The Biomodulatory Capacities of Low-Dose Metronomic Chemotherapy: Complex Modulation of the Tumor Microenvironment

The cyclic administration of conventional (i.e., maximum tolerated dose [MTD]) chemotherapy targets primarily the tumor cell population. In contrast, chemotherapeutics used at lower doses but on a more frequent basis, and without treatment-free breaks, preferentially affect the tumor vasculature. This so-called low-dose metronomic (LDM) form of chemotherapy administration can be considered as a complementary and/or alternative form of antiangiogenic therapy to the use of targeted antiangiogenic agents such as antibodies or small molecule drugs that interfere with vascular endothelial growth factor (VEGF) pathways. However, it becomes increasingly clear that LDM chemotherapy affects also aspects of the tumor microenvironment other than angiogenesis such as immune responses. Herein, we summarize the complex effects of LDM chemotherapy on the tumor microenvironment, with special emphasis on angiogenesis. We also compare the effects of LDM versus MTD chemotherapy. Finally, we outline how pharmacogenetic characteristics of the tumor host and microenvironment may be exploited in the future to predict response to LDM therapy.