Combination Cancer Therapy by Hapten-Targeted Prodrug-Activating Enzymes and Cytokines
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- 作者：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 ; and Tian-Lu Cheng
- 刊名：Bioconjugate Chemistry
- 出版年：2006
- 出版时间：May 2006
- 年：2006
- 卷：17
- 期：3
- 页码：707 - 714
- 全文大小：323K
- 年卷期：v.17,no.3(May 2006)
- ISSN：1520-4812
文摘
Combination therapy can help overcome limitations in the treatment of heterogeneous tumors. In the currentstudy, 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 stablyexpressed on CT-26 colon cancer cells both in vitro and in vivo. Dansyl moieties were covalently attached torecombinant 
-glucuronidase (G) and interleukin 2 (IL-2) via a flexible poly(ethylene glycol) linker to formDNS-PEG-G and DNS-PEG-IL-2 conjugates. The conjugates displayed enzymatic and splenocyte-stimulatoryactivities, respectively, that were similar to those of the unmodified proteins. The conjugates selectively boundCT-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-G preferentially activated a glucuronide prodrug (BHAMG) of p-hydroxyaniline mustard at CT-26/DNS cells in culture and accumulated in subcutaneous CT-26/DNS tumors afterintravenous administration. Systemic administration of DNS-PEG-IL-2 or DNS-PEG-G and BHAMGsignificantly delayed the growth of CT-26/DNS but not control CT-26/phOx tumors. Combination treatment withDNS-PEG-G and BHAMG followed by DNS-PEG-IL-2 therapy significantly suppressed the growth ofCT-26/DNS tumors as compared to either single-agent regimen. These results show that at least two DNS-modifiedtherapeutic agents can be selectively delivered to DNS scFv receptors in vitro and in vivo, allowing combinationtherapy of DNS scFv-modified tumors.
-glucuronidase (G) and interleukin 2 (IL-2) via a flexible poly(ethylene glycol) linker to formDNS-PEG-G and DNS-PEG-IL-2 conjugates. The conjugates displayed enzymatic and splenocyte-stimulatoryactivities, respectively, that were similar to those of the unmodified proteins. The conjugates selectively boundCT-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-G preferentially activated a glucuronide prodrug (BHAMG) of p-hydroxyaniline mustard at CT-26/DNS cells in culture and accumulated in subcutaneous CT-26/DNS tumors afterintravenous administration. Systemic administration of DNS-PEG-IL-2 or DNS-PEG-G and BHAMGsignificantly delayed the growth of CT-26/DNS but not control CT-26/phOx tumors. Combination treatment withDNS-PEG-G and BHAMG followed by DNS-PEG-IL-2 therapy significantly suppressed the growth ofCT-26/DNS tumors as compared to either single-agent regimen. These results show that at least two DNS-modifiedtherapeutic agents can be selectively delivered to DNS scFv receptors in vitro and in vivo, allowing combinationtherapy of DNS scFv-modified tumors.