title: Vascular effects of plinabulin (NPI-2358) and the influence on tumour response when given alone or combined with radiation.
abstract: OBJECTIVE
  This study investigated the anti-tumour effects of the novel vascular disrupting agent plinabulin (NPI-2358) when given alone or combined with radiation.
  
  
  METHODS
  Foot implanted C3H mammary carcinomas or leg implanted KHT sarcomas were used, with plinabulin injected intraperitoneally. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measurements were made with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) on a 7-tesla magnet. Treatment response was assessed using regrowth delay (C3H tumours), clonogenic survival (KHT sarcomas) or histological estimates of necrosis for both models.
  
  
  RESULTS
  Plinabulin (7.5 mg/kg) significantly reduced the initial area under curve (IAUC) and the transfer constant (K(trans)) within 1 hour after injection, reaching a nadir at 3 h, but returning to normal within 24 h. A dose-dependent decrease in IAUC and K(trans), was seen at 3 h. No significant anti-tumour effects were observed in the C3H tumours until doses of 12.5 mg/kg were achieved, but started at 1.5 mg/kg in the KHT sarcoma. Irradiating tumours 1 h after injecting plinabulin enhanced response in both models.
  
  
  CONCLUSIONS
  Plinabulin induced a time- and dose-dependent decrease in tumour perfusion. The KHT sarcoma was more sensitive than the C3H tumour to the anti-tumour effects of plinabulin, while radiation response was enhanced in both models.
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital-NBG, Aarhus, Denmark.
authors.forename: Lotte B
authors.initials: LB
authors.lastname: Bertelsen
authors.forename: Yuan Yuan
authors.initials: YY
authors.lastname: Shen
authors.forename: Thomas
authors.initials: T
authors.lastname: Nielsen
authors.forename: Hans
authors.initials: H
authors.lastname: Stødkilde-Jørgensen
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Lloyd
authors.forename: Dietmar W
authors.initials: DW
authors.lastname: Siemann
authors.forename: Michael R
authors.initials: MR
authors.lastname: Horsman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D059248:Chemoradiotherapy; D054659:Diketopiperazines; D004305:Dose-Response Relationship, Drug; D005260:Female; D007093:Imidazoles / Q000627:therapeutic use*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D008809:Mice, Inbred C3H; D010879:Piperazines / Q000627:therapeutic use*; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy
chemical_list: D000970:Antineoplastic Agents; D054659:Diketopiperazines; D007093:Imidazoles; C514351:NPI 2358; D010879:Piperazines