I. David Goldman

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Folates are essential nutrients that are required for one-carbon biosynthetic and epigenetic processes. While folates are absorbed in the acidic milieu of the upper small intestine, the underlying absorption mechanism has not been defined. We now report the identification of a human proton-coupled, high-affinity folate transporter that recapitulates(More)
Until recently, the transport of folates into cells and across epithelia has been interpreted primarily within the context of two transporters with high affinity and specificity for folates, the reduced folate carrier and the folate receptors. However, there were discrepancies between the properties of these transporters and characteristics of folate(More)
PURPOSE This study was undertaken to select the optimal combination schedule of erlotinib and pemetrexed for the treatment of relapsed non-small cell lung cancer (NSCLC) using a panel of human NSCLC lines. EXPERIMENTAL DESIGN Human NSCLC cell lines, with variable expression of the known molecular determinants of erlotinib sensitivity, were exposed to(More)
Whereas the major folate transporter, the reduced folate carrier (RFC), has a physiological pH optimum, transport activities for folates and antifolates have been detected with low pH optima. Because the interstitial pH in solid tumors is generally acidic, the mechanisms by which antifolates are transported at low pH could be an important determinant of(More)
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(More)
Transport of methotrexate (4amino-lo-methylpteroylglutamic acid), a structural analogue of folic acid, was studied in L1210 mouse leukemia cells grown in tissue culture. Intracellular methotrexate was present in two states. (a) There was an essentially nonexchangeable intracellular fraction probably bound to the enzyme dihydrofolate reductase. (b) The(More)
The antifolates were the first class of antimetabolites to enter the clinics more than 50 years ago. Over the following decades, a full understanding of their mechanisms of action and chemotherapeutic potential evolved along with the mechanisms by which cells develop resistance to these drugs. These principals served as a basis for the subsequent(More)
The reduced folate carrier (RFC1) is a major route for the transport of folates in mammalian cells. The localization of RFC1 in murine tissues was evaluated by immunohistochemical analysis using a polyclonal antibody to the C-terminus of the carrier. There was expression of RFC1 in the brush-border membrane of the jejunum, ileum, duodenum and colon. RFC1(More)
Recently, this laboratory identified a proton-coupled folate transporter (PCFT), with optimal activity at low pH. PCFT is critical to intestinal folate absorption and transport into the central nervous system because there are loss-of-function mutations in this gene in the autosomal recessive disorder, hereditary folate malabsorption. The current study(More)