Levels and distribution of BCNU in GBM tumors following intratumoral injection of DTI-015 (BCNU-ethanol).
Levels and distribution of BCNU in GBM tumors following intratumoral injection of DTI-015 (BCNU-ethanol).
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DOI：
10.1215/15228517-2006-014
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发表时间：
2007
期刊：
影响因子：
15.9
通讯作者：
W. Bodell;Alexander P Bodell;D. D. Giannini-D.
中科院分区：
文献类型：
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作者：
W. Bodell;Alexander P Bodell;D. D. Giannini-D.
用氚标记的1，3-双（2-氯乙基）-1-亚硝基脲（（3）H-BCNU）体外处理DNA形成的烷基化产物被鉴定和定量。采用高效液相色谱法（HPLC）对12种加合物进行了分离。BCNU处理形成的主要DNA加合物对应于N-7-（2-羟乙基）鸟嘌呤（N7-HOEtG）（26%）、N-7-（2-氯乙基）鸟嘌呤（15%）和磷酸三酯（19%）。此外，几种次要产物被鉴定为1，2-（地关-7-基）乙烷、N-1-（2-羟乙基）-2-脱氧鸟苷、1-（N-1-2-脱氧鸟苷基）、2-（N-3-2-脱氧胞苷基）乙烷交联和O-6-（2-羟乙基）-2-脱氧鸟苷，它们分别占总烷基化的1%至5%。应用HPLC-电化学方法定量用BCNU处理的样品中N7-HOEtG的水平。用不同量的BCNU处理纯化的DNA或U87 MG细胞，产生N7-HOEtG量的线性增加。这些结果表明，BCNU处理形成的N7-HOEtG水平可以用作BCNU处理剂量的分子剂量计。我们测量了在立体定向瘤内注射DTI-015（BCNU-乙醇）后从四名GBM肿瘤患者的肿瘤样品中分离的DNA中N7-HOEtG的水平。这些样品中N7-HOEtG的水平在注射部位1 cm内的范围为14.7至121.9 μ mol N7-HOEtG/mol DNA。随着距注射部位距离的增加，肿瘤DNA中N7-HOEtG的水平降低。在两个样品中，在距离注射部位3.5至3.9 cm处，N7-HOEtG的水平为0.2至0.3 μ mol N7-HOETG/mol DNA，表明BCNU在肿瘤中的显著分布。这些肿瘤样品中N7-HOEtG的水平对应于0.02至43.0 mM的BCNU治疗浓度。这些研究表明，立体定向瘤内注射DTI-015进入人GBM肿瘤产生高浓度的BCNU，在一些肿瘤中，距离注射部位2.5 cm。这些观察结果表明，瘤内注射DTI-015可能有益于治疗原发性和复发性GBM肿瘤。
The alkylation products formed by in vitro treatment of DNA with tritium-labeled 1,3-bis(2-chloroethyl)-1-nitrosourea ((3)H-BCNU) were identified and quantified. Twelve adducts were resolved by high-performance liquid chromatography (HPLC). The principal DNA adducts formed by BCNU treatment corresponded to N-7-(2-hydroxyethyl)guanine (N7-HOEtG) (26%), N-7-(2-chloroethyl)guanine (15%), and phosphotriesters (19%). In addition, several minor products were identified as 1,2-(diguan-7-yl)ethane, N-1-(2-hydroxyethyl)-2-deoxyguanosine, 1-(N-1-2-deoxyguanosinyl), 2-(N-3-2-deoxycytidyl)ethane cross-link, and O-6-(2-hydroxyethyl)-2-deoxyguanosine, and individually they represented 1% to 5% of the total alkylation. An HPLC-electrochemical method was applied to quantify the levels of N7-HOEtG in samples treated with BCNU. Treatment of either purified DNA or U87MG cells with various amounts of BCNU produced a linear increase in the amount of N7-HOEtG. These results demonstrated that the levels of N7-HOEtG formed by BCNU treatment could be used as a molecular dosimeter of BCNU treatment dose. We measured the levels of N7-HOEtG in DNA isolated from tumor samples taken from four patients with GBM tumors following stereotactic intratumoral injection with DTI-015 (BCNU-ethanol). The level of N7-HOEtG in these samples ranged from 14.7 to 121.9 micromol N7-HOETG/mol DNA within 1 cm of the site of injection. As the distance from the site of injection increased, the levels of N7-HOEtG in tumor DNA decreased. In two of the samples, the levels of N7-HOEtG were 0.2 to 0.3 micromol N7-HOETG/mol DNA at 3.5 to 3.9 cm from the site of injection, demonstrating significant distribution of BCNU in the tumor. The levels of N7-HOEtG in these tumor samples corresponded to BCNU treatment concentrations of 0.02 to 43.0 mM. These studies demonstrate that stereotactic intratumoral injection of DTI-015 into human GBM tumors produces high concentrations of BCNU up to 2.5 cm from the site of injection in some of the tumors. These observations suggest that intratumoral injection of DTI-015 may be of benefit in the treatment of primary and recurrent GBM tumors.