Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy☆
Section snippets
The folate receptor: its enigmatic role in physiology and its promise in therapeutics
The folate receptor (FR), also known as the folate binding protein (FBP or Folbp), is a glycopolypeptide with a high affinity (KD<10−9 M) for folic acid and the physiologic circulating form of the vitamin, N5-methyltetrahydrofolate [1]. Human FR is encoded by a family of genes whose homologous products are termed FR types -α, -β and -γ [2], [3], [4], [5], [6], [7]. A fourth isoform, named FR-δ has been tentatively identified from genome database mining, but neither its tissue expression nor its
The FR gene family: diversity that aids targeted therapies
The occurrence of multiple, functionally distinguishable, tissue-specific FR isoforms provides an added level of tissue selectivity in FR-mediated therapy/prognosis/diagnosis. The different ligand specificities of FR-α versus -β (discussed in Section 2.3) may be particularly beneficial in the design of folate-based low molecular weight drugs to selectively target FR-β-positive pathologic tissues avoiding nephrotoxicity due to drug uptake via FR-α expressed in proximal kidney tubules.
Mechanisms governing FR gene expression: opportunities to selectively modulate FR levels for more effective targeting
In recent years, a variety of transcriptional and post-transcriptional mechanisms have been identified as likely contributors to the unique tissue expression patterns of FR genes. Some of these mechanisms offer novel insights into gene regulation in general. From a clinical perspective, the concept of utilizing these regulatory mechanisms to obtain a selective overexpression of the receptor in malignant cells is proving to be a feasible approach to enhancing the efficacy of FR-targeted
Future prospects
The detailed tissue distribution patterns of FR isoforms in normal and pathologic tissues have been established by several groups using different methodologies. The results of those studies and the inherent properties of FR in these tissues have made the receptor a seemingly ideal marker/target, for therapeutic intervention. In recent years FR has been a paradigm for many novel experimental approaches in targeted therapeutics. Conceptual and technical innovations and refinements in the
Acknowledgements
We wish to thank Robert Trumbly, Ph.D. for carrying out the BLAST searches of the NCBI databases. This work was supported by NIH RO1 grants CA 80183 and CA 70873 to M.R.
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Supported by NIH RO1 grants CA 80183 and CA 70873 to M.R.