title: The differential effects of metronomic gemcitabine and antiangiogenic treatment in patient-derived xenografts of pancreatic cancer: treatment effects on metabolism, vascular function, cell proliferation, and tumor growth.
abstract: BACKGROUND
  Metronomic chemotherapy has shown promising activity against solid tumors and is believed to act in an antiangiogenic manner. The current study describes and quantifies the therapeutic efficacy, and mode of activity, of metronomic gemcitabine and a dedicated antiangiogenic agent (DC101) in patient-derived xenografts of pancreatic cancer.
  
  
  METHODS
  Two primary human pancreatic cancer xenograft lines were dosed metronomically with gemcitabine or DC101 weekly. Changes in tumor growth, vascular function, and metabolism over time were measured with magnetic resonance imaging, positron emission tomography, and immunofluorescence microscopy to determine the anti-tumor effects of the respective treatments.
  
  
  RESULTS
  Tumors treated with metronomic gemcitabine were 10-fold smaller than those in the control and DC101 groups. Metronomic gemcitabine, but not DC101, reduced the tumors' avidity for glucose, proliferation, and apoptosis. Metronomic gemcitabine-treated tumors had higher perfusion rates and uniformly distributed blood flow within the tumor, whereas perfusion rates in DC101-treated tumors were lower and confined to the periphery. DC101 treatment reduced the tumor's vascular density, but did not change their function. In contrast, metronomic gemcitabine increased vessel density, improved tumor perfusion transiently, and decreased hypoxia.
  
  
  CONCLUSIONS
  The aggregate data suggest that metronomic gemcitabine treatment affects both tumor vasculature and tumor cells continuously, and the overall effect is to significantly slow tumor growth. The observed increase in tumor perfusion induced by metronomic gemcitabine may be used as a therapeutic window for the administration of a second drug or radiation therapy. Non-invasive imaging could be used to detect early changes in tumor physiology before reductions in tumor volume were evident.
authors.affiliation: Department of Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. dyapp@bccrc.ca.|Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada. dyapp@bccrc.ca.
authors.forename: Donald T
authors.initials: DT
authors.lastname: Yapp
authors.affiliation: Department of Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: May Q
authors.initials: MQ
authors.lastname: Wong
authors.affiliation: Integrative Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Alastair H
authors.initials: AH
authors.lastname: Kyle
authors.affiliation: Department of Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Valdez
authors.affiliation: Magnetic Resonance Imaging Research Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jenny
authors.initials: J
authors.lastname: Tso
authors.affiliation: Magnetic Resonance Imaging Research Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Yung
authors.affiliation: Magnetic Resonance Imaging Research Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Piotr
authors.initials: P
authors.lastname: Kozlowski
authors.affiliation: Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Owen
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Andrzej K
authors.initials: AK
authors.lastname: Buczkowski
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Chung
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Scudamore
authors.affiliation: Integrative Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Minchinton
authors.affiliation: The Department of Radiation Oncology, Princess Margaret Cancer Centre, 5th Floor, 610 University Avenue, Toronto, ON, M5G 2M9, Canada. sylvia.ng@rmp.uhn.ca.
authors.forename: Sylvia S W
authors.initials: SS
authors.lastname: Ng
mesh_terms: D059250:Administration, Metronomic; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D016513:Mice, SCID; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010477:Perfusion; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; C511761:DC101 monoclonal antibody; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Anti-angiogenesis; Gemcitabine; MRI; Metronomic chemotherapy; PET-CT; Pancreatic cancer; Patient-derived xenografts; Tumor physiology