Novel delivery of SN38 markedly inhibits tumor growth in xenografts, including a camptothecin-11 - Refractory model

被引:143
作者
Sapra, Puja [1 ]
Zhao, Hong [1 ]
Mehlig, Mary [1 ]
Malaby, Jennifer [1 ]
Kraft, Patricia [1 ]
Longley, Clifford [1 ]
Greenberger, Lee M. [1 ]
Horak, Ivan D. [1 ]
机构
[1] Enzon Pharmaceut Inc, Piscataway, NJ 08854 USA
关键词
D O I
10.1158/1078-0432.CCR-07-4456
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Clinical development of SN38, the active metabolite of camptothecin-11 (CPT-11), has been hampered due to its poor solubility. We have developed a novel polymer-drug conjugate, EZN-2208, made by linking SN38 with a multiarm polyethylene glycol via a glycine linker. Experimental Design: The in vitro cytotoxicity of EZN-2208 was tested using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. The therapeutic efficacy of EZN-2208 was evaluated in various xenografts, including an in vivo selected CPT-11 - refractory model. Tumor and blood concentration of EZN-2208, CPT-11, and SN38 was determined by high-performance liquid chromatography. Results: In vitro, EZN-2208 was 10- to 245-fold more potent than CPT-11 in a panel of human tumor cell lines. In xenograft models of MX-1 breast, MiaPaCa-2 pancreatic, or HT-29 colon carcinoma, treatment with either a single dose or multiple injections of EZN-2208 was more efficacious (and in some cases produced tumor eradication for >16 weeks) compared with CPT-11 at their respective maximum tolerated doses or corresponding dose levels (P < 0.01). Most interestingly, EZN-2208 showed marked antitumor activity in animals that developed resistance to an 8-day course of CPT-11 treatment, as well as outperformed CPT-11 as second-round therapy in mice initially sensitive to CPT-11. EZN-2208 had prolonged circulation in the blood compared with CPT-11, resulting in high tumor exposure. This resulted in higher and longer-lasting tumor exposure of free SN38 in mice given EZN-2208 compared with those given CPT-11. Conclusions: Preclinical data suggest that EZN-2208 may be a promising anticancer agent in a wide variety of clinical settings, including tumors refractory to CPT-11 treatment.
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页码:1888 / 1896
页数:9
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