Preclinical Antitumor Activity of a Novel Folate-Targeted Dual Drug Conjugate
| Autor: | Hari Krishna Santhapuram, Elaine Westrick, Yu Wang, Ryan Dorton, Marilynn Vetzel, Iontcho Radoslavov Vlahov, Joseph A. Reddy, Christopher P. Leamon, Alicia Dawson |
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| Rok vydání: | 2007 |
| Předmět: |
Drug
medicine.drug_class media_common.quotation_subject medicine.medical_treatment Drug Evaluation Preclinical Mice Nude Pharmaceutical Science Phases of clinical research Antineoplastic Agents Pharmacology Biology Substrate Specificity Vinca alkaloid Mice Folic Acid Cell Line Tumor Neoplasms Drug Discovery medicine Animals Humans media_common Chemotherapy Molecular Structure Ligand (biochemistry) Xenograft Model Antitumor Assays In vitro Disease Models Animal Folate receptor Molecular Medicine Female Conjugate |
| Zdroj: | Molecular Pharmaceutics. 4:659-667 |
| ISSN: | 1543-8392 1543-8384 |
| Popis: | We have designed a new type of tumor-targeted agent by tethering two different drug molecules, with distinct biological mechanisms of action, to the same ligand. This compound, named EC0225, represents the "first in class" multidrug, folate receptor (FR)-targeted agent to be disclosed. It was constructed with a single folate molecule, extended by a hydrophilic peptide-based spacer, which was in turn attached to mitomycin and Vinca alkaloid units via two separate disulfide-containing linkers. EC0225 produced potent, dose-responsive activity in vitro, and curative activity was observed against FR-positive syngeneic and xenograft tumors following the administration of well-tolerated dosing regimens. Multiple complete responses and cures were also noted when EC0225 was used to treat mice initially bearing tumors as large as 750 mm (3) in volume. Overall, EC0225's impressive preclinical activity allowed for its selection as a development candidate and for the start of Phase 1 clinical trials, which began in March of 2007, for the treatment of advanced malignancies. |
| Databáze: | OpenAIRE |
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