Formation of active products of benzaldehyde dimethane sulfonate (NSC 281612, DMS612) in human blood and plasma and their activity against renal cell carcinoma lines.
Formation of active products of benzaldehyde dimethane sulfonate (NSC 281612, DMS612) in human blood and plasma and their activity against renal cell carcinoma lines.
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DOI：
10.1007/s00280-012-1980-1
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发表时间：
2013-01
影响因子：
3
通讯作者：
Beumer, Jan H.
中科院分区：
文献类型：
--
作者：
Parise, Robert A.;Anyang, Bean N.;Eiseman, Julie L.;Egorin, Merrill J.;Covey, Joseph M.;Beumer, Jan H.
关键词：
苯甲醛二甲磺酸盐（BEN，DMS 612，NSC 281612）是一种具有抗肾细胞癌活性的烷化剂，正在进行临床评价。为了支持临床试验，我们开发了一种LC-MS/MS测定法来检测和定量BEN及其代谢物/分解产物。本研究对苯甲酸二甲磺酸钠（BA）和苯甲酸苄酯（BEN）在血浆、血液和五种肾癌细胞株中的稳定性和产物进行了体外检测。此外，我们测定了BEN、BA及其四种产物在这些细胞系中的IC 50。低温和pH稳定分析物，并利用这导致准确，精密和可重现的测定。BEN和BA在体外血浆中的半衰期分别为220和5 min，而BEN在全血中的半衰期为18 min。监测了多达12种分析物的生成和降解，并使用可用的真实标准确认了结构。BEN的IC 50比其任何产品低5- 500倍，而对BEN的细胞代谢活性与ALDH活性和IC 50值相关。我们检测到六个体外产品和它们各自的葡萄糖醛酸苷在小鼠血浆给药后BEN。从这些实验中获得的信息将有助于在正在进行的人体试验中评价BEN的药理学。
Benzaldehyde dimethane sulfonate (BEN, DMS612, NSC281612) is an alkylating agent with activity against renal cell carcinoma and is being evaluated clinically. To support clinical trials, we developed an LC–MS/MS assay to detect and quantitate BEN and its metabolites/decomposition products. We tested the stability and products of BEN and benzoic acid dimethane sulfonate (BA) in plasma, blood and five renal carcinoma cell lines in vitro. Further, we determined the IC50 of BEN, BA and four of their products in these cell lines. Low temperature and pH stabilized the analytes, and utilizing this resulted in an accurate, precise and reproducible assay. The half-lives of BEN and BA added to plasma in vitro were 220 and 5 min, while the half-life of BEN in whole blood was 18 min. The generation and degradation of up to 12 analytes were monitored, and structures confirmed with available authentic standards. The IC50 for BEN was 5- to 500-fold lower than that of any of its products, while the cellular metabolic activity toward BEN correlated with ALDH activity and IC50 values. We detected six of the in vitro products and their respective glucuronides in murine plasma after dosing BEN. The information gained from these experiments will be instrumental in the evaluation of the pharmacology of BEN in ongoing human trials.
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影响因子：
3
作者：
Beumer, Jan H.;Eiseman, Julie L.;Gilbert, Judith A.;Holleran, Julianne L.;Yellow-Duke, Archibong E.;Clausen, Dana M.;D'Argenio, David Z.;Ames, Matthew M.;Hershberger, Pamela A.;Parise, Robert A.;Bai, Lihua;Covey, Joseph M.;Egorin, Merrill J.
通讯作者：
Egorin, Merrill J.
影响因子：
3.8
作者：
Jumaa, M;Chimilio, L;Stella, VJ
通讯作者：
Stella, VJ
影响因子：
2.2
作者：
Karamanakos, Petros N.;Pappas, Periklis;Marselos, Marios
通讯作者：
Marselos, Marios
影响因子：
2.9
作者：
Wierzchowski, J;Wroczynski, P;Interewicz, E
通讯作者：
Interewicz, E
影响因子：
4.8
作者：
Ma, Irene;Allan, Alison L.
通讯作者：
Allan, Alison L.