title: Mucin overexpression limits the effectiveness of 5-FU by reducing intracellular drug uptake and antineoplastic drug effects in pancreatic tumours.
abstract: Current treatments for pancreatic cancer have failed to effectively manage the disease, and hence, more effective treatment approaches are urgently needed. Studies suggest that mucin O-glycosylation limits the cytotoxic effect of fluorouracil (5-FU) against the growth of human pancreatic cancer cells in vitro. In the present study, we investigated the relationship between the levels of mucin O-glycosylation expressed in pancreatic tumours and the antitumour effect of 5-FU. The inhibition of O-glycosylation was achieved by intratumoural (IT) injections of benzyl-alpha-GalNAc. Immunohistochemical staining of human pancreatic tumours revealed relatively high (Capan-1) and moderate (HPAF-II) expression levels of MUC1 mucin compared to MUC1 negative control (U-87 MG human glioblastoma) tumours. The antitumour effects of 5-FU (given systemically) against Capan-1 tumours improved significantly following IT injections of benzyl-alpha-GalNAc. Histochemical staining of tumour sections revealed a reduced number of neoplastic cells in tumours exposed to benzyl-alpha-GalNAc prior to 5-FU treatment compared to 5-FU alone. Furthermore, intracellular uptake of 5-FU by Capan-1 cells was significantly greater following injections of benzyl-alpha-GalNAc; however, no such effect was observed with U-87 MG cells. Mucin overexpression reduces intracellular drug uptake, antineoplastic and antitumour drug effects, which may have important clinical implications in treatment.
authors.affiliation: Northeastern University, Bouvé College of Health Sciences, Department of Pharmaceutical Sciences, Boston, MA 02115, USA.
authors.forename: Ashish V
authors.initials: AV
authors.lastname: Kalra
authors.forename: Robert B
authors.initials: RB
authors.lastname: Campbell
mesh_terms: D000116:Acetylgalactosamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001593:Benzyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D005472:Fluorouracil / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006031:Glycosylation / Q000187:drug effects; D051379:Mice; D018396:Mucin-1 / Q000032:analysis / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism; D017211:Treatment Failure; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001593:Benzyl Compounds; D018396:Mucin-1; C080739:benzyl-alpha-N-acetylgalactosamine; D000116:Acetylgalactosamine; D005472:Fluorouracil