A new delivery system for 5-fluorouracil using prodrug and converting enzyme

Area of Science:

• Ophthalmology
• Molecular Biology
• Pharmacology

Background:

• 5-fluorouracil (5-FU) is a chemotherapy agent.
• Developing targeted drug delivery systems is crucial for improving therapeutic efficacy and reducing side effects.
• Prodrug strategies offer a way to activate drugs specifically at the target site.

Purpose of the Study:

• To evaluate a novel drug delivery system for 5-fluorouracil (5-FU) using 5-fluorocytosine (5-FC) as a prodrug.
• To assess the efficacy of cytosine deaminase-induced activation of 5-FC in inhibiting fibroblast proliferation in vitro and in vivo.

Main Methods:

• Rabbit Tenon's capsule fibroblasts were cultured and treated with 5-FU and 5-FC, with or without induced cytosine deaminase via recombinant adenovirus.
• In vitro assays included MTS and BrdU to measure cell proliferation and DNA synthesis.
• An in vivo model involved transplanting cells into mice, followed by topical 5-FC administration and subsequent evaluation.

Main Results:

• 5-FU inhibited cell proliferation in a dose-dependent manner.
• 5-FC alone did not affect proliferation, but inhibited it when combined with induced cytosine deaminase.
• Inhibition was time-dependent, and cell growth resumed after 5-FC removal.
• The effect was replicated in an in vivo subconjunctival proliferation model with no corneal erosion.

Conclusions:

• Co-exposure of 5-FC and cytosine deaminase effectively inhibits fibroblast proliferation.
• This prodrug delivery system demonstrates potential for controlled 5-FU release post-filtering surgery.
• The findings support the development of this system for ophthalmic applications.