Molecular and cellular biology of the human reduced folate carrier.

The natural folates are water-soluble members of the B class of vitamins that are essential for cell proliferation and tissue regeneration. Since mammalian cells cannot synthesize folates de novo, tightly regulated and sophisticated cellular uptake processes have evolved to sustain sufficient levels of intracellular tetrahydrofolate cofactors to support the biosynthesis of purines, pyrimidines, serine, and methione. Membrane transport is also a critical determinant of the antitumor activity of antifolate therapeutics (methotrexate, Tomudex) used in cancer chemotherapy, and impaired uptake of antifolates is a frequent mode of drug resistance. The reduced folate carrier is the major transport system for folates and classical antifolates in mammalian cells and tissues. This review summarizes the remarkable advances in the cellular and molecular biology of the human reduced folate carrier over the past decade, relating to its molecular structure and transport function, mechanisms of transcriptional and posttranscriptional regulation, and its critical role in antifolate response and resistance. Many key in vitro findings have now begun to be extended to studies of reduced folate carrier levels and function in patient specimens, paving the way for translating basic laboratory studies in cultured cells to improvements in human health and treatment of disease. The results of research into the human reduced folate carrier should clarify the roles of changes in expression and function of this system that accompany nutritional folate deficiency and human disease, and may lead to improved therapeutic strategies for enhancing drug response and circumventing resistance in cancer patients undergoing chemotherapy with antifolates.