title: Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model.
abstract: BACKGROUND
  Combining anti-angiogenesis agents with cytotoxic agents for the treatment of malignant gliomas may affect the cytotoxic drug distribution by normalizing the blood-brain barrier (BBB). This study examines the intratumoral concentration of temozolomide (TMZ) in the presence and absence of the pan-VEGF receptor tyrosine kinase inhibitor, cediranib.
  
  
  METHODS
  Seven nude rats bearing U87 intracerebral gliomas had a microdialysis probe centered within the tumor. Ten-days after tumor implantation, TMZ (50 mg/kg) was given orally. The extracellular fluid (ECF) concentrations of TMZ within the tumor were assessed via microdialysis for 6 h following TMZ administration. Cediranib (6 mg/kg) was then given orally, and 12 h later, TMZ was re-administered with subsequent microdialysis collection. A subset of animals also underwent functional MRI to assess angiogenesis in vivo at post-inoculation days 12 and 21, before and after the cediranib treatment.
  
  
  RESULTS
  After dosing of oral TMZ only, ECF-TMZ mean-C(max) and area under the concentration curve(AUC(0-∞)) within the tumor were 0.59 μg/mL and 1.82 μg h/mL, respectively. Post-cediranib, ECF-TMZ mean-C(max) and AUC(0-∞) were 0.83 μg/mL and 3.72 ± 0.61 μg h/mL within the tumor, respectively. This represented a 1.4-fold (p = 0.3) and 2.0-fold (p = 0.06) increase in the ECF-TMZ C(max) and AUC(0-∞), respectively, after cediranib administration. In vivo MRI measurements of the various vascular parameters were consistent with a BBB "normalization" profile following cediranib treatment.
  
  
  CONCLUSIONS
  In the U87 intracerebral glioma model, within the first day of administration of cediranib, the intratumoral concentrations of TMZ in tumor ECF were slightly, but not statistically significantly, increased when compared to the treatment of TMZ alone with radiographic evidence of a normalized BBB.
authors: Department of Neurosurgery, Johns Hopkins University School of Medicine Baltimore, Baltimore, MD 21231, USA.
authors: Rachel
authors: R
authors: Grossman
authors: Betty
authors: B
authors: Tyler
authors: Michelle A
authors: MA
authors: Rudek
authors: Eugene
authors: E
authors: Kim
authors: Patti
authors: P
authors: Zadnik
authors: Ursalan
authors: U
authors: Khan
authors: Jaishri O
authors: JO
authors: Blakeley
authors: Arvind P
authors: AP
authors: Pathak
authors: Henry
authors: H
authors: Brem
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002551:Cerebral Ventricle Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D002552:Cerebral Ventricles / Q000187:drug effects / Q000378:metabolism; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D004357:Drug Synergism; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D017551:Microdialysis; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D011923:Rats, Nude; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; D000077204:Temozolomide; C500926:cediranib; D007211:Indoles
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