title: Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer.
abstract: BACKGROUND
  Many prostate cancers demonstrate an increased expression of growth factor receptors such as vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) which have been correlated with increased resistance to radiotherapy and poor prognosis in other tumors. Therefore, response to radiation could potentially be improved by using inhibitors of these abnormally activated pathways. We have investigated the radiosensitizing effects of sunitinib, a potent, multi-tyrosine kinase inhibitor of the VEGFR and PDGFR receptors, on human prostate cancer cells.
  
  
  METHODS
  The radiosensitizing effects of sunitinib were assessed on human prostate cancer cell lines DU145, PC3 and LNCaP by clonogenic assay. Sunitinib's ability to inhibit the activities of its key targets was determined by immunoblot analysis. The radiosensitizing effects of sunitinib in vivo were tested on human tumor xenografts growing in nude mice where response was assessed by tumor growth delay.
  
  
  RESULTS
  Clonogenic survival curve assays for both DU145 and PC3 cells showed that the surviving fraction at 2 Gy was reduced from 0.70 and 0.52 in controls to 0.44 and 0.38, respectively, by a 24 hr pretreatment with 100 nM sunitinib. LNCaP cells were not radiosensitized by sunitinib. Dose dependent decreases in VEGFR and PDGFR activation were also observed following sunitinib in both DU145 and PC3 cells. We assessed the ability of sunitinib to radiosensitize PC3 xenograft tumors growing in the hind limb of nude mice. Sunitinib given concurrently with radiation did not prolong tumor growth delay. However, when animals were treated with sunitinib commencing the day after fractionated radiation was complete, tumor growth delay was enhanced compared to radiation alone.
  
  
  CONCLUSIONS
  We conclude, based on the in vivo results, that sunitinib and radiation do not interact directly to radiosensitize the PC3 tumor cells in vivo as they did in vitro. The fact that tumor growth delay was enhanced when sunitinib was given after radiotherapy was completed suggests that sunitinib may be acting on the irradiated tumor stroma and suppressing its ability to sustain regrowth of the irradiated tumor. Based on these preclinical findings, we suggest that the combination of sunitinib and radiation for the treatment of prostate cancer deserves further development.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas M, D, Anderson Cancer Center, Houston, TX, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Brooks
authors.forename: Tommy
authors.initials: T
authors.lastname: Sheu
authors.forename: Kathleen
authors.initials: K
authors.lastname: Bridges
authors.forename: Kathy
authors.initials: K
authors.lastname: Mason
authors.forename: Deborah
authors.initials: D
authors.lastname: Kuban
authors.forename: Paul
authors.initials: P
authors.lastname: Mathew
authors.forename: Raymond
authors.initials: R
authors.lastname: Meyn
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077210:Sunitinib; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011838:Radiation-Sensitizing Agents; C497970:FLT3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2; D051941:fms-Like Tyrosine Kinase 3; D000077210:Sunitinib