title: Tumor-specific targeting of pancreatic cancer with Shiga toxin B-subunit.
abstract: Pancreatic carcinoma is one of the most aggressive tumor entities, and standard chemotherapy provides only modest benefit. Therefore, specific targeting of pancreatic cancer for early diagnosis and therapeutic intervention is of great interest. We have previously shown that the cellular receptor for Shiga toxin B (STxB), the glycosphingolipid globotriaosylceramide (Gb(3) or CD77) is strongly increased in colorectal adenocarcinoma and their metastases. Here, we report an upregulation of Gb(3) in pancreatic adenocarcinoma (21 of 27 cases) as compared with matched normal tissue (n = 27). The mean expression was highly significantly increased from 30 ± 16 ng Gb(3)/mg tissue in normal pancreas to 61 ± 41 ng Gb(3)/mg tissue (mean ± SD, P = 0.0006), as evidenced by thin layer chromatography. Upregulation of Gb(3) levels did not depend on tumor stage or grading and showed no correlation with clinical outcome. Tumor cells and endothelial cells were identified as the source of increased Gb(3) expression by immunocytochemistry. Pancreatic cancer cell lines showed rapid intracellular uptake of STxB to the Golgi apparatus, following the retrograde pathway. The therapeutic application of STxB was tested by specific delivery of covalently coupled SN38, an active metabolite of the topoisomerase I inhibitor irinotecan. The cytotoxic effect of the STxB-SN38 compound in pancreatic cancer cell lines was increased more than 100-fold compared with irinotecan. Moreover, this effect was effectively blocked by competing incubation with nonlabeled STxB, showing the specificity of the targeting. Thus, STxB constitutes a promising new tool for specific targeting of pancreatic cancer.
authors.affiliation: Department of Surgery, Klinikum Rechts der Isar, TU München, Ismaninger Str. 22, 81675 Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Maak
authors.forename: Ulrich
authors.initials: U
authors.lastname: Nitsche
authors.forename: Larissa
authors.initials: L
authors.lastname: Keller
authors.forename: Petra
authors.initials: P
authors.lastname: Wolf
authors.forename: Marianne
authors.initials: M
authors.lastname: Sarr
authors.forename: Marine
authors.initials: M
authors.lastname: Thiebaud
authors.forename: Robert
authors.initials: R
authors.lastname: Rosenberg
authors.forename: Rupert
authors.initials: R
authors.lastname: Langer
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.forename: Ludger
authors.initials: L
authors.lastname: Johannes
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Janssen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000096:biosynthesis* / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D022603:Shiga Toxins / Q000493:pharmacokinetics / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; C472766:Gb3 antigen; D022603:Shiga Toxins; D059004:Topoisomerase I Inhibitors; C077239:stxB toxin; D000077146:Irinotecan; D002166:Camptothecin