Foster Paul A, Stengel C, Ali Tauhid, Leese Mathew P, Potter Barry V L, Reed Michael J, Purohit Atul, Newman Simon P
Endocrinology and Metabolic Medicine and Sterix Ltd., Faculty of Medicine, Imperial College London, St. Mary's Hospital, London W2 1NY, UK.
Anticancer Res. 2008 May-Jun;28(3A):1483-91.
This study characterises two recently developed anticancer agents in vitro and in vivo, 2-methoxyoestra-1,3,5(10), 16-tetraene-3-carboxamide (IRC-110160) and STX140.
Hormone-dependent (MCF-7), hormone-independent (MDA-MB-231) and P-glycoprotein overexpressing (MCF-7Dox) cells were used for proliferation experiments. For the tumour efficacy studies, female nude mice were inoculated with MDA-MB-231 cells.
IRC-110160 is a potent inhibitor of both MCF-7 and MDA-MB-231 cell proliferation. Furthermore, the potency of IRC-110160 was unaffected by the over-expression of the P-glycoprotein drug efflux pump. IRC-110160 and 2-methoxyoestradiol-3,17-O,O-bis-sulfamate (STX140) induced apoptosis in a similar timeframe in the MDA-MB-231 cell line, but only STX140 caused G2/M arrest in these cells. In the MDA-MB-231 xenograft model 300 mg/kg p.o. (daily) of IRC-110160 and 20 mg/kg p.o. STX140 (daily) both completely inhibited tumour growth; however some toxicity was observed with IRC-110160. After 28 days of daily dosing STX140 (20 mg/kg p.o.) had minimal effect on the white blood population of mice with tumours. The masking of STX140 from white blood cells may be due to its interaction with carbonic anhydrase II (CAII) in the red blood cells. In contrast to STX140, IRC-110160 does not inhibit CAII. These studies highlight the activity of two orally bioavailable anti-cancer agents one of which, STX140, may offer a significant clinical advantage over existing drugs as a common dose limiting factor, haemotoxicity, may be minimised.
本研究在体外和体内对两种最近研发的抗癌药物进行了特性分析，即2-甲氧基雌-1,3,5(10),16-四烯-3-甲酰胺（IRC-110160）和STX140。
使用激素依赖性（MCF-7）、激素非依赖性（MDA-MB-231）和过表达P-糖蛋白（MCF-7Dox）的细胞进行增殖实验。对于肿瘤疗效研究，将MDA-MB-231细胞接种到雌性裸鼠体内。
IRC-110160是MCF-7和MDA-MB-231细胞增殖的有效抑制剂。此外，IRC-110160的效力不受P-糖蛋白药物外排泵过表达的影响。IRC-110160和2-甲氧基雌二醇-3,17-O,O-双磺酸酯（STX140）在MDA-MB-231细胞系中于相似的时间范围内诱导细胞凋亡，但只有STX140导致这些细胞发生G2/M期阻滞。在MDA-MB-231异种移植模型中，口服IRC-110160 300 mg/kg（每日）和口服STX140 20 mg/kg（每日）均完全抑制肿瘤生长；然而，IRC-110160观察到一些毒性。每日给药28天后，STX（20 mg/kg口服）对荷瘤小鼠的白细胞群体影响极小。STX140在白细胞中被掩盖可能是由于其与红细胞中的碳酸酐酶II（CAII）相互作用。与STX140相反，IRC-110160不抑制CAII。这些研究突出了两种口服生物可利用抗癌药物的活性，其中一种，即STX140，作为常见的剂量限制因素血液毒性可能最小化，相比现有药物可能具有显著的临床优势。
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