title: Concentration rather than dose defines the local brain toxicity of agents that are effectively distributed by convection-enhanced delivery.
abstract: BACKGROUND
  Convection-enhanced delivery (CED) has been developed as a potentially effective drug-delivery strategy into the central nervous system. In contrast to systemic intravenous administration, local delivery achieves high concentration and prolonged retention in the local tissue, with increased chance of local toxicity, especially with toxic agents such as chemotherapeutic agents. Therefore, the factors that affect local toxicity should be extensively studied.
  
  
  METHODS
  With the assumption that concentration-oriented evaluation of toxicity is important for local CED, we evaluated the appearance of local toxicity among different agents after delivery with CED and studied if it is dose dependent or concentration dependent.
  
  
  RESULTS
  Local toxicity profile of chemotherapeutic agents delivered via CED indicates BCNU was dose-dependent, whereas that of ACNU was concentration-dependent. On the other hand, local toxicity for doxorubicin, which is not distributed effectively by CED, was dose-dependent. Local toxicity for PLD, which is extensively distributed by CED, was concentration-dependent.
  
  
  CONCLUSIONS
  Traditional evaluation of drug induced toxicity was dose-oriented. This is true for systemic intravascular delivery. However, with local CED, toxicity of several drugs exacerbated in concentration-dependent manner. From our study, local toxicity of drugs that are likely to distribute effectively tended to be concentration-dependent.
  
  
  CONCLUSIONS
  Concentration rather than dose may be more important for the toxicity of agents that are effectively distributed by CED. Concentration-oriented evaluation of toxicity is more important for CED.
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. Electronic address: ryuta@nsg.med.tohoku.ac.jp.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Saito
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Mano
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kanamori
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sonoda
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kumabe
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity*; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002330:Carmustine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D018481:Convection; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D004058:Diffusion; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity; D016503:Drug Delivery Systems / Q000379:methods*; D007150:Immunohistochemistry; D008297:Male; D015376:Nimustine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D011916:Rats, Inbred F344
chemical_list: D000970:Antineoplastic Agents; C506643:liposomal doxorubicin; D015376:Nimustine; D011092:Polyethylene Glycols; D004317:Doxorubicin; D002330:Carmustine
keywords: 4′,6-diamidino-2-phenylindole; ACNU; BBB; BCNU; Brain tumor; CED; Chemotherapy; Convection-enhanced delivery; DAPI; Drug delivery; NeuN; PBS; PEGylated liposomal doxorubicin; PLD; Toxicity; blood–brain barrier; carmustine; convection-enhanced delivery; neuronal nuclear antigen; nimustine hydrochloride; phosphate buffered saline