Version 2.1.0.0

Abstract

Abstract: DESCRIPTION (provided by applicant): The objective of this proposal is to advance the development of a novel tumor- targeted antineoplastic drug conjugate. Our concept is based on the use of the vitamin folate to deliver a potent, covalently-attached chemotherapeutic drug to folate receptor (FR)-positive tumors in vivo and to potentiate a greater anti-tumor response in syngeneic animal models relative to that obtained with the un-conjugated drug. It is well-known that many types of human cancers vastly over-express FR and that folate-macromolecule conjugates specifically bind to and enter FR-expressing tumor cells via an endocytosis mechanism. Importantly, internalized folate-drug conjugates are exposed to both acidic and reducing environments within these intracellular endocytic compartments. Thus, high therapeutic efficacy may result from the use of potent folate-drug conjugates constructed with endosome-labile linkers. As such, the following specific aims are proposed: i) synthesize a novel acid- cleavable folate-drug conjugate, ii) synthesize a related thiol-labile folate- drug conjugate, iii) conduct in vitro dose-response cytotoxicity studies, and iv) conduct an initial therapeutic animal study with the more potent folate- drug conjugate. Following the completion of these specific aims, a Phase II project will be initiated which will include the submission of a corporate IND application for a folate-drug conjugate to the FDA and the initiation of an IND Phase I clinical study.

Thesaurus Terms:
antineoplastic, chemical conjugate, drug design /synthesis /production, drug screening /evaluation, folate, mitomycin
chemical synthesis, cytotoxicity, endocytosis, thiol

Institution:	ENDOCYTE, INC.
	1205 KENT AVE
	WEST LAFAYETTE, IN 47906
Fiscal Year:	2002
Department:
Project Start:	21-MAY-2002
Project End:	20-MAY-2003
ICD:	NATIONAL CANCER INSTITUTE
IRG:	ZCA1