A Poly (Ortho Esters)–Based Drug Delivery System as an Adjunct Treatment in Filtering Surgery: Comparison Between 5–Fluorouracil and 5–Chlorouracil

Abstract

Abstract: : Purpose: To study the in vitro anti proliferation effects and the in vivo influence in an experimental model of filtering surgery in the rabbit eye of 5–fluorouracil (5–FU) and 5–chlorouracil (5–CU). Methods: In vitro cell toxicity and anti proliferation effects of various 5–CU and 5–FU concentrations is evaluated by MTT test, Neutral Red test, Hoechst test and direct cell counting after 24 and 72h incubation. For the in vivo studies, trabeculectomy is performed in pigmented rabbit eyes. 200µl of polyorthoesters (POE) containing 1% wt/wt 5–FU or 5–CU are injected under the conjunctival flap on completion of the filtering surgery. Ocular inflammatory reaction, intraocular pressure (IOP) and bleb persistence are monitored after surgery for a period of 34 days. A comparison between rabbit eyes treated with POE/5CU or trabeculectomy alone is performed during a 10 months period using high frequency echography. Results: In vitro tests showed that 5FU has a higher anti proliferation effect and cell toxicity than 5CU. While 5CU increases the apoptotic rate of the cultured Tenon’s capsule cells, 5FU induces evident cell necrosis. In vivo, treatment with POE/5CU or POE/5FU retained a lower IOP when compared to trabeculectomy alone or trabeculectomy with injection of empty POE. One month post surgery, IOP in the POE/5CU group was 6.20 +/– 2.68 mmHg, it was 3.42 +/– 1.07 mmHg in the POE/5FU group, 9.19 +/– 4.12 mmHg in the empty POE group. The "only trabeculectomy" group had an IOP of 8.38 +/– 4.12 mmHg. 6 months later, IOP was maintained significantly lower in the POE/5CU group related to the control. Conclusions: 5–FU and 5–CU in POE stabilize the decrease of IOP after glaucoma filtering surgery in the rabbit eye. 5–FU has a more marked inhibitory effect on cell proliferation of fibroblasts from Tenon’s capsule than 5–CU. In vivo however, 5–CU also induces a sustained IOP decrease.

Keywords: intraocular pressure • drug toxicity/drug effects • clinical laboratory testing