Safety and efficacy of convection-enhanced delivery of ACNU, a hydrophilic nitrosourea, in intracranial brain tumor models.

Abstract

Convection-enhanced delivery (CED) is a local infusion technique, which delivers chemotherapeutic agents directly to the central nervous system, circumventing the blood-brain barrier and reducing systemic side effects. CED distribution is significantly increased if the infusate is hydrophilic. This study evaluated the safety and efficacy of CED of nimustine hydrochloride: 3-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU), a hydrophilic nitrosourea, in rat 9 L: brain tumor models. The local neurotoxicity of ACNU delivered via CED was examined in normal rat brains, and the maximum tolerated dose (MTD) was estimated at 0.02 mg/rat. CED of ACNU at the MTD produced significantly longer survival time than systemic administration (P < 0.05, log-rank test). Long-term survival (80 days) and eradication of the tumor occurred only in the CED-treated rats. The tissue concentration of ACNU was measured by high-performance liquid chromatography, which revealed that CED of ACNU at the dose of 100-fold less total drug than intravenous injection carried almost equivalent concentrations of ACNU into rat brain tissue. CED of hydrophilic ACNU is a promising strategy for treating brain tumors.

• Authors: Shin-ichiro Sugiyama, Yoji Yamashita, Toshio Kikuchi, Ryuta Saito, Toshihiro Kumabe, Teiji Tominaga
• Journal: Journal of neuro-oncology (J Neurooncol) Vol. 82 Issue 1 Pg. 41-7 (Mar 2007) ISSN: 0167-594X [Print] United States
• PMID: 17031554 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antineoplastic Agents
• Nimustine

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Brain (drug effects, metabolism)
• Brain Neoplasms (drug therapy, mortality)
• Cell Line, Tumor
• Chemotherapy, Cancer, Regional Perfusion (methods)
• Convection
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Delivery Systems (methods)
• Gliosarcoma (drug therapy, mortality)
• Humans
• Male
• Maximum Tolerated Dose
• Nimustine (administration & dosage, pharmacokinetics)
• Random Allocation
• Rats
• Rats, Inbred F344
• Rats, Sprague-Dawley
• Survival Analysis
• Tissue Distribution
• Treatment Outcome
• Xenograft Model Antitumor Assays