Toxicity of subretinal ribozyme to the proliferating cell nuclear antigen and 5-fluorouracil in rat eyes.
OBJECTIVE
To investigate the subretinal toxicity profile of the ribozyme to the proliferating cell nuclear antigen (PCNA-Rz) and 5-fluorouracil (5-FU), as well as the highest nontoxic subretinal dose of the mixture of the two agents in rat eyes.


METHODS
Brown-Norway rats received subretinal injections of 1 microg, 10 microg, and 100 microg/microl PCNA-Rz and 0.06 microg/microl, 0.3 microg/microl, and 1.5 microg/microl 5-FU in the right eyes, and the left eyes were injected with H-BSS as control. Each dose was tested on 5 eyes in a 5 microl volume. In a second study, a combination of 5-FU (1.5 microg/microL) with varying 10-30-50 microg/microl doses of PCNA-Rz was tested in a regimen of four sequential subretinal injections. Toxicity was monitored by biomicroscopy, indirect ophthalmoscopy, electroretinography (ERG), and histology.


RESULTS
The highest nontoxic dose for subretinal PCNA-Rz was 10 microg/microl, whereas 100 microg/microl showed disturbance of pigmentation with corresponding histological changes of retinal photoreceptor loss and retinal pigment epithelium proliferation or irregularities. Subretinal injection of all three doses of 5-FU did not show any toxicity. Serial injections of a mixture of 1.5 microg/microl 5-FU with 10 microg/microl of PCNA-Rz was found to be safe in rat eyes.


CONCLUSIONS
Subretinal injections of the combination of PCNA-Rz (10 microg/microl) and 5-FU (1.5 microg/microl) demonstrated to be safe in rat eyes during the course of this study, even with a multiple administration of four injections.
Kayikcioglu
O R
OR
Joan and Irwin Jacobs Retina Center at UCSD/Shiley Eye Center, University of California-San Diego, 9415 Campus Point Drive, La Jolla, CA 92037, USA.
Cheng
L
L
Kozak
I
I
Bergeron-Lynn
G
G
Schulteis
C T
CT
Rhoades
K L
KL
Freeman
W R
WR
D000818:Animals; D004338:Drug Combinations; D004596:Electroretinography / Q000187:drug effects; D005472:Fluorouracil / Q000633:toxicity*; D007267:Injections; D008297:Male; D009887:Ophthalmoscopy; D018809:Proliferating Cell Nuclear Antigen / Q000633:toxicity*; D016337:RNA, Catalytic / Q000633:toxicity*; D051381:Rats; D011914:Rats, Inbred BN; D012160:Retina / Q000187:drug effects* / Q000648:ultrastructure
D004338:Drug Combinations; D018809:Proliferating Cell Nuclear Antigen; D016337:RNA, Catalytic; D005472:Fluorouracil