Pharmacokinetics and Efficacy of the Spleen Tyrosine Kinase Inhibitor R406 after Ocular Delivery for Retinoblastoma
| Autor: | Jiakun Zhang, Elizabeth Stewart, Praveen Kumar Suryadevara, Michael A. Dyer, Cori Bradley, Lei Yang, Fangyi Zhu, Lyra Griffiths, R. Kiplin Guy, Eleanor M. Pritchard, Burgess B. Freeman |
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| Rok vydání: | 2014 |
| Předmět: |
Programmed cell death
Retinal Neoplasm Pyridines Retinal Neoplasms medicine.medical_treatment Pharmaceutical Science Syk Antineoplastic Agents R406 Pharmacology Biology Eye Targeted therapy Mice 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Oxazines medicine Animals Humans Syk Kinase Pharmacology (medical) Protein Kinase Inhibitors Epigenomics Ocular drug delivery Cell Death Retinoblastoma Organic Chemistry Intracellular Signaling Peptides and Proteins Spleen tyrosine kinase Protein-Tyrosine Kinases medicine.disease eye diseases 3. Good health Mice Inbred C57BL Clinical trial Disease Models Animal 030220 oncology & carcinogenesis 030221 ophthalmology & optometry Cancer research Molecular Medicine Female Research Paper Biotechnology |
| Zdroj: | Pharmaceutical Research |
| ISSN: | 1573-904X 0724-8741 |
| Popis: | Purpose Retinoblastoma is a childhood cancer of the retina. Clinical trials have shown that local delivery of broad spectrum chemotherapeutic agents is efficacious. Recent studies characterizing the genomic and epigenomic landscape of retinoblastoma identified spleen tyrosine kinase (SYK) as a promising candidate for targeted therapy. The purpose of this study was to conduct preclinical testing of the SYK antagonist R406 to evaluate it as a candidate for retinoblastoma treatment. Methods The efficacy of the SYK antagonist R406 delivered locally in a human orthotopic xenograft mouse model of retinoblastoma was tested. Intraocular exposure of R406 was determined for various routes and formulations. Results There was no evidence of efficacy for subconjunctival. R406. Maximal vitreal concentration was 10-fold lower than the minimal concentration required to kill retinoblastoma cells in vitro. Dosage of R406 subconjunctivally from emulsion or suspension formulations, direct intravitreal injection of the soluble prodrug of R406 (R788), and repeated topical administration of R406 all increased vitreal exposure, but failed to reach the exposure required for retinoblastoma cell death in culture. Conclusion Taken together, these data suggest that R406 is not a viable clinical candidate for the treatment of retinoblastoma. This study highlights the importance of pharmacokinetic testing of molecular targeted retinoblastoma therapeutics. Electronic supplementary material The online version of this article (doi:10.1007/s11095-014-1399-y) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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