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The mechanisms by which folates are transported across cell membranes have been an area of research interest for nearly five decades. Major transport systems include the facilitative carriers, the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), and the high affinity folate receptors (FRs) α and β which transport folates by endocytosis. RFC is the major transport system...
The folate receptors (FRs) are a family of proteins coded by genes located on chromosome 11 at 11q13 telomeric to Cyclin D1. There are now four members: α, β, γ, and δ. The first two isoforms are the best studied, and they are targets for both pharmacological and immunotherapies. There is little known about the last two isoforms relative to folate homeostasis. The first two are both glycosylphosphatidylinositol-linked...
The two major human folate receptor (FR) isoforms, α and β, are glycosyl phosphatidylinositol-anchored glycoproteins with limited expression in normal tissues including epithelial cells (FRα) and hematopoietic cells (FRβ). FRα plays a critical role during pregnancy in ensuring an adequate supply of folate to the fetus. FRs are a potential means of delivering a range of therapeutics in cancer and inflammatory...
Diagnostic nuclear medicine makes use of two molecular imaging technologies, single-photon emission computed tomography (SPECT) and positron emission tomography (PET). SPECT and PET can be used to noninvasively identify and localize cancerous tumors through the use of marker proteins which are overproduced in cancer cells. The folate receptor (FR) is one such protein which is overexpressed in a variety...
Antifolate drugs used for cancer treatment lack the level of tissue targeting desired by the new drug development paradigm. This is because their most pharmacologically relevant cell membrane transporter (the reduced-folate carrier [RFC]) and intracellular targets are not tumor specific. A number of folate receptor (FR)-targeted agents for the imaging and treatment of cancer have entered clinical...
Lack of drug selectivity is one of the major causes of the failure of cancer chemotherapy. This Chapter describes studies that explore the concept of therapeutic targeting solid tumors using folate-receptor (FR) and proton-coupled folate transporter (PCFT)-targeted antifolates that exhibit limited transport by the ubiquitously expressed reduced folate carrier (RFC). We describe our recent studies...
The membrane-bound folate receptor (FR) is overexpressed on a wide range of human cancers. The vitamin folic acid is a high affinity ligand of the FR which retains its receptor binding and receptor-mediated endocytosis properties when conjugated to other molecules. Consequently, folate targeting technology has successfully been applied for the delivery of various chemotherapeutic agents to FR-positive...
The discovery of the methodology to raise mouse monoclonal antibodies (mAbs) represents a milestone in the history of medicine and has opened the way to antibody therapy development. In the oncologic field, antibody-based therapy seems an attractive strategy for those tumors, such as epithelial ovarian cancer and glioblastoma, for which the existing treatment options are still not sufficient. Initial...
FRβ constitutes a unique and selective marker for activated human monocytes and macrophages. Based on numerous criteria, most FR+ macrophages appear to be highly inflammatory and important in the development/maintenance of many inflammatory and autoimmune diseases, however, some appear to be activated and anti-inflammatory. Inflammatory pathologies in which FR+ macrophages are commonly enriched include...
The folate receptor expressed by activated macrophages associated with chronic inflammation is fully functional in binding/internalization of high-affinity folate ligands. The recent effort in developing folate-targeted anti-macrophage therapies has yielded some encouraging results. However, the challenges lie not so much in finding the right ligand, but rather its multifaceted nature in identifying...
In this chapter, we will address the therapeutic potential of targeting liposomes and polymers to the folate receptor for delivery of anticancer drugs and review the experimental data in this field. By exploiting the pharmacologic attributes of liposomes and polymers together with their cellular internalization by folate receptor-mediated endocytosis, these systems should allow for improved selectivity...
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