@article {Kizaka-Kondoh3433, author = {Kizaka-Kondoh, Shinae and Itasaka, Satoshi and Zeng, Lihua and Tanaka, Shotaro and Zhao, Tao and Takahashi, Yumi and Shibuya, Keiko and Hirota, Kiichi and Semenza, Gregg L. and Hiraoka, Masahiro}, title = {Selective Killing of Hypoxia-Inducible Factor-1{\textendash}Active Cells Improves Survival in a Mouse Model of Invasive and Metastatic Pancreatic Cancer}, volume = {15}, number = {10}, pages = {3433--3441}, year = {2009}, doi = {10.1158/1078-0432.CCR-08-2267}, publisher = {American Association for Cancer Research}, abstract = {Purpose: Pancreatic cancer is characterized by intratumoral hypoxia, early and aggressive local invasion, and metastatic potential. Hypoxia-inducible factor-1 (HIF-1) is the major transcriptional activator of hypoxia-responsive genes and intratumoral hypoxia is associated with increased risk of metastasis. However, the behavior of the cells having HIF-1 activity during the malignant progression in pancreatic cancer has not been tested. Experimental Design: We orthotopically transplanted pancreatic cancer cells stably transfected with a HIF-1{\textendash}dependent luciferase reporter gene and monitored HIF-1 activity in vivo in control and POP33-treated mice. POP33 is a novel prodrug, which has potential to increase caspase-3 activity and induce apoptosis in HIF-1{\textendash}active/hypoxic cells. Results:In vivo optical imaging showed that HIF-1 activity proceeded along with local invasion, the peritoneal dissemination, and the liver metastasis. HIF-1{\textendash}active hypoxic cells were selectively eradicated by POP33. Moreover, selective killing of HIF-1{\textendash}active hypoxic cells significantly suppressed malignant progression, resulting in a significant improvement in survival rate. Conclusions: These results show that HIF-1{\textendash}active cells constitute a large proportion of invading and metastatic cells and suggest that eradication of these cells may improve the outcome in advanced pancreatic cancer, a condition for which no effective therapy currently exists.}, issn = {1078-0432}, URL = {https://clincancerres.aacrjournals.org/content/15/10/3433}, eprint = {https://clincancerres.aacrjournals.org/content/15/10/3433.full.pdf}, journal = {Clinical Cancer Research} }