An improved human carboxylesterase for enzyme/prodrug therapy with CPT-11

被引:40
作者
Wierdl, M. [1 ]
Tsurkan, L. [1 ]
Hyatt, J. L. [1 ]
Edwards, C. C. [1 ]
Hatfield, M. J. [1 ]
Morton, C. L. [1 ]
Houghton, P. J. [1 ]
Danks, M. K. [1 ]
Redinbo, M. R. [2 ]
Potter, P. M. [1 ]
机构
[1] St Jude Childrens Res Hosp, Dept Mol Pharmacol, Memphis, TN 38105 USA
[2] Univ N Carolina, Dept Chem & Biochem, Chapel Hill, NC USA
关键词
carboxylesterase; CPT-11; enzyme/prodrug therapy; xenograft;
D O I
10.1038/sj.cgt.7701112
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
CPT-11 is a potent antitumor agent that is activated by carboxylesterases (CE) and intracellular expression of CEs that can activate the drug results in increased cytotoxicity to the drug. As activation of CPT-11 (irinotecan-7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) by human CEs is relatively inefficient, we have developed enzyme/prodrug therapy approaches based on the CE/CPT-11 combination using a rabbit liver CE (rCE). However, the in vivo application of this technology may be hampered by the development of an immune response to rCE. Therefore, we have developed a mutant human CE (hCE1m6), based on the human liver CE hCE1, that can activate CPT-11 approximately 70-fold more efficiently than the wild-type protein and can be expressed at high levels in mammalian cells. Indeed, adenoviral-mediated delivery of hCE1m6 with human tumor cells resulted in up to a 670-fold reduction in the IC50 value for CPT-11, as compared to cells transduced with vector control virus. Furthermore, xenograft studies with human tumors expressing hCE1m6 confirm the ability of this enzyme to activate CPT-11 in vivo and induce antitumor activity. We propose that this enzyme should likely be less immunogenic than rCE and would be suitable for the in vivo application of CE/CPT-11 enzyme/prodrug therapy.
引用
收藏
页码:183 / 192
页数:10
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