Antiangiogenic properties of metronomic chemotherapy in breast cancer

Chemotherapeutic agents cause DNA damage and disrupt DNA replication in proliferating cells. Drug regimens have been designed to kill as many tumor cells as possible with the use of the maximum-tolerated doses of these cytotoxic agents. Damage in proliferating tissues (the bone marrow, gut and skin) and healthy tissues place serious constraints on the use of chemotherapy. To balance toxicity with efficacy, cytotoxic agents are administered in a pulsed manner with breaks between cycles to allow for the recovery of normal tissues. Many chemotherapy regimens are initially efficacious, determining tumor regression or stabilization and prolonged survival. However, responses are generally short-lived, with relapses often marked by aggressive cancers that are resistant to the cytotoxic drug. Cytotoxic chemotherapy remains an important part of optimal therapy for patients in all stages of disease, but its use is limited by toxicity, nonspecificity and the inevitable development of resistance, with serious consequences on the patients quality of life. For these reasons, clinical research is moving to improve our understanding of the altered molecular events in cancer cells and find new targets to be inhibited in order to optimize cytotoxicity and overcome resistance mechanisms. This review aims to explain the rationale behind metronomic and targeted therapies in breast cancer and to examine the main preclinical and clinical (neoadjuvant, adjuvant and advanced settings) studies conducted.