Abstract
Metronomic chemotherapy has shown promising activity in numerous preclinical studies and also some phase II clinical studies involving various tumor types, and is currently undergoing phase III trial evaluation. Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Herein, we evaluated the potential therapeutic impact and molecular mechanisms of topotecan administered in a continuous low-dose metronomic (LDM) manner, alone or in concurrent combination with pazopanib, an antiangiogenic tyrosine kinase inhibitor (TKI), in a triple-negative, primary and metastatic breast cancer orthotopic model; potential molecular mechanisms of efficacy were also studied, especially the impact of hypoxic conditions. The combination of metronomic topotecan and pazopanib significantly enhanced antitumor activity compared to monotherapy with either drug and prolonged survival, even in the advanced metastatic survival setting, with a marked decrease in tumor vascularity, proliferative index, and the induction of apoptosis. Significant changes in tumor angiogenesis, cancer cell proliferation, apoptosis, HIF1α levels, HIF-1 target genes and ABCG2 were found both in vitro and in tumor tissue. Notably, the pazopanib and metronomic topotecan combination treatment inhibited expression of HIF1α and ABCG2 genes in cells grown under hypoxic conditions, and this was associated with an increased intracellular concentration of the active form of topotecan. Our results suggest a potential novel therapeutic option for the treatment of metastatic triple-negative breast cancer patients.
Highlights
Metronomic chemotherapy refers to the close, regular administration of conventional chemotherapy drugs at low, minimally toxic doses, with no prolonged break periods [1]
Sunitinib or topotecan and various concurrent combinations of these drugs at concentration corresponding to the experimental IC50 of cell proliferation, HIF1α gene expression and protein levels were evaluated in cells treated in hypoxic conditions
On the other hand the disease free survival results of several adjuvant therapy trials evaluating bevacizumab plus chemotherapy followed by bevacizumab maintenance in early stage breast cancer patients have been disappointing despite a clear initial benefit while patients receive treatment, and for a period after the maintenance treatment is stopped [31, 37]
Summary
Metronomic chemotherapy refers to the close, regular administration of conventional chemotherapy drugs at low, minimally toxic doses, with no prolonged break periods [1]. Metronomic oral topotecan showed an enhanced antitumor activity as a result of combination with concurrent administration of pazopanib, in preclinical models of advanced human ovarian cancer [16, 17], aggressive pediatric solid tumors [18], pediatric sarcomas [19], and renal cell carcinoma [20]. Few preclinical and clinical data are currently available concerning the impact of topotecan in metastatic breast cancer and its metronomic dosing and scheduling concept has not yet been explored in this indication either alone or in combination with TKIs [29]. The purpose of our study was to investigate metronomic topotecan alone or in combination with pazopanib in a model of a primary established triple-negative or advanced metastatic breast cancer elucidating possible molecular mechanisms accounting for efficacy of this treatment combination
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