title: Preclinical evaluation of Laromustine for use in combination with radiation therapy in the treatment of solid tumors.
abstract: OBJECTIVE
  These studies explored questions related to the potential use of Laromustine in the treatment of solid tumors and in combination with radiotherapy.
  
  
  METHODS
  The studies used mouse EMT6 cells (both parental and transfected with genes for O(6)-alkylguanine-DNA transferase [AGT]), repair-deficient human Fanconi Anemia C and Chinese hamster VC8 (BRCA2(-/-)) cells and corresponding control cells, and EMT6 tumors in mice assayed using cell survival and tumor growth assays.
  
  
  RESULTS
  Hypoxia during Laromustine treatment did not protect EMT6 cells or human fibroblasts from this agent. Rapidly proliferating EMT6 cells were more sensitive than quiescent cultures. EMT6 cells expressing mouse or human AGT, which removes O(6)-alkyl groups from DNA guanine, thereby protecting against G-C crosslink formation, increased resistance to Laromustine. Crosslink-repair-deficient Fanconi Anemia C and VC8 cells were hypersensitive to Laromustine, confirming the importance of crosslinks as lethal lesions. In vitro, Laromustine and radiation produced additive toxicities to EMT6 cells. Studies using tumor cell survival and tumor growth assays showed effects of regimens combining Laromustine and radiation that were compatible with additive or subadditive interactions.
  
  
  CONCLUSIONS
  The effects of Laromustine on solid tumors and with radiation are complex and are influenced by microenvironmental and proliferative heterogeneity within these malignancies.
authors: Department of Therapeutic Radiology, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520-8040, USA. sara.rockwell@yale.edu
authors: Sara
authors: S
authors: Rockwell
authors: Yanfeng
authors: Y
authors: Liu
authors: Helen A
authors: HA
authors: Seow
authors: Kimiko
authors: K
authors: Ishiguro
authors: Raymond P
authors: RP
authors: Baumann
authors: Philip G
authors: PG
authors: Penketh
authors: Krishnamurthy
authors: K
authors: Shyam
authors: Oluwatoyin M
authors: OM
authors: Akintujoye
authors: Peter M
authors: PM
authors: Glazer
authors: Alan C
authors: AC
authors: Sartorelli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D006224:Cricetinae; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology* / Q000627:therapeutic use; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D059016:Tumor Microenvironment / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006834:Hydrazines; D013449:Sulfonamides; C483604:laromustine; D019853:O(6)-Methylguanine-DNA Methyltransferase