title: Phosphodiesterase type 5 inhibitors increase Herceptin transport and treatment efficacy in mouse metastatic brain tumor models.
abstract: BACKGROUND
  Chemotherapeutic drugs and newly developed therapeutic monoclonal antibodies are adequately delivered to most solid and systemic tumors. However, drug delivery into primary brain tumors and metastases is impeded by the blood-brain tumor barrier (BTB), significantly limiting drug use in brain cancer treatment.
  
  
  RESULTS
  We examined the effect of phosphodiesterase 5 (PDE5) inhibitors in nude mice on drug delivery to intracranially implanted human lung and breast tumors as the most common primary tumors forming brain metastases, and studied underlying mechanisms of drug transport. In vitro assays demonstrated that PDE5 inhibitors enhanced the uptake of [(14)C]dextran and trastuzumab (Herceptin, a humanized monoclonal antibody against HER2/neu) by cultured mouse brain endothelial cells (MBEC). The mechanism of drug delivery was examined using inhibitors for caveolae-mediated endocytosis, macropinocytosis and coated pit/clathrin endocytosis. Inhibitor analysis strongly implicated caveolae and macropinocytosis endocytic pathways involvement in the PDE5 inhibitor-enhanced Herceptin uptake by MBEC. Oral administration of PDE5 inhibitor, vardenafil, to mice with HER2-positive intracranial lung tumors led to an increased tumor permeability to high molecular weight [(14)C]dextran (2.6-fold increase) and to Herceptin (2-fold increase). Survival time of intracranial lung cancer-bearing mice treated with Herceptin in combination with vardenafil was significantly increased as compared to the untreated, vardenafil- or Herceptin-treated mice (p<0.01). Log-rank survival analysis of mice bearing HER2-positive intracranial breast tumor also showed a significant survival increase (p<0.02) in the group treated with Herceptin plus vardenafil as compared to other groups. However, vardenafil did not exert any beneficial effect on survival of mice bearing intracranial breast tumor with low HER2 expression and co-treated with Herceptin (p>0.05).
  
  
  CONCLUSIONS
  These findings suggest that PDE5 inhibitors may effectively modulate BTB permeability, and enhance delivery and therapeutic efficacy of monoclonal antibodies in hard-to-treat brain metastases from different primary tumors that had metastasized to the brain.
authors.affiliation: Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Jinwei
authors.initials: J
authors.lastname: Hu
authors.forename: Julia Y
authors.initials: JY
authors.lastname: Ljubimova
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Bindu
authors.initials: B
authors.lastname: Konda
authors.forename: Rameshwar
authors.initials: R
authors.lastname: Patil
authors.forename: Hui
authors.initials: H
authors.lastname: Ding
authors.forename: Andres
authors.initials: A
authors.lastname: Espinoza
authors.forename: Kolja A
authors.initials: KA
authors.lastname: Wawrowsky
authors.forename: Chirag
authors.initials: C
authors.lastname: Patil
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Ljubimov
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001943:Breast Neoplasms; D004705:Endocytosis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008175:Lung Neoplasms; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use; D000068878:Trastuzumab; D016896:Treatment Outcome; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use; D000069058:Vardenafil Dihydrochloride
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D000068878:Trastuzumab