Oya N, Shibamoto Y, Shibata T, Murata R, Iwai H, Sugiyama T, Abe M
Dept. of Radiology, Faculty of Medicine, Kyoto University, Japan.
Int J Radiat Oncol Biol Phys. 1994 Jun 15;29(3):595-600. doi: 10.1016/0360-3016(94)90464-2.
The in vitro and in vivo effects of two promising hypoxic cell radiosensitizers, KIN-804 (KIN) and KU-2285 (KU), were compared using four types of assays, and the acute toxicity and pharmacokinetics of KIN were investigated to evaluate the clinical applicability of the compounds.
To evaluate the in vitro effect at low radiation doses (1-4.5 Gy), the cytokinesis-block micronucleus (MN) assay using SCCVII or EMT-6 cells and the chromosomal aberration (CA) assay using EMT-6 cells were performed. In addition, an in vivo-in vitro colony assay, a growth delay assay, and a pharmacokinetic study were performed using C3H mice bearing SCCVII tumors, and the LD50/7 was determined in ICR mice.
In the in vitro MN assay, the sensitizer enhancement ratio (SER) at 0.1, 0.25, 1, and 5 mM with SCCVII cells, and at 1 mM with EMT-6 cells was respectively, 1.45, 1.61, 2.57, 4.22, and 1.96 for KIN, and 1.57, 1.62, 2.59, 5.66, and 2.21 for KU. In the in vitro CA assay, the SER at 1 mM was 1.78 for KIN and 1.79 for KU. In the in vivo-in vitro colony assay, the SER of KIN at 50, 100, and 200 mg/kg was 1.24, 1.30, and 1.45, respectively, while the SER of KU at 100 mg/kg was 1.41. In the growth delay assay, the growth delay time for 100 and 200 mg/kg of the drug plus 20 Gy of radiation was respectively, 16.5 and 19.1 days for KIN, and 18.9 and 24.0 days for KU. In all experiments, the sensitizing effect of KIN was almost equal to that of KU. The LD50/7 of KIN was 3.6 g/kg by intraperitoneal injection, while that of KU was 3.6 g/kg by intraperitoneal injection, and the pharmacokinetic study of KIN revealed a low uptake of the drug by the brain.
Both KIN and KU had a definite sensitizing effect even at lower drug concentrations or doses, suggesting their potential usefulness in clinical radiotherapy.
使用四种检测方法比较两种有前景的低氧细胞放射增敏剂KIN - 804（KIN）和KU - 2285（KU）的体外和体内效应，并研究KIN的急性毒性和药代动力学，以评估这些化合物的临床适用性。
为评估低辐射剂量（1 - 4.5 Gy）下的体外效应，使用SCCVII或EMT - 6细胞进行胞质分裂阻滞微核（MN）检测，以及使用EMT - 6细胞进行染色体畸变（CA）检测。此外，对携带SCCVII肿瘤的C3H小鼠进行体内 - 体外集落检测、生长延迟检测和药代动力学研究，并在ICR小鼠中测定LD50/7。
在体外MN检测中，KIN在0.1、0.25、1和5 mM浓度下与SCCVII细胞作用时以及在1 mM浓度下与EMT - 6细胞作用时的增敏增强率（SER）分别为1.45、1.61、2.57、4.22和1.96，KU的相应SER分别为1.57、1.62、2.59、5.66和2.21。在体外CA检测中，KIN在1 mM浓度下的SER为1.78，KU为1.79。在体内 - 体外集落检测中，KIN在50、100和200 mg/kg剂量下的SER分别为1.24、1.30和1.45，而KU在100 mg/kg剂量下的SER为1.41。在生长延迟检测中，100和200 mg/kg药物加20 Gy辐射时KIN的生长延迟时间分别为16.5天和19.1天，KU分别为18.9天和24.0天。在所有实验中，KIN的增敏作用与KU几乎相当。KIN腹腔注射的LD50/7为3.6 g/kg，KU腹腔注射的LD50/7为3.6 g/kg，KIN的药代动力学研究显示该药物在脑中的摄取较低。
即使在较低药物浓度或剂量下，KIN和KU均具有明确的增敏作用，表明它们在临床放射治疗中具有潜在应用价值。
