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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.|
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
|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.|
|Appears in Collections:||[藥學系(所)] 期刊論文|
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