Journal
EUROPEAN JOURNAL OF CANCER
Volume 45, Issue 1, Pages 164-173Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2008.10.008
Keywords
Anticancer activity; Antitumour; Cancer; Fluorouracil; Human diseases; Mice; Mucin; Mucus overproduction; Pancreatic cancer; Therapeutic mechanism
Categories
Funding
- Provost Research Scholarship
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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. (c) 2008 Elsevier Ltd. All rights reserved.
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