Mucin Protects Pancreatic Tumors from Anticancer Drugs

By thinning out the mucin layer that coats pancreatic tumor cells, cancer researchers have dramatically increased the effectiveness of the chemotherapeutic agent 5-fluorouracil (5-FU).

As current treatments for pancreatic cancer fail to adequately manage the disease, more effective treatment approaches are urgently being sought. Previous studies have suggested that mucin O-glycosylation limits the cytotoxic effect of 5-FU against the growth of human pancreatic cancer cells in vitro. In the current study, investigators at Northeastern University (Boston, MA, USA) extended their in vitro research on pancreatic cancer by using a mouse model to specifically address the question of whether the mucin layer diminishes the effect of anticancer therapy.

To examine the relationship between the mucin layer and 5-FU the investigators inhibited mucin O-glycosylation with intratumoral (IT) injections of benzyl-alpha-GalNAc (N-acetyl-galactose). The mice were then treated with different concentrations of 5-FU.

Results published in the January 2009 issue of the European Journal of Cancer (EJC) revealed that antitumor effects of 5-FU (given systemically) against pancreatic tumors improved significantly following IT injections of benzyl-alpha-GalNAc. Histochemical staining of tumor sections revealed a reduced number of neoplastic cells in tumors exposed to benzyl-alpha-GalNAc prior to 5-FU treatment compared to 5-FU alone. Furthermore, intracellular uptake of 5-FU by pancreatic cancer cells was significantly greater following injections of benzyl-alpha-GalNAc. In contrast, no such effect was observed with cells taken from human glioblastoma tumors, which do not produce mucin.

"We are beating down the barrier that stands in the way of effective cancer treatment," said senior author Dr. Robert B. Campbell, assistant professor of pharmaceutical sciences at Northeastern University. "Our goal is to help improve the efficacy of drugs and limit the amount of these toxic drugs needed for treatment. Improving efficacy of chemotherapeutic drugs plus reducing toxicity in pancreatic cancer patients by limiting the amount of drugs needed to get the same results are hugely important steps toward effective treatment of pancreatic cancer. These findings also have the potential to improve the effectiveness of other conventional chemotherapeutic drugs."

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