title: 18F-EF5 PET imaging as an early response biomarker for the hypoxia-activated prodrug SN30000 combined with radiation treatment in a non-small cell lung cancer xenograft model.
abstract: Hypoxia is a significant therapeutic problem for solid tumors because hypoxic cells are treatment-resistant and more aggressive. Hypoxia-activated prodrugs such as SN30000 use a mechanism of activation in hypoxic cells similar to that of 2-nitroimidazole hypoxia PET tracers. Therefore, we have evaluated the usefulness of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-(18)F-pentafluoropropyl)-acetamide ((18)F-EF5) PET to monitor and predict tumor response to SN30000 plus radiation treatment (RT).
  
  
  METHODS
  Human non-small cell lung cancer xenografts (H460) in athymic rats were imaged with (18)F-EF5 PET before and after treatment with SN30000 (90 mg/kg), with or without 15-Gy RT. The feasibility of imaging early changes in hypoxia in response to SN30000 was examined 24 h after treatment, followed by ex vivo γ-counting and immunohistochemical examination to study drug-induced apoptosis. Subsequently, the therapeutic effects of SN30000 with or without RT were evaluated in tumor growth delay studies and compared with early treatment-induced changes observed by (18)F-EF5 PET. Changes in tumor hemoglobin oxygen saturation as a function of time after treatment measured by optical spectroscopy were compared with PET data.
  
  
  RESULTS
  The uptake of (18)F-EF5 was significantly lower in SN30000-treated tumors than in saline controls 24 h after treatment (mean standardized uptake value, 0.44 ± 0.08 vs. 0.56 ± 0.08 for control group; P < 0.05). Apoptosis was significantly higher in SN30000-treated tumors than in controls. Early treatment-induced changes in (18)F-EF5 uptake were indicative of tumor response in growth delay studies at the group level. SN30000 plus RT significantly decreased (18)F-EF5 uptake relative to baseline and resulted in complete tumor remission in 5 of 7 animals. SN30000 alone decreased (18)F-EF5 uptake, generally in tumors with high initial standardized uptake values, and showed a minor tumor growth delay effect. The changes induced by SN30000 with or without RT in (18)F-EF5 uptake correlated with baseline hypoxia levels. RT caused significant increases in tumor oxygen concentration and hemoglobin oxygen saturation.
  
  
  CONCLUSIONS
  A hypoxia PET imaging agent can measure changes in tumor hypoxic fraction in response to SN30000. These results suggest the utility of (18)F-EF5 PET for monitoring early response to tumor treatment with SN30000 plus RT in the clinical development of this novel hypoxia-activated prodrug.
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA. satish.chitneni@duke.edu
authors.forename: Satish K
authors.initials: SK
authors.lastname: Chitneni
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Bida
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Palmer
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hay
authors.forename: Thorsten
authors.initials: T
authors.lastname: Melcher
authors.forename: William R
authors.initials: WR
authors.lastname: Wilson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic; D003497:Cyclic N-Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D017341:Etanidazole / Q000031:analogs & derivatives*; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D049268:Positron-Emission Tomography; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D016896:Treatment Outcome; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use*; D005466:Fluorocarbons
chemical_list: D003497:Cyclic N-Oxides; D017341:Etanidazole; D005462:Fluorine Radioisotopes; D006845:Hydrocarbons, Fluorinated; D011355:Prodrugs; D014227:Triazines; C570601:CEN-209; C096011:2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide; D005466:Fluorocarbons
keywords: 18F-EF5; PET; SN30000; hypoxia; prodrug; response