Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment

Abstract

The concept of cancer as a systemic disease, and the therapeutic implications of this, has gained special relevance. This concept encompasses the interactions between tumor and stromal cells and their microenvironment in the complex setting of primary tumors and metastases. These factors determine cellular co-evolution in time and space, contribute to tumor progression, and could counteract therapeutic effects. Additionally, cancer therapies can induce cellular and molecular responses in the tumor and host that allow them to escape therapy and promote tumor progression. In this study, we describe the vascular network, tumor-infiltrated immune cells, and cancer-associated fibroblasts as sources of heterogeneity and plasticity in the tumor microenvironment, and their influence on cancer progression. We also discuss tumor and host responses to the chemotherapy regimen, at the maximum tolerated dose, mainly targeting cancer cells, and a multimodal metronomic chemotherapy approach targeting both cancer cells and their microenvironment. In a combination therapy context, metronomic chemotherapy exhibits antimetastatic efficacy with low toxicity but is not exempt from resistance mechanisms. As such, a better understanding of the interactions between the components of the tumor microenvironment could improve the selection of drug combinations and schedules, as well as the use of nano-therapeutic agents against certain malignancies.

Addressing Genetic Tumor Heterogeneity, Post-Therapy Metastatic Spread, Cancer Repopulation, and Development of Acquired Tumor Cell Resistance

“…Metronomic, very low-dose chemotherapy promotes a continuous pattern of stress responses [ 55 , 123 , 124 , 125 ]. The present clinical data reveal that metronomic chemotherapy at ‘very’ low-doses limits tumor tissue plasticity by stress response, probably decreasing phenotypic heterogeneity of tumor cell niches as tissue stress generally induces a tighter phenotype [ 123 , 126 , 127 , 128 , 129 , 130 , 131 ]. Thus, metronomic chemotherapy might induce phenotypic integration of inflammation control or differentiation by editing techniques and, consecutively, may serve as an enhancer of pro-anakoinotic effects mediated by added transcriptional modulators [ 55 , 123 ].…”

The double-edged role of hydrogen sulfide in the pathomechanism of multiple liver diseases

“…Studies have revealed that angiogenesis and immune evasion are key core issues in the tumor microenvironment for liver cancer progression and treatment failure (Motz and Coukos, 2011;Fousek et al, 2021;Pinter et al, 2021;Zhou et al, 2021). In a complex tumor microenvironment composed of hepatocytes, liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), immune cells, and extracellular matrix, the development of HCC is closely related to the infiltration of immune cells and immune evasion in the tumor microenvironment (TME) (Muñoz et al, 2021). Increasing evidence has shown that H 2 S plays a key role in the occurrence and development of HCC.…”

Real-World Experience of Metronomic Chemotherapy in Metastatic Breast Cancer: Results of a Retrospective Unicenter Study

“…Dose accumulations associated with intolerable side effects are rare, so the medication can be administered for longer periods of time [ 11 ]. The mechanisms of action are not truly cytotoxic but rather multimodal, particularly via inhibition of angiogenesis, immunomodulation, and effects on tumor stroma [ 6 , 7 , 12 , 13 ]. It is assumed that MCT is not simply a different way of administering chemotherapy (CT) but a truly new treatment option [ 14 , 15 ].…”