Department of Biochemical Sciences, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, Hradec Králové, CZ 500 05, Czech Republic.
Pharmacol Rep. 2013;65(2):445-52. doi: 10.1016/s1734-1140(13)71020-x.
The limitation of carbonyl reduction represents one possible way to increase the effectiveness of anthracycline doxorubicin (DOX) in cancer cells and decrease its toxicity in normal cells. In vitro, isoquinoline derivative oracin (ORC) inhibited DOX reduction and increased the antiproliferative effect of DOX in MCF-7 breast cancer cells. Moreover, ORC significantly decreases DOX toxicity in non-cancerous MCF-10A breast cells and in hepatocytes. The present study was designed to test in mice the in vivo effect of ORC on plasma and tissue concentrations of DOX and its main metabolite DOXOL. The effect of ORC on DOX efficacy in mice bearing solid Ehrlich tumors (EST) was also studied.
DOX and DOX + ORC combinations were iv administered to healthy mice. Blood samples, livers and hearts were collected during the following 48 h. DOX and DOXOL concentrations were assayed using HPLC. The mice with inoculated EST cells were treated repeatedly iv with DOX and DOX + ORC combinations, and the growth of tumors was monitored.
ORC in combination with DOX significantly decreased DOXOL plasma concentrations during four hours after administration, but this significantly affected neither DOX plasma concentrations nor DOX or DOXOL concentrations in the liver and heart at any of intervals tested. In EST bearing mice, ORC did not significantly affect DOX efficacy on tumor growth. However, EST was shown to be an improper model for the testing of ORC efficacy in vivo, as ORC did not inhibit DOXOL formation in EST.
In vivo, ORC was able to retard DOXOL formation but was not able to improve DOX efficacy in EST-bearing mice.
羰基还原的限制可能是增加蒽环类药物阿霉素（DOX）在癌细胞中的有效性并降低其在正常细胞中毒性的一种方法。在体外，异喹啉衍生物奥嗪（ORC）抑制 DOX 的还原，并增加 MCF-7 乳腺癌细胞中 DOX 的抗增殖作用。此外，ORC 可显著降低非癌细胞 MCF-10A 乳腺细胞和肝细胞中 DOX 的毒性。本研究旨在测试 ORC 对荷实体 Ehrlich 肿瘤（EST）小鼠体内 DOX 及其主要代谢物 DOXOL 的血浆和组织浓度的影响。还研究了 ORC 对荷 EST 小鼠中 DOX 疗效的影响。
DOX 和 DOX+ORC 组合经静脉注射给予健康小鼠。在接下来的 48 小时内收集血液样本、肝脏和心脏。使用 HPLC 测定 DOX 和 DOXOL 浓度。用接种 EST 细胞的小鼠反复经静脉注射 DOX 和 DOX+ORC 组合，并监测肿瘤的生长。
ORC 与 DOX 联合使用可显著降低给药后 4 小时内的 DOXOL 血浆浓度，但在任何测试间隔内，这均不会显著影响 DOX 或 DOXOL 在血浆、肝脏和心脏中的浓度。在荷 EST 小鼠中，ORC 对 DOX 对肿瘤生长的疗效没有显著影响。然而，EST 并不适合作为体内测试 ORC 疗效的模型，因为 ORC 不能抑制 EST 中 DOXOL 的形成。
在体内，ORC 能够延缓 DOXOL 的形成，但不能提高荷 EST 小鼠中 DOX 的疗效。
