Journal
CANCER AND METASTASIS REVIEWS
Volume 26, Issue 1, Pages 129-139Publisher
SPRINGER
DOI: 10.1007/s10555-007-9047-1
Keywords
proton-coupled folate transporter (PCFT); hereditary folate malabsorption (HFM) methotrexate; pemetrexed; intestinal folate absorption; heme carrier protein (HCP1)
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Membrane transport of folates is essential for the survival of all mammalian cells and transport of antifolates is an important determinant of antifolate activity. While a major focus of attention has been on transport mediated by the reduced folate carrier and folate receptors, a very prominent carrier-mediated folate transport activity has been recognized for decades with a low-pH optimum and substrate specificity distinct from that of the reduced folate carrier which operates most efficiently at neutral pH. This low-pH transporter represents the mechanism by which folates are absorbed in the small intestine and it is also widely expressed in other human tissues and solid tumors. Recently, this laboratory discovered the molecular identity of this transporter which is genetically unrelated to the reduced folate carrier. This transporter is proton-coupled, electrogenic, and manifests a substrate specificity that is similar to that of the low-pH transport activity previously described in mammalian cells. The key role this transporter plays in intestinal folate absorption has been confirmed by the demonstration of a mutation in this gene in the rare autosomal recessive disorder, hereditary folate malabsorption. This article reviews (1) the its relationship to, and properties of, the recently identified Proton-Coupled Folate Transporter (PCFT), (3) the physiological and pharmacological roles of this transporter, particularly with respect to pemetrexed, and (4) the historical controversy, now resolved, on the mechanism of intestinal folate absorption.
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