxoSmithKline), a VEGF receptor inhibitor, with metronomic TPT, is synergistic and resulted in 100% survival of the drug combination (but not the individual monotherapies) after 6 months of continuous therapy in an aggressive, metastatic, orthotropic xenograft ovarian model. 122 Two orthotropic ovarian cancer model studies showed that combining pazopanib with metronomic TPT is synergistic and resulted in a significant improvement in survival vs. the individual monotherapies. 123 Burkitt et al at the University of Michigan Comprehensive Cancer Center demonstrated that genetic disruption of both HIF-1a and HIF-2a had synergistic anti-tumour activity when combined with sunitinib in a colorectal xenograft model.…”