title: Modulation of the tumor microvasculature by phosphoinositide-3 kinase inhibition increases doxorubicin delivery in vivo.
abstract: OBJECTIVE
  Because effective drug delivery is often limited by inadequate vasculature within the tumor, the ability to modulate the tumor microenvironment is one strategy that may achieve better drug distribution. We have previously shown that treatment of mice bearing tumors with phosphoinositide-3 kinase (PI3K) inhibitors alters vascular structure in a manner analogous to vascular normalization and results in increased perfusion of the tumor. On the basis of that result, we asked whether inhibition of PI3K would improve chemotherapy delivery.
  
  
  METHODS
  Mice with xenografts using the cell line SQ20B bearing a hypoxia marker or MMTV-neu transgenic mice with spontaneous breast tumors were treated with the class I PI3K inhibitor GDC-0941. The tumor vasculature was evaluated by Doppler ultrasound, and histology. The delivery of doxorubicin was assessed using whole animal fluorescence, distribution on histologic sections, high-performance liquid chromatography on tumor lysates, and tumor growth delay.
  
  
  RESULTS
  Treatment with GDC-0941 led to approximately three-fold increases in perfusion, substantially reduced hypoxia and vascular normalization by histology. Significantly increased amounts of doxorubicin were delivered to the tumors correlating with synergistic tumor growth delay. The GDC-0941 itself had no effect on tumor growth.
  
  
  CONCLUSIONS
  Inhibition of PI3K led to vascular normalization and improved delivery of a chemotherapeutic agent. This study highlights the importance of the microvascular effects of some novel oncogenic signaling inhibitors and the need to take those changes into account in the design of clinical trials many of which use combinations of chemotherapeutic agents.
authors: Gray Institute for Radiation Oncology and Biology, Oxford University, Oxford, United Kingdom.
authors: Naseer
authors: N
authors: Qayum
authors: Jaehong
authors: J
authors: Im
authors: Michael R
authors: MR
authors: Stratford
authors: Eric J
authors: EJ
authors: Bernhard
authors: W Gillies
authors: WG
authors: McKenna
authors: Ruth J
authors: RJ
authors: Muschel
mesh_terms: D000818:Animals; D004317:Doxorubicin / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy; D007124:Immunoenzyme Techniques; D007191:Indazoles / Q000494:pharmacology*; D015674:Mammary Neoplasms, Animal / Q000098:blood supply* / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D055806:Microvessels / Q000187:drug effects*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D004317:Doxorubicin; D007191:Indazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine