Anti-tumor effects of metronomic topotecan alone and in combination with angiokinase inhibitors: just a mechanism involved?

Low-dose metronomic chemotherapy has shown promising activity in many preclinical and some phase II clinical studies involving various tumor types and is currently undergoing phase III trial evaluation. We evaluate the potential therapeutic impact of a topoisomerase-1 inhibitor, oral topotecan, alone or in concurrent combination with pazopanib, a tyrosine kinase inhibitor (TKI), in mice with primary orthotopic tumors and advanced metastatic disease using a serially selected metastatic variant of the MDA-MB-231 breast cancer-cell line, 231/LM2-4. TKIs significantly enhanced the antitumor activity of low dose metronomic topotecan, which itself had only modest activity. Changes in tumor oxygenation, angiogenesis, proliferation, apoptosis, HIF1α levels, HIF-1 target genes and ABCG2 were evaluated in in vitro experiments and tumor tissue in order to find a possible mechanism involved in the efficacy of the combination oral low-dose daily metronomic chemotherapy, using topotecan and tyrosine kinase inhibitor. The addition of pazopanib to topotecan was associated to an antiproliferative effect and proapoptotic activity on endothelial and cancer cells. Pazopanib and low dose topotecan combined treatment inhibited the expression of HIF1α and ABCG2 genes in cells, increasing the topotecan intracellular concentration. In vivo, low dose topotecan showed an enhanced antitumor activity when administered with pazopanib, with a marked decrease in tumor volume, vascularity and proliferative index, an induction of apoptosis and a remarkable prolongation of survival.