Platelet-derived growth factor receptor kinase inhibitor AG1295 and inhibition of experimental proliferative vitreoretinopathy.

Abstract

PURPOSE:

Receptor tyrosine kinase (RTK) activation is critical for growth factor-mediated cell proliferation. The present study was designed to determine the effect of tyrphostin AG1295, a selective blocker of platelet-derived growth factor (PDGF) RTK, on proliferative vitreoretinopathy (PVR) development.

METHODS:

Rabbit conjunctival fibroblasts cells (1 x 10(4)) were seeded into 96-well plates and maintained in Dulbecco's modified essentialmedium (DMEM) with 0.5% fetal bovine serum. The cells were exposed to 50 ng/mL PDGF-AAor PDGF-BBor phosphate-buffered saline with or without AG1295 (1 microM, 10 microM, and 100 microM). After 3 days, the viable cells in each well were measured by 3,(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Homologous rabbit conjunctival fibroblasts were injected intravitreally, followed by injection of 100 microM of AG1295. The development of tractional retinal detachment (TRD) was assessed to evaluate the effect of AG1295 in vivo. Electroretinography and histologic studies were performed after intravitreal injection of AG1295 into untreated eyes to evaluate toxicity.

RESULTS:

Two concentrations of AG1295 (10 and 100 microM) significantly inhibited rabbit conjunctival fibroblast cell growth stimulated by PDGF-AA or PDGF-BB in vitro. Development of TRD was significantly attenuated (P <.01) with 100 microM of AG1295 until day 21. No significant histologic or retinal functional damage was found in the AG1295-treated group.

CONCLUSIONS:

PDGF receptor specific inhibitor AG1295 attenuated PVR without significant side effects in rabbits. This reagent could be a useful treatment to prevent PVR.

• Authors: Yuping Zheng, Yasushi Ikuno, Masahito Ohj, Shunji Kusaka, Rui Jiang, Osman Cekiç, Miki Sawa, Yasuo Tano
• Journal: Japanese journal of ophthalmology (Jpn J Ophthalmol) 2003 Mar-Apr Vol. 47 Issue 2 Pg. 158-65 ISSN: 0021-5155 [Print] Japan
• PMID: 12738549 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6,7-dimethoxy-2-phenylquinoxaline
• Platelet-Derived Growth Factor
• Proto-Oncogene Proteins c-sis
• Tyrphostins
• platelet-derived growth factor A
• Becaplermin
• PDGF receptor tyrosine kinase
• Receptors, Platelet-Derived Growth Factor

Topics

• Animals
• Becaplermin
• Cell Division (drug effects)
• Cells, Cultured
• Conjunctiva (cytology)
• Disease Models, Animal
• Electroretinography
• Female
• Fibroblasts (drug effects, physiology)
• Male
• Platelet-Derived Growth Factor (pharmacology)
• Proto-Oncogene Proteins c-sis
• Rabbits
• Receptors, Platelet-Derived Growth Factor (antagonists & inhibitors)
• Retina (drug effects, physiology)
• Safety
• Tyrphostins (pharmacology)
• Vitreoretinopathy, Proliferative (pathology, prevention & control)
• Vitreous Body (pathology)