Eldridge Sandy R, Covey Joseph, Morris Joel, Fang Bingliang, Horn Thomas L, Elsass Karen E, Hamre John R, McCormick David L, Davis Myrtle A
Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20892, USA.
The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Toxicol Appl Pharmacol. 2014 Dec 15;281(3):303-9. doi: 10.1016/j.taap.2014.10.015. Epub 2014 Oct 28.
NSC-743380 (1-[(3-chlorophenyl)-methyl]-1H-indole-3-carbinol) is in early stages of development as an anticancer agent. Two metabolites reflect sequential conversion of the carbinol functionality to a carboxaldehyde and the major metabolite, 1-[(3-chlorophenyl)-methyl]-1H-indole-3-carboxylic acid. In an exploratory toxicity study in rats, NSC-743380 induced elevations in liver-associated serum enzymes and biliary hyperplasia. Biliary hyperplasia was observed 2 days after dosing orally for 2 consecutive days at 100mg/kg/day. Notably, hepatotoxicity and biliary hyperplasia were observed after oral administration of the parent compound, but not when major metabolites were administered. The toxicities of a structurally similar but pharmacologically inactive molecule and a structurally diverse molecule with a similar efficacy profile in killing cancer cells in vitro were compared to NSC-743380 to explore scaffold versus target-mediated toxicity. Following two oral doses of 100mg/kg/day given once daily on two consecutive days, the structurally unrelated active compound produced hepatic toxicity similar to NSC-743380. The structurally similar inactive compound did not, but, lower exposures were achieved. The weight of evidence implies that the hepatotoxicity associated with NSC-743380 is related to the anticancer activity of the parent molecule. Furthermore, because biliary hyperplasia represents an unmanageable and non-monitorable adverse effect in clinical settings, this model may provide an opportunity for investigators to use a short-duration study design to explore biomarkers of biliary hyperplasia.
NSC - 743380（1 - [(3 - 氯苯基)-甲基]-1H - 吲哚 - 3 - 甲醇）作为一种抗癌药物正处于研发早期阶段。两种代谢产物反映了甲醇官能团依次转化为羧醛，主要代谢产物为1 - [(3 - 氯苯基)-甲基]-1H - 吲哚 - 3 - 羧酸。在一项大鼠探索性毒性研究中，NSC - 743380导致肝脏相关血清酶升高和胆汁增生。在以100mg/kg/天连续口服给药2天之后的第2天观察到胆汁增生。值得注意的是，口服母体化合物后观察到肝毒性和胆汁增生，但给予主要代谢产物时未观察到。将一种结构相似但无药理活性的分子以及一种在体外杀死癌细胞方面具有相似功效特征的结构不同的分子的毒性与NSC - 743380进行比较，以探究支架介导毒性与靶点介导毒性。在连续两天每天口服一次100mg/kg/天的两次给药后，结构不相关的活性化合物产生了与NSC - 743380相似的肝毒性。结构相似的无活性化合物未产生肝毒性，但其暴露水平较低。现有证据表明，与NSC - 743380相关的肝毒性与母体分子的抗癌活性有关。此外，由于胆汁增生在临床环境中代表一种难以控制且无法监测的不良反应，该模型可能为研究人员提供一个机会，利用短期研究设计来探索胆汁增生的生物标志物。
