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| 標題: | Synthesis and Antitumor Properties of BQC-Glucuronide, a Camptothecin Prodrug for Selective Tumor Activation |
| 作者: | Prijovich, Zeljko M.
Burnouf, Pierre-Alain
Chou, Hua-Cheng
Huang, Ping-Ting
Chen, Kai-Chuan
Cheng, Tian-Lu
Leu, Yu-Lin
Roffler, Steve R. |
| 貢獻者: | Acad Sinica, Inst Biomed Sci, Acad Rd
Natl Yang Ming Univ, Taiwan Int Grad Program Mol Med
Acad Sinica, Acad Rd
Kaohsiung Med Univ, Fac Biomed Sci & Environm Biol
Chia Nan Univ |
| 關鍵字: | camptothecin
glucuronide
prodrug
cancer
targeted therapy
beta-glucuronidase
albumin influence
ADEPT
metastasis |
| 日期: | 2016-04 |
| 上傳時間: | 2018-01-18 11:38:46 (UTC+8) |
| 出版者: | Amer Chemical Soc |
| 摘要: | Major limitations of camptothecin anticancer drugs (toxicity, nonselectivity, water insolubility, inactivation by human serum albumin) may be improved by creating glucuronide prodrugs that rely on beta-glucuronidase for their activation. We found that the camptothecin derivative 5,6dihydro-4H-benzo [de] quinoline-camptothecin (BQC) displays greater cytotoxicity against cancer cells than the clinically used Norma tissue camptothecin derivatives SN-38 and topotecan even in the presence of human serum albumin. We synthesized the prodrug BQC-glucuronide (BQC-G), which was 4000 times more water soluble and 20-40 times less cytotoxic than BQC. Importantly, even in the presence of human serum albumin, BQC-G was efficiently hydrolyzed by beta-glucuronidase and produced greater cytotoxicity (IC50 = 13 nM) than camptothecin, 9-aminocamptothecin, SN-38, or topotecan (IC50 > 3000, 1370, 48, and 28 nM, respectively). BQC-G treatment of mice bearing human colon cancer xenografts with naturally or artificially elevated beta-glucuronidase activity produced significant antitumor activity, showing that BQC-G is a potent prodrug suitable for selective intratumoral drug activation. |
| 關聯: | Molecular Pharmaceutics, v.13 n.4, pp.1242-1250 |
| 顯示於類別: | [藥學系(所)] 期刊論文
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