TY - JOUR
T1 - Safety and efficacy of convection-enhanced delivery of ACNU, a hydrophilic nitrosourea, in intracranial brain tumor models
AU - Sugiyama, Shin Ichiro
AU - Yamashita, Yoji
AU - Kikuchi, Toshio
AU - Saito, Ryuta
AU - Kumabe, Toshihiro
AU - Tominaga, Teiji
PY - 2007/3
Y1 - 2007/3
N2 - 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.
AB - 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.
KW - Brain tumor
KW - Convection-enhanced delivery
KW - High-performance liquid chromatography
KW - Nimustine hydrochloride
KW - Nitrosourea
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U2 - 10.1007/s11060-006-9247-5
DO - 10.1007/s11060-006-9247-5
M3 - Article
C2 - 17031554
AN - SCOPUS:33846993762
VL - 82
SP - 41
EP - 47
JO - Journal of Neuro-Oncology
JF - Journal of Neuro-Oncology
SN - 0167-594X
IS - 1
ER -