Synergistic effects of combined cytotoxic and apoptosis-inducing drugs on Tenon's capsule fibroblasts in vitro and in vivo.
BACKGROUND
Highly toxic antimetabolites have gained access to routine clinical use to modulate and reduce the amount of postoperative scarring following glaucomatous filtering procedures. It could be speculated that by combining two different antiproliferative substances with different mechanisms of action total amounts of the substances could be decreased and side effects reduced.


METHODS
Twenty-two substances were tested that had antiproliferative effects by acting cytotoxically, inhibiting growth factors, or inducing apoptosis. With combinations of each two substances, cell culture experiments using 3T3 and human Tenon's capsule fibroblasts were performed evaluating cell toxicity, proliferation and migration, the extent of free radicals, and the amount of apoptosis (TUNEL, electron microscopy). The five most potent combinations were used in an animal experiment with rabbits performing filtering procedures. The extent of episcleral scarring was evaluated by histopathology.


RESULTS
The results of the various assays revealed consistently strong effects in 5 of the 462 combinations. Of these five combinations, two were highly effective in the rabbit model. Substances with strong effects when applied in combination included staurosporine, mitomycin, and CD95L.


CONCLUSIONS
We found synergistic effects in assays that evaluated different aspects of cell function. The amount of scarring in an animal experiment was inhibited to a level comparable with a high single dose of mitomycin. Combination therapy of two antiproliferative acting substances may be a promising concept.
Mietz
Holger
H
Department of Ophthalmology, University of Cologne, Cologne, Germany.
Welsandt
Gerhard
G
Hueber
Arno
A
Esser
Christina
C
Krieglstein
Günter K
GK
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003239:Connective Tissue Cells / Q000187:drug effects* / Q000648:ultrastructure; D004357:Drug Synergism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000648:ultrastructure; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D041681:NIH 3T3 Cells / Q000187:drug effects; D011817:Rabbits; D014945:Wound Healing / Q000187:drug effects
D005609:Free Radicals