title: Combined Antitumor Therapy with Metronomic Topotecan and Hypoxia-Activated Prodrug, Evofosfamide, in Neuroblastoma and Rhabdomyosarcoma Preclinical Models.
abstract: Tumor cells residing in tumor hypoxic zones are a major cause of drug resistance and tumor relapse. In this study, we investigated the efficacy of evofosfamide, a hypoxia-activated prodrug, and its combination with topotecan in neuroblastoma and rhabdomyosarcoma preclinical models.
  
  
  
  Neuroblastoma and rhabdomyosarcoma cells were tested in vitro to assess the effect of evofosfamide on cell proliferation, both as a single agent and in combination with topotecan. In vivo antitumor activity was evaluated in different xenograft models. Animal survival was studied with the neuroblastoma metastatic tumor model.
  
  
  
  All tested cell lines showed response to evofosfamide under normoxic conditions, but when exposed to hypoxia overnight, a 2- to 65-fold decrease of IC50 was observed. Adding topotecan to the evofosfamide treatment significantly increased cytotoxicity in vitro In neuroblastoma xenograft models, single-agent evofosfamide treatment delayed tumor growth. Complete tumor regression was observed in the combined topotecan/evofosfamide treatment group after 2-week treatment. Combined treatment also improved survival in a neuroblastoma metastatic model, compared to single-agent treatments. In rhabdomyosarcoma xenograft models, combined treatment was more effective than single agents. We also showed that evofosfamide mostly targeted tumor cells within hypoxic regions while topotecan was more effective to tumor cells in normoxic regions. Combined treatment induced tumor cell apoptosis in both normoxic and hypoxic regions.
  
  
  
  Evofosfamide shows antitumor effects in neuroblastoma and rhabdomyosarcoma xenografts. Compared with single-agent, evofosfamide/topotecan, combined therapy improves tumor response, delays tumor relapse, and enhances animal survival in preclinical tumor models. Clin Cancer Res; 22(11); 2697-708. ©2015 AACR.
authors.affiliation: New Agent and Innovative Therapy Program, The Hospital for Sick Children, Toronto, Ontario, Canada. Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Libo
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Paula
authors.initials: P
authors.lastname: Marrano
authors.affiliation: New Agent and Innovative Therapy Program, The Hospital for Sick Children, Toronto, Ontario, Canada. Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Bing
authors.initials: B
authors.lastname: Wu
authors.affiliation: New Agent and Innovative Therapy Program, The Hospital for Sick Children, Toronto, Ontario, Canada. Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Sushil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Thorner
authors.affiliation: New Agent and Innovative Therapy Program, The Hospital for Sick Children, Toronto, Ontario, Canada. Division of Hematology and Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada. Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada. sylvain.baruchel@sickkids.ca.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Baruchel
mesh_terms: D065767:Activation, Metabolic; D059250:Administration, Metronomic; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D020128:Inhibitory Concentration 50; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009447:Neuroblastoma / Q000188:drug therapy*; D009593:Nitroimidazoles / Q000008:administration & dosage; D010752:Phosphoramide Mustards / Q000008:administration & dosage; D011355:Prodrugs / Q000008:administration & dosage; D012208:Rhabdomyosarcoma / Q000188:drug therapy*; D019772:Topotecan / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; D011355:Prodrugs; C552526:TH 302; D019772:Topotecan