title: Sonoporation-enhanced chemotherapy significantly reduces primary tumour burden in an orthotopic pancreatic cancer xenograft.
abstract: OBJECTIVE
  Adenocarcinoma of the pancreas remains one of the most lethal human cancers. The high mortality rates associated with this form of cancer are subsequent to late-stage clinical presentation and diagnosis, when surgery is rarely possible and of modest chemotherapeutic impact. Survival rates following diagnosis with advanced pancreatic cancer are very low; typical mortality rates of 50% are expected within 3 months of diagnosis. However, adjuvant chemotherapy improves the prognosis of patients even after palliative surgery, and successful newer neoadjuvant chemotherapeutical modalities have recently been reported. For patients whose tumours appear unresectable, chemotherapy remains the only option. During the past two decades, the nucleoside analogue gemcitabine has become the first-line chemotherapy for pancreatic adenocarcinoma. In this study, we aim to increase the delivery of gemcitabine to pancreatic tumours by exploring the effect of sonoporation for localised drug delivery of gemcitabine in an orthotopic xenograft mouse model of pancreatic cancer.
  
  
  METHODS
  An orthotopic xenograft mouse model of luciferase expressing MIA PaCa-2 cells was developed, exhibiting disease development similar to human pancreatic adenocarcinoma. Subsequently, two groups of mice were treated with gemcitabine alone and gemcitabine combined with sonoporation; saline-treated mice were used as a control group. A custom-made focused ultrasound transducer using clinically safe acoustic conditions in combination with SonoVue® ultrasound contrast agent was used to induce sonoporation in the localised region of the primary tumour only. Whole-body disease development was measured using bioluminescence imaging, and primary tumour development was measured using 3D ultrasound.
  
  
  RESULTS
  Following just two treatments combining sonoporation and gemcitabine, primary tumour volumes were significantly lower than control groups. Additional therapy dramatically inhibited primary tumour growth throughout the course of the disease, with median survival increases of up to 10% demonstrated in comparison to the control groups.
  
  
  CONCLUSIONS
  Combined sonoporation and gemcitabine therapy significantly impedes primary tumour development in an orthotopic xenograft model of human pancreatic cancer, suggesting additional clinical benefits for patients treated with gemcitabine in combination with sonoporation.
authors.affiliation: National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Jonas Liesvei 65, 5021, Bergen, Norway.
authors.forename: Spiros
authors.initials: S
authors.lastname: Kotopoulis
authors.forename: Anthony
authors.initials: A
authors.lastname: Delalande
authors.forename: Mihaela
authors.initials: M
authors.lastname: Popa
authors.forename: Veronika
authors.initials: V
authors.lastname: Mamaeva
authors.forename: Georg
authors.initials: G
authors.lastname: Dimcevski
authors.forename: Odd Helge
authors.initials: OH
authors.lastname: Gilja
authors.forename: Michiel
authors.initials: M
authors.lastname: Postema
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D045423:Microbubbles; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D015203:Reproducibility of Results; D013010:Sonication / Q000379:methods*; D016019:Survival Analysis; D014159:Transducers; D047368:Tumor Burden / Q000187:drug effects; D014465:Ultrasonics / Q000295:instrumentation; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D000093542:Gemcitabine