Dose-dependent bidirectional pharmacological effects of vinorelbine-based metronomic combination chemotherapy on tumor growth and metastasis and mechanisms in melanoma mouse model.

BACKGROUND: There is evidence that the empirical setting of doses and schedules of antineoplastic agents in metronomic chemotherapy (MC) might lead to undesirable outcomes, such as promoting tumor growth or metastasis at certain low doses. However, details about the dose effect of antineoplastic agents in MC have not been fully known yet. OBJECTIVES: Vinorelbine combined with cisplatin or fluorouracil (VNR/CDDP or VNR/FU) was selected to investigate its effects on tumor growth or metastasis as well as mechanisms. METHODS: Experimental techniques, including immunohistochemistry, western blot, immunofluorescence, and flow cytometry, were used to explore the mechanisms, along with cell proliferation, apoptosis, migration, and invasion. RESULTS: The results showed that VNR/CDDP or VNR/FU promoted tumor growth and metastasis at low doses and inhibited them at high ones. Except that expressions of apoptotic proteins were elevated at both low and high doses, low-dose treatments enhanced angiogenesis and promoted the mobilization and recruitment of myeloid-derived suppressor cells (MDSCs), while high-dose treatments reversed these effects. Additionally, low concentrations of VNR/CDDP or VNR/FU stimulated tumor cell functions such as anti-apoptosis, migration, and invasion, but high concentrations only suppressed cell proliferation and increased apoptosis. CONCLUSION: This study elucidated a bidirectional action mode regulated by multiple mechanisms at different doses in MC and also highlighted the risks of low-dose metronomic administration of antineoplastic agents in the clinic. More preclinical and clinical studies focusing on the dose-effect of metronomic regimens are urgently needed because an effective therapeutic regimen should be an optimal setting of drugs, doses, schedules, or combinations.

Metronomic combination chemotherapy using everolimus and etoposide for the treatment of non-Hodgkin lymphoma.

Patients with Non-Hodgkin lymphoma (NHL) treated by conventional chemotherapeutic drugs usually require a long recovery period. However, metronomic combination chemotherapy (MCC) enhances therapeutic efficacy and decreases side effects in the treatment of NHL. In this study, we tested and compared the effects of metronomic chemotherapy (MC) using podophyllotoxin derivative etoposide (VP-16) alone and that of MCC using both VP-16 and everolimus (RAD001) in the treatment of NHL. Two types of NHL cells, OCI-LY-10 and SU-DHL-6, were employed for the experiments. Cell proliferation, apoptosis, and cell senescence were measured to test the effects of drugs in each experiment. In addition, the influences of MC and MCC on the cell cycle and autophagy pathway were evaluated to study the functional mechanisms behind their effects. Finally, we conducted analyses of the growth inhibitory effect and synergistic activity for different MCC. The results showed that MC using low-dose VP-16 alone demonstrated strong treatment effects in terms of inducing apoptosis, cell senescence, and reducing tumor cell proliferation, and this treatment also led to changes of the cell cycle. Compared with MC, MCC using VP-16 and RAD001 together demonstrated even stronger treatment effects, with both the cell cycle and autophagy-related proteins being affected. Considering the synergistic activity, our results showed the MCC of VP-16 48 hours + RAD001 24 hours is the optimal method for treating NHL.

Metronomic combination of Vinorelbine and 5Fluorouracil is able to inhibit triple-negative breast cancer cells. Results from the proof-of-concept VICTOR-0 study.

Triple Negative Breast Cancer (TNBC) is an aggressive neoplasia with median Overall Survival (OS) less than two years. Despite the availability of new drugs, the chance of survival of these patients did not increase. The combination of low doses of drugs in a metronomic schedule showed efficacy in clinical trials, exhibiting an anti-proliferative and anti-tumour activity. In Victor-2 study we recently evaluated a new metronomic combination (mCHT) of Capecitabine (CAPE) and Vinorelbine (VNR) in breast cancer patients showing a disease control rate with a median Progression-Free Survival (PFS) of 4.7 months in 28 TNBC patients. Here in Victor-0 study, we examined the effect of mCHT vs standard (STD) schedule of administration of different combinations of 5-Fluorouracil (5FU), the active metabolite of CAPE, and VNR in TNBC cell lines MDA-MB-231 and BT-549. A significant anti-proliferative activity was observed in cells treated with metronomic vs STD administration of 5FU or VNR alone. Combination of the two drugs showed an additive inhibitor effect on cell growth in both cell lines. Moreover, after exposure of cells to 5FU and VNR under mCHT or conventional schedule of administration we also observed a downregulation of chemoresistance factor Bcl-2, changes in pro-apoptotic protein Bax and in cleaved effector caspase-3 and increased expression of LC3A/B autophagy protein. Our results therefore suggest that molecular mechanisms implicated in apoptosis and autophagy as well as the cross-talk between these two forms of cell death in MDA-MB-231 and BT-549 cells treated with 5FU and VNR is dose- and schedule-dependent and provide some insights about the roles of autophagy and senescence in 5FU/VNR-induced cell death.