title: Radiosensitization of non-small-cell lung cancer cells and xenografts by the interactive effects of pemetrexed and methoxyamine.
abstract: The anti-folate pemetrexed is a radiosensitizer. In pre-clinical models, pemetrexed is more effective along with the base-excision-repair inhibitor methoxyamine. We tested whether methoxyamine enhances pemetrexed-mediated radiosensitization of lung adenocarcinoma cells and xenografts.
  
  
  
  A549 and H1299 cells were evaluated for cell cycle distribution by flow cytometry, radiosensitization by clonogenic assay, and DNA repair by neutral comet assay and repair protein activation. H460 cells were included in some studies. Xenografts in nude mice received drug(s) and/or radiation, and tumor growth was monitored by caliper and in vivo toxicity by animal weight.
  
  
  
  Exposure to pemetrexed/methoxyamine for 24 (H1299, H460) or 48 (A549)hours before irradiation resulted in accumulation of cells near the radiosensitive G1/S border; dose-enhancement factors of 1.62±0.19, 1.97±0.25, and 1.67±0.30, respectively; reduction of mean inactivation dose by 32%, 30%, and 46%, respectively; and significant reductions of SF2 and SF4 (p<0.05). Radiosensitization was associated with rapid DNA double-strand-break rejoining and increased levels of DNA-PKcs. Both tumor-growth rate and tumor-growth delay were significantly improved by adding methoxyamine to pemetrexed pre-irradiation (p<0.0001); no mice lost weight during treatment.
  
  
  
  Addition of methoxyamine to pemetrexed and fractionated radiotherapy may improve outcome for patients with locally advanced non-squamous non-small-cell lung cancer.
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA; Case Comprehensive Cancer Center, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA. Electronic address: nlo@case.edu.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Oleinick
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA; Case Comprehensive Cancer Center, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA.
authors.forename: Tithi
authors.initials: T
authors.lastname: Biswas
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA; Department of Pharmacology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA.
authors.forename: Rutulkumar
authors.initials: R
authors.lastname: Patel
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA.
authors.forename: Mingfang
authors.initials: M
authors.lastname: Tao
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Patel
authors.affiliation: Department of Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA.
authors.forename: Lachelle
authors.initials: L
authors.lastname: Weeks
authors.affiliation: Department of Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA; Case Comprehensive Cancer Center, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA.
authors.forename: Neelesh
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Department of Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA; Case Comprehensive Cancer Center, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA.
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
authors.affiliation: Department of Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA; Case Comprehensive Cancer Center, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA.
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA; Case Comprehensive Cancer Center, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA.
authors.forename: Pingfu
authors.initials: P
authors.lastname: Fu
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA; Case Comprehensive Cancer Center, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA.
authors.forename: Junran
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA; Case Comprehensive Cancer Center, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Machtay
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D000077192:Adenocarcinoma of Lung; D000818:Animals; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D002453:Cell Cycle / Q000528:radiation effects; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D019583:Dose Fractionation, Radiation; D004357:Drug Synergism; D005260:Female; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000378:metabolism; D000068437:Pemetrexed / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D006898:Hydroxylamines; D009687:Nuclear Proteins; D011838:Radiation-Sensitizing Agents; D000068437:Pemetrexed; C005214:methoxyamine; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human
keywords: Methoxyamine; Non-small-cell lung cancer; Pemetrexed; Radiosensitization