title: Synthesis, pharmacokinetics, efficacy, and rat retinal toxicity of a novel mitomycin C-triamcinolone acetonide conjugate.
abstract: A novel conjugate of mitomycin C (MMC) and triamcinolone acetonide (TA) was synthesized using glutaric acid as a linker molecule. To determine the rate of hydrolysis, the conjugate was dissolved in aqueous solution and the rate of appearance of free MMC and TA was determined by high-performance liquid chromatography analysis. Antiproliferative activity of the MMC-TA conjugate and parent compounds was assessed using an NIH 3T3 fibroblast cell line. Cell growth was quantified using the MTT assay. Kinetic analysis of the hydrolysis rate demonstrated that the conjugate had a half-life of 23.6 h in aqueous solutions. The antiproliferative activities of the MMC-TA conjugate and MMC were both concentration dependent, with similar IC(50) values of 2.4 and 1.7 microM, respectively. However, individual responses at concentrations above 3 microM showed that the conjugate was less active than MMC alone. TA alone showed only limited inhibition of cell growth. Studies evaluating intravitreal injection of the conjugate demonstrate that this agent produced no measurable toxicity. Our data provide evidence that the MMC-TA conjugate could be used as a slow-release drug delivery system. This could in turn be used to modulate a posttreatment wound healing process or to treat various proliferative diseases.
authors.affiliation: Department of Ophthalmology, Medical University of South Carolina, 280 Calhoun Street, Charleston, South Carolina 29425-2301, USA.
authors.forename: Tamer A
authors.initials: TA
authors.lastname: Macky
authors.forename: Carsten
authors.initials: C
authors.lastname: Oelkers
authors.forename: Uwe
authors.initials: U
authors.lastname: Rix
authors.forename: Martin L
authors.initials: ML
authors.lastname: Heredia
authors.forename: Eva
authors.initials: E
authors.lastname: Künzel
authors.forename: Mark
authors.initials: M
authors.lastname: Wimberly
authors.forename: Baerbel
authors.initials: B
authors.lastname: Rohrer
authors.forename: Craig E
authors.initials: CE
authors.lastname: Crosson
authors.forename: Jürgen
authors.initials: J
authors.lastname: Rohr
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D004596:Electroretinography; D005260:Female; D005977:Glutarates / Q000737:chemistry*; D006868:Hydrolysis; D051379:Mice; D016685:Mitomycin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000033:anatomy & histology / Q000187:drug effects*; D014222:Triamcinolone Acetonide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D005977:Glutarates; D016685:Mitomycin; D014222:Triamcinolone Acetonide; C035736:glutaric acid