The folate receptor as a potential therapeutic anticancer target.

Abstract

The folate receptor, a 38,000 Dalton glycosylphosphatidylinositol-linked membrane protein, has been identified qualitatively in selected normal tissues and is relatively overexpressed in certain neoplastic tissues [1]. Three receptor subtypes have been identified in humans: the high-affinity (Kd = nM) α-subtype which is found in the kidney and is relatively overexpressed in epithelial tumors, the more abundant, low-affinity (Kd = mM) β-subtype which is found in the placenta, and the γ -subtype which is the secretory form. The mechanism of folic acid uptake by the receptor, through a process termed potocytosis, has been well described [2]. While the role of the receptor in folate homeostasis has not been well delineated, it is thought to provide a selective advantage for tumor growth over normal tissue or, because of the glycosylphosphatidylinositol tail, it may have a role in cell activation or communication. Since the folate receptor is relatively overexpressed in epithelial tumors, particularly in ovarian tumors in adults, in ependymoma in children, and choroid plexus tumors in both populations, there has been considerable interest in exploiting the folate receptor in tumor imaging, drug and antisense delivery, immunotherapy, and antifolate drug design. It has been shown that folic acid, when covalently linked to other macromolecules, retains its high affinity for the folate receptor [3]. Radionuclides, antineoplastic agents, antibodies, antisense DNA and toxins have been targeted to cell lines and tumors which overexpress the folate receptor using folic acid conjugates. The purified receptor has been used to produce monospecific antibodies against choriocarcinoma, renal, lung and ovarian tumors [4,5,6] and bispecific antibody against ovarian tumors [7] which have shown potential in clinical trials as immunotherapy and radiotherapy. Recent studies of new antifolate compounds have evaluated their affinity for the folate receptor or the reduced folate carrier as well as for enzymes of the folate pathway [8,9]. The purpose of this paper is to review the current preclinical and clinical studies and to identify future directions for investigations of the receptor with respect to treatment of pediatric and adult tumors.