title: Synthesis and biological evaluation of EC72: a new folate-targeted chemotherapeutic.
abstract: A novel folate conjugate of mitomycin C, herein referred to as EC72, was designed and evaluated for biological activity against FR-positive cells and tumors. EC72 was produced by coupling folic acid-gamma-cysteine to 7-N-modified MMC via a disulfide bond. This water soluble conjugate was found to retain high affinity for FR-positive cells, and it produced dose responsive activity in vitro against a panel of folate receptor (FR)-positive cell lines. EC72's activity was considered to be targeted and specific for the FR since (i) excess folic acid blocked biological activity, and (ii) FR-negative cell lines were unresponsive to this drug. Initial in vivo tests confirmed EC72's activity in both syngeneic and xenograft models, and this activity occurred in the apparent absence of gross or pathological toxicity. These results are significant, since daily dosing of EC72 for more than 30 consecutive days yielded no evidence of myelosuppression or toxicity to major organs, including the FR-positive kidneys. The latter observation supports published data, indicating that the apically oriented kidney proximal tubule FRs function to salvage folates prior to their excretion and to return these molecules back into systemic circulation. Overall, EC72's performance in vitro and in vivo warrants further preclinical study before this novel targeted chemotherapeutic is considered for clinical investigation.
authors: Endocyte, Inc., 3000 Kent Avenue, West Lafayette, Indiana 47906, USA. chrisleamon@endocyte.com
authors: Christopher P
authors: CP
authors: Leamon
authors: Joseph A
authors: JA
authors: Reddy
authors: Iontcho R
authors: IR
authors: Vlahov
authors: Marilynn
authors: M
authors: Vetzel
authors: Nikki
authors: N
authors: Parker
authors: Jeffrey S
authors: JS
authors: Nicoson
authors: Le-Cun
authors: LC
authors: Xu
authors: Elaine
authors: E
authors: Westrick
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D000970:Antineoplastic Agents; C505633:EC72 compound; D005492:Folic Acid