Reduced folate carrier RFC

Thymidylate Synthase Gene Reduced Folate Carrier (RFC) Gene Discussion References... 

The classic antifolate methotrexate MTX continues to be an important component of the chemotherapeutic armamentarium for a variety of cancers including pediatric ALL, osteogenic sarcoma, lymphoma, and breast cancer. Raltitrexed, another anti-folate, is used throughout much of the world outside of the United States for advanced colorectal cancer. Finally, Peme-trexed was approved in 2004 for the treatment of pleural mesothelioma and shortly thereafter as a second line treatment for nonsmall cell lung cancer. These drugs mimic the natural folate molecule and in so doing utilize the membrane-bound reduced folate carrier (RFC) protein system to gain entry into the cell. 

Folic acid conjugation is also a derivatization method potentially applicable to CP copolymer modification for target specialty toward cancerous cells. The underlying rationale pertains to the relatively strong binding of foUc add to folate receptors (FRs) overexpressed on carcinoma. In fact, in virtually all bodily tissues, the reduced folate carrier (RFC) is expressed. RFC is presumed to be the major route for the uptake of reduced folate cofactors such as 5-methyltetrahydiofolate (5MTHF), which accounts for approximately 99% of folates in our circulation. In addition to RFC, another type of folate transporters for cellular folate uptake is FRs, which can prindpaUy be... 

The reduced folate carrier is the major transporter of methotrexate into cells. The RFC gene is comprised of 40,719 base pairs, has 12 exons, and is located on 21q22.3. The primary polymorphisms studied to date is the RFCl G80A variant, which is associated with a decrease in MTX transport into cells. Rady et al. noted similar rates of variation in several ethnic groups variant homozygosity rates were 28.7% in individuals of Ashkenazi-Jewish decent, 20.8% in African-American, 29% in Caucasians, and 26% in Hispanics (23). 

The ubiquitous existence of folate receptor in mammalian cells, tissues and body fluids is now well-established. Folate receptor occurs in isoforms equipped with a hydrophobic glycosylphosphatidyl inositol tail enabling anchorage to plasma membranes. The RFCl, which is an anion exchanger, has the properties of a classical facilitative carrier with high affinity for reduced folates. The 5-CH3-THF is taken up by the folate receptor with high affinity (.K = 1-10 nM) (Table 44.3) and by the RFC with relatively low affinity (.K = 1-10 pM). 

Folates are transported from the extracellular milieu to the inside of cells by either receptor-mediated (FRa) or carrier-mediated uptake (RFC). Because folates are essential for proper cellular function and necessary for neural tube closure, it is easy to envision how mutations in these receptor genes could lead to reduced levels of intracellular folates and thereby NTDs. Thus, several groups have searched for... 

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