title: Molecular mechanism of local drug delivery with Paclitaxel-eluting membranes in biliary and pancreatic cancer: new application for an old drug.
abstract: Implantation of self-expanding metal stents (SEMS) is palliation for patients suffering from inoperable malignant obstructions associated with biliary and pancreatic cancers. Chemotherapeutic agent-eluting stents have been developed because SEMS are susceptible to occlusion by tumor in-growth. We reported recently that paclitaxel-eluting SEMS provide enhanced local drug delivery in an animal model. However, little is known about the molecular mechanisms by which paclitaxel-eluting stents attenuate tumor growth. We investigated the signal transduction pathways underlying the antiproliferative effects of a paclitaxel-eluting membrane (PEM) implanted in pancreatic/cholangiocarcinoma tumor bearing nude mice. Molecular and cellular alterations were analyzed in the PEM-implanted pancreatic/cholangiocarcinoma xenograft tumors by Western blot, immunoprecipitation, and immunofluorescence. The quantities of paclitaxel released into the tumor and plasma were determined by liquid chromatography-tandem mass spectroscopy. Paclitaxel from the PEM and its diffusion into the tumor inhibited angiogenesis, which involved suppression of mammalian target of rapamycin (mTOR) through regulation of hypoxia inducible factor (HIF-1) and increased apoptosis. Moreover, implantation of the PEM inhibited tumor-stromal interaction-related expression of proteins such as CD44, SPARC, matrix metalloproteinase-2, and vimentin. Local delivery of paclitaxel from a PEM inhibited growth of pancreatic/cholangiocarcinoma tumors in nude mice by suppressing angiogenesis via the mTOR and inducing apoptosis signal pathway.
authors.affiliation: Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 712 Eonjuro, Gangnam-gu, Seoul 135-720, Republic of Korea.
authors.forename: Sookhee
authors.initials: S
authors.lastname: Bang
authors.affiliation: Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sung Ill
authors.identifier: 0000-0003-4937-6167
authors.initials: SI
authors.lastname: Jang
authors.affiliation: Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 712 Eonjuro, Gangnam-gu, Seoul 135-720, Republic of Korea.
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 712 Eonjuro, Gangnam-gu, Seoul 135-720, Republic of Korea.
authors.forename: Yi-Yong
authors.initials: YY
authors.lastname: Baek
authors.affiliation: Department of Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongwon, Republic of Korea.
authors.forename: Jieun
authors.initials: J
authors.lastname: Yun
authors.affiliation: Department of Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongwon, Republic of Korea.
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: Department of Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongwon, Republic of Korea.
authors.forename: Chang Woo
authors.initials: CW
authors.lastname: Lee
authors.affiliation: Department of Research and Development, Taewoong Medical Co., Gimpo, Republic of Korea.
authors.forename: Eun Ae
authors.initials: EA
authors.lastname: Jo
authors.affiliation: Department of Biotechnology, The Catholic University, Bucheon, Republic of Korea.
authors.forename: Kun
authors.identifier: 0000-0002-9629-0289
authors.initials: K
authors.lastname: Na
authors.affiliation: Department of New Drug Development, School of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: Sugeun
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, School of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: Don Haeng
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 712 Eonjuro, Gangnam-gu, Seoul 135-720, Republic of Korea.
authors.forename: Dong Ki
authors.initials: DK
authors.lastname: Lee