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.