Abstract
Folate is an essential vitamin which acts as a precursor for cofactors that regulate a variety of biochemical reactions. Cellular uptake of endogenous folates as well as antifolate agents such as methotrexate may be regulated by two independent transport proteins, the folate receptor and the reduced folate carrier. This paper reviews the molecular and functional characteristics of these transport systems and potential therapeutic approaches exploiting these targets in the treatment of cancer. Understanding of the molecular basis and functional characteristics of the transport of endogenous folates and folate analogs via the folate receptor and the reduced folate carrier has led to the development of novel antifolate agents through rational drug design and targeted therapeutic approaches for tumors that express or lack the presence of these transport proteins. With this knowledge, new and selective treatment will become available to more effectively treat patients with a variety of malignancies.