title: Inhibitory effects of castration in an orthotopic model of androgen-independent prostate cancer can be mimicked and enhanced by angiogenesis inhibition.
abstract: OBJECTIVE
  Today, the most important treatment of advanced prostate cancer is castration; unfortunately, however, the long-term effect of this therapy is insufficient. Recent studies suggest that castration-induced prostate involution could be caused by primary effects in the prostate vasculature; therefore, we examined if antivascular treatments could mimic the effects of castration.
  
  
  METHODS
  Androgen-independent AT-1 prostate cancer cells were grown inside the ventral prostate in adult rats. Tumor-bearing animals were treated with an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor signaling, N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine (ZD6474, AstraZeneca, Södertälje, Sweden), and short-term effects (after 3 days) were compared with those induced by castration.
  
  
  RESULTS
  Castration caused decreased vascular density in the normal tissue surrounding the tumor and consequently increased tumor hypoxia and apoptosis, and moderately decreased tumor growth. ZD6474 treatment resulted in decreased tumor vascular density accompanied by increased tumor hypoxia, apoptosis, and decreased tumor growth, suggesting that castration and antiangiogenic therapy work through similar mechanisms. Interestingly, castration or ZD6474 alone worked by reducing vascular density in the surrounding normal tissue and ZD6474 also in the tumor. Combined treatment with castration + ZD6474 was more effective than castration and ZD6474 alone in inducing tumor hypoxia, apoptosis, necrosis, and decreasing tumor vascular density.
  
  
  CONCLUSIONS
  These findings show that a drug that targets the vasculature in the tumor and in the surrounding ventral prostate lobe could mimic and even enhance the effects of castration. Our present findings thus suggest that castration + ZD6474 could be a particularly effective way to treat prostate tumors.
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Hammarsten
authors.forename: Sofia
authors.initials: S
authors.lastname: Halin
authors.forename: Pernilla
authors.initials: P
authors.lastname: Wikstöm
authors.forename: Roger
authors.initials: R
authors.lastname: Henriksson
authors.forename: Stina Häggström
authors.initials: SH
authors.lastname: Rudolfsson
authors.forename: Anders
authors.initials: A
authors.lastname: Bergh
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D002369:Castration / Q000379:methods; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D008297:Male; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D020533:Angiogenesis Inhibitors; D010880:Piperidines; D011799:Quinazolines; C452423:vandetanib