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Title: Combination Cancer Therapy by Hapten-Targeted Prodrug-Activating Enzymes and Cytokines
Authors: Kuo-Hsiang Chuang;Chiu-Min Cheng;Steve R. Roffler;Yu-Lin Lu;Shiu-Ru Lin;Jaw-Yuan Wang;Wen-Shyong Tzou;Yu-Cheng Su;Bing-Mae Chen;Tian-Lu Cheng
Contributors: NTOU:Institute of Bioscience and Biotechnology
Date: 2006
Issue Date: 2011-10-21T02:22:23Z
Publisher: Bioconjugate Chemistry
Abstract: Abstract:Combination therapy can help overcome limitations in the treatment of heterogeneous tumors. In the current study, we examined whether multiple therapeutic agents could be targeted to anti-dansyl single-chain antibodies (DNS scFv) that were anchored on the plasma membrane of cancer cells. Functional DNS scFv could be stably expressed on CT-26 colon cancer cells both in vitro and in vivo. Dansyl moieties were covalently attached to recombinant β-glucuronidase (βG) and interleukin 2 (IL-2) via a flexible poly(ethylene glycol) linker to form DNS−PEG−βG and DNS−PEG−IL-2 conjugates. The conjugates displayed enzymatic and splenocyte-stimulatory activities, respectively, that were similar to those of the unmodified proteins. The conjugates selectively bound CT-26 cells that expressed anti-DNS scFv (CT-26/DNS cells) but not CT-26 cells that expressed control scFv (CT-26/phOx cells). DNS−PEG−βG preferentially activated a glucuronide prodrug (BHAMG) of p-hydroxy aniline mustard at CT-26/DNS cells in culture and accumulated in subcutaneous CT-26/DNS tumors after intravenous administration. Systemic administration of DNS−PEG−IL-2 or DNS−PEG−βG and BHAMG significantly delayed the growth of CT-26/DNS but not control CT-26/phOx tumors. Combination treatment with DNS−PEG−βG and BHAMG followed by DNS−PEG−IL-2 therapy significantly suppressed the growth of CT-26/DNS tumors as compared to either single-agent regimen. These results show that at least two DNS-modified therapeutic agents can be selectively delivered to DNS scFv receptors in vitro and in vivo, allowing combination therapy of DNS scFv-modified tumors.
Relation: 17(3), pp.707–714
Appears in Collections:[Department of Bioscience and Biotechnology ] Periodical Articles

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