Investigating short-term toxicity of melphalan in a model of an isolated and superfused bovine retina.
BACKGROUND
Melphalan, as a treatment for retinoblastoma, has been applied intra-arterially by catheterisation of the ophthalmic artery or intravitreally, aiming to reduce systemic side effects of intravenous drug therapy. This study evaluates retinal toxicity of different melphalan concentrations measured by electroretinogram (ERG) in an isolated and perfused retinal whole mount culture.


METHODS
For functional testing, bovine retinas were prepared and perfused with an oxygen-saturated standard solution and the ERG was recorded until stable b-wave or a-wave amplitudes were reached. Thereafter, retinae were exposed to 80, 160 and 320 μg/ml of melphalan for 30 min. After exposure, a washout was performed thrice for 5 min each and the ERG amplitude recovery was monitored for 60 min. To investigate the effects on photoreceptor function, 1-mM asparate was added to suppress the b-wave and obtain isolated a-waves.


RESULTS
While no toxic effects for a concentration of 80 μg/ml were observed, both b- and a-waves were significantly reduced after application of 160 (b-wave 43.8 %, p = 0.03; a-wave 28.2 %, p = 0.04) and 320 μg/ml (b-wave 20.0 %, p = 0.04; a-wave 35.8 %, p = 0.02). For 320 μg/ml, this reduction remained significant at the end of the washout (b-wave 40.0 % p = 0.02; a-wave 26.4 %, p = 0.02).


CONCLUSIONS
Epiretinal or intraretinal concentrations of 80-μg/ml melphalan do not cause toxic effects in this in vitro model. Concentrations higher than 160 μg/ml should be avoided.
Centre for Ophthalmology, University Eye Hospital Tübingen, Schleichstr. 12, D-72076, Tübingen, Germany. Kai.januschowski@med.uni-tuebingen.de.|Eye hospital, Knappschaftklinikum, Sulzbach, Saar, Germany. Kai.januschowski@med.uni-tuebingen.de.
Kai
K
Januschowski
Centre for Ophthalmology, University Eye Hospital Tübingen, Schleichstr. 12, D-72076, Tübingen, Germany.
Carlo
C
Krupp
Centre for Ophthalmology, University Eye Hospital Tübingen, Schleichstr. 12, D-72076, Tübingen, Germany.
Sebastian
S
Mueller
Centre for Ophthalmology, University Eye Hospital Tübingen, Schleichstr. 12, D-72076, Tübingen, Germany.
Kathleen
K
Hofmann
Centre for Ophthalmology, University Eye Hospital Tübingen, Schleichstr. 12, D-72076, Tübingen, Germany.
Sven
S
Schnichels
Centre for Ophthalmology, University Eye Hospital Tübingen, Schleichstr. 12, D-72076, Tübingen, Germany.
Ulrike
U
Hagemann
Centre for Ophthalmology, University Eye Hospital Tübingen, Schleichstr. 12, D-72076, Tübingen, Germany.
Martin S
MS
Spitzer
Centre for Ophthalmology, University Eye Hospital Tübingen, Schleichstr. 12, D-72076, Tübingen, Germany.
Karl-Ulrich
KU
Bartz-Schmidt
University Eye Hospital, University of Oldenburg, Oldenburg, Germany.
Sabine
S
Aisenbrey
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D001224:Aspartic Acid / Q000494:pharmacology; D002417:Cattle; D003623:Dark Adaptation; D004596:Electroretinography / Q000187:drug effects*; D008558:Melphalan / Q000633:toxicity*; D009924:Organ Culture Techniques; D010775:Photic Stimulation; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000502:physiology; D012160:Retina / Q000187:drug effects* / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology
D018906:Antineoplastic Agents, Alkylating; D001224:Aspartic Acid; D008558:Melphalan
Electroretinogram; Melphalan; Retina; Retinal toxicity; Retinoblastoma