Is metronomic vinorelbine (mVRL) able to inhibit both HUVEC and triple-negative breast cancer (TNBC) cells? The proof-of-concept VICTOR-0 study.

Abstract

e14014 Background: TNBC represents an important clinical challenge because of poor prognosis. One of the emerging strategy to achieve disease control while reducing toxicity is metronomic chemotherapy (mCHT) which targets the endothelial cells (ECs) and inhibits the tumor growth. mVRL is a promising option in patients (pts) with metastatic breast cancer (MBC), resulting in a median PFS of 7.7 months and median OS of 15.9. To better explain the effect of mVRL we studied the effects of metronomic doses of VRL in in vitro models and compared them with standard doses of the same drug. Methods: Cell viability and cytotoxicity assays were performed on TNBC cancer cells (MDA-MB-231) and Human Umbilical Vein Endothelial Cells (HUVEC). Cell lines were exposed to different concentration (0,01nM-1mM) of VRL for 4 and 96 h. To simulate the metronomic dosing schedule, we replaced the drug-enriched medium every 24h, while to simulate the conventional administration protocol (sCHT) cells were exposed to VRL for 4h, then the medium was changed and replaced with fresh medium without drug every 24 h. The IC50was calculated by non-linear regression fit of the mean values of data obtained in triplicate experiments. Results: A significant anti-proliferative activity was observed on both HUVEC and MDA cells treated with VRL in mCHT as compared to sCHT protocol (see Table). These lower drug concentrations did not have remarkable effects on cell death. Conversely, the higher dose utilized in sCHT produced important cell death in MDA as well as in HUVEC, even if in vivo, the higher dose of drug inducing the largest apoptosis of cancer cells also affectd healthy proliferating cells causing toxicity. Our findings suggest that mCHT inhibited the proliferation of both endothelial and tumour cells and can block cancer progression with minor side effects. Conclusions: This study provides the proof-of-concept that metronomic doses of VRL, but not the standard ones, are able to inhibit, at the same concentration, both the ECs and the TNBC cells. The clinical trial TEMPO-BREAST, which compares metronomic vs standard VRL, is ongoing in MBC pts. [Table: see text]