Hypoxia-inducible factor-1α expression and gemcitabine chemotherapy for pancreatic cancer.

Authors:
Kazuhiko Kasuya
Kazuhiko Kasuya
Tokyo Medical University
Japan
Akihiko Tsuchida
Akihiko Tsuchida
Tokyo Medical University
Japan
Yuichi Nagakawa
Yuichi Nagakawa
Tokyo Medical University
Minako Suzuki
Minako Suzuki
Graduate School of Life Dentistry at Niigata
Niigata | Japan
Yuta Abe
Yuta Abe
Tokyo Medical University
Japan
Takao Itoi
Takao Itoi
Tokyo Medical University
Shinjuku | Japan
Hiromi Serizawa
Hiromi Serizawa
Tokyo Medical University
Japan
Toshitaka Nagao
Toshitaka Nagao
Tokyo Medical University
Japan

Oncol Rep 2011 Dec 12;26(6):1399-406. Epub 2011 Sep 12.

Department of Digestive Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

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.
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December 2011
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