Evaluation of mucin glycosylation as a barrier to drug uptake: a quantitative approach.

• Online Access: http://hdl.handle.net/2047/d20000236

Mucins are heavily glycosylated glycoproteins that form a thick layer (glycocalyx) through which all molecules must diffuse to gain access to intracellular targets. They are overexpressed in cancerous conditions and have been implicated in invasion and metastasis of variety of tumors. Over 85% of human cancers are solid tumors in which the effectiveness of cancer therapy depends on adequate delivery of the therapeutic agent to tumor cells. Inadequate delivery would result in residual tumor cells, which in turn could lead to the re growth of tumors and the development of resistant cells. It has recently been shown that pre-exposing human pancreatic cancer cells to glycosylation inhibitors significantly enhances the cytotoxic effects of 5-FU against those cells. Further investigation of this observation led to the conclusion that O-glycosyaltion inhibition of mucin is responsible for the enhanced cytotoxic effects of 5-FU. In this study we explore the role N-glycosylation of mucin (second predominant glycosylation after type O), alone and in combination with O-glycosylation, in the cytotoxic effects of 5-FU in vitro. The study also aims to correlate the effects of inhibiting mucin glycosylation with the intracellular concentration of the cytotoxic prodrug 5-FU and its most active metabolites.