title: Hypoxia-inducible factor-1α expression and gemcitabine chemotherapy             for pancreatic cancer.
abstract: The normal pancreas has an abundant blood flow, in contrast to pancreatic             cancer, which is a hypovascular tumor. During hypoxia under a hypovascular environment,             the transcription factor hypoxia-inducible factor-1α (HIF-1α) is activated. High             HIF-1α expression reduces sensitivity to gemcitabine (GEM) which is used as a             treatment for pancreatic cancer. The objective of this study was to clarify HIF-1α             expression in pancreatic cancer and the association of its effects to GEM treatment.             We used the human pancreatic ductal carcinoma cell lines AsPC-1 and BxPC-3 to             evaluate cell proliferation, HIF-1α protein expression and sensitivity to GEM             in a hypoxic environment of 1% O2 in 48 pancreatic cancer patients who received             adjuvant GEM treatment after pancreatectomy. We divided the patients according             to HIF-1α expression and the presence of single nucleotide polymorphisms, and             we based our evaluation on the adverse events associated with GEM chemotherapy             and patient outcome. The hypoxic environment promoted cell proliferation, induced             HIF-1α expression and increased GEM resistance, especially in AsPC-1 cells, which             included a mutant homozygote for HIF-1α(C1772T). There were no significant differences             between the HIF-1α(-) and HIF-1α(+) groups in either adverse events or patient             outcomes. HIF-1α enhanced neo-microvascularity in a hypoxic environment and increased             drug resistance. The period until recurrence was shorter in the patients with             a strong HIF-1α expression, than that in those with a weak HIF-1α expression.
authors.affiliation: Department of Digestive Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. kasuya-k@jcom.home.ne.jp
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kasuya
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tsuchida
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nagakawa
authors.forename: Minako
authors.initials: M
authors.lastname: Suzuki
authors.forename: Yuta
authors.initials: Y
authors.lastname: Abe
authors.forename: Takao
authors.initials: T
authors.lastname: Itoi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Serizawa
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nagao
authors.forename: Motohide
authors.initials: M
authors.lastname: Shimazu
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Aoki
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D003841:Deoxycytidine; D000093542:Gemcitabine