Pharmacologically increased tumor hypoxia can be measured by 18F-Fluoroazomycin arabinoside positron emission tomography and enhances tumor response to hypoxic cytotoxin PR-104.
OBJECTIVE
Solid tumors contain microenvironmental regions of hypoxia that present a barrier to traditional radiotherapy and chemotherapy, and this work describes a novel approach to circumvent hypoxia. We propose to overcome hypoxia by augmenting the effectiveness of drugs that are designed to specifically kill hypoxic tumor cells.


METHODS
We have constructed RKO colorectal tumor cells that express a small RNA hairpin that specifically knocks down the hypoxia-inducible factor 1a (HIF1a) transcription factor. We have used these cells in vitro to determine the effect of HIF1 on cellular sensitivity to the hypoxic cytotoxin PR-104, and its role in cellular oxygen consumption in response to the pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA). We have further used these cells in vivo in xenografted tumors to determine the role of HIF1 in regulating tumor hypoxia in response to DCA using (18)F-fluoroazomycin arabinoside positron emission tomography, and its role in regulating tumor sensitivity to the combination of DCA and PR-104.


RESULTS
HIF1 does not affect cellular sensitivity to PR-104 in vitro. DCA transiently increases cellular oxygen consumption in vitro and increases the extent of tumor hypoxia in vivo as measured with (18)F-fluoroazomycin arabinoside positron emission tomography. Furthermore, we show that DCA-dependent alterations in hypoxia increase the antitumor activity of the next-generation hypoxic cytotoxin PR-104.


CONCLUSIONS
DCA interferes with the HIF-dependent "adaptive response," which limits mitochondrial oxygen consumption. This approach transiently increases tumor hypoxia and represents an important method to improve antitumor efficacy of hypoxia-targeted agents, without increasing toxicity to oxygenated normal tissue.
Cairns
Rob A
RA
Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.
Bennewith
Kevin L
KL
Graves
Edward E
EE
Giaccia
Amato J
AJ
Chang
Daniel T
DT
Denko
Nicholas C
NC
D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D009593:Nitroimidazoles / Q000494:pharmacology*; D010101:Oxygen Consumption; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000494:pharmacology
D005462:Fluorine Radioisotopes; D009588:Nitrogen Mustard Compounds; D009593:Nitroimidazoles; C522381:PR-104; D019275:Radiopharmaceuticals; C498052:fluoroazomycin arabinoside