Exploring the potential of folate targeting in anticancer therapies

Yingjuan Lu, Purdue University

Abstract

The discovery of high levels of the folate receptor (FR) on human tumor cells has rendered this folate binding protein an attractive candidate for tumor-specific therapeutics. Using folic acid, a natural ligand with high affinity (KD < 0.1 nM) for the FR, we have explored the selective targeting of FR-positive tumors with a wide spectrum of folate-derived antitumor agents. More specifically, we have evaluated the potential of folate targeting to develop tumor-specific enzyme/prodrug therapy, recombinant tissue factor-mediated tumor thrombosis, taxol-based chemotherapy, and most importantly, antibody-based immunotherapy. Selective killing of FR-positive tumor cells was first mediated by a folate-linked fungal enzyme (penicillin-V amidase) that converts a relatively nontoxic prodrug to its potent parent drug, doxorubicin. For the induction of tumor-localized thrombosis, a coaguligand consisting of recombinant human tissue factor covalently linked to folate demonstrated its ability to promote specific clotting of plasma on a FR-positive murine tumor cell line that lacks basal tissue factor activity. For the purpose of targeting of low-molecular-weight cytotoxic drugs, a folate-taxol derivative was compared to the parent drug taxol in both in-vitro and in-vivo studies. With the intention of inducing a humoral immune response against FR-positive tumors in-vivo, an innovative strategy of folate-targeted immunotherapy demonstrated impressive therapeutic efficacy in normal mice with syngeneic transplantable tumors. Finally, preinjected bisfolate-PEG600 and free folic acid were examined for their abilities to reduce normal tissue uptake of a tumor radioimaging agent (111In-DTPA-folate) in an attempt to improve the overall therapeutic benefit of folate-targeted anticancer therapies.

Degree

Ph.D.

Advisors

Low, Purdue University.

Subject Area

Biochemistry|Pharmacology

COinS