Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West Room M-719, Montreal, Quebec H3A 1A1, Canada.
J Med Chem. 2010 Mar 11;53(5):2104-13. doi: 10.1021/jm9016043.
Here, we report on the first synthesis of fluorescent-labeled epidermal growth factor receptor-DNA targeting combi-molecules, and we studied the influence of P-glycoprotein status of human sarcoma MES-SA cells on their growth inhibitory effect and cellular uptake. The results showed that 6, bearing a longer spacer between the quinazoline ring and the dansyl group, was more stable and more cytotoxic than 4. In contrast to the latter, it induced significant levels of DNA damage in human tumor cells. Moreover, in contrast to doxorubicin, a drug known to be actively effluxed by P-gp, the more stable combi-molecule 6 induced almost identical levels of drug uptake and DNA damage in P-gp-proficient and -deficient cells. Likewise, in contrast to doxorubicin, 4 and 6 exerted equal levels of antiproliferative activity against the two cell types. The results in toto suggest that despite their size, the antiproliferative effects of 4 and 6 were independent of P-gp status of the cells.
在这里，我们报告了首例荧光标记表皮生长因子受体-DNA 靶向组合分子的合成，并研究了人肉瘤 MES-SA 细胞中 P-糖蛋白状态对其生长抑制作用和细胞摄取的影响。结果表明，6 在喹唑啉环和丹磺酰基之间具有更长的间隔基，比 4 更稳定且细胞毒性更强。与后者相比，它在人肿瘤细胞中诱导了显著水平的 DNA 损伤。此外，与阿霉素不同，阿霉素是一种已知被 P-糖蛋白主动外排的药物，更稳定的组合分子 6 在 P-糖蛋白阳性和阴性细胞中诱导了几乎相同水平的药物摄取和 DNA 损伤。同样，与阿霉素不同，4 和 6 对两种细胞类型均表现出相同水平的抗增殖活性。总的来说，这些结果表明，尽管它们的大小不同，但 4 和 6 的增殖抑制作用与细胞的 P-糖蛋白状态无关。
