title: Tumor targeting carboxylesterase fused with anti-CEA scFv improve the anticancer effect with a less toxic dose of irinotecan.
abstract: Irinotecan (CPT-11) is a key drug for the treatment of various cancers. CPT-11 can be considered to be a prodrug, since it needs to be activated into the toxic drug SN-38 by the enzyme carboxylesterase. However, CPT-11 may induce severe diarrhea and bone marrow suppression as adverse effects, thus leading to treatment interruption. The tumor-specific activation of CPT-11 is a possible strategy to avoid the severe toxicities by reducing the serum concentration of CPT-11. In this study, we constructed human liver carboxylesterase-2 fused with anticarcinoembryonic antigen (CEA) scFv as a targeting molecule. The recombinant enzyme anchors onto the tumor cell surface CEA, and thus metabolize CPT-11 extracellularly. In addition a secreted tumor-targeted form of carboxylesterase should help prevent the leakage of the enzyme from the site of the tumor into the circulation. This fusion protein showed CPT-11 activation to SN-38 and specific binding to CEA-expressing cells. In combination with CPT-11, the recombinant carboxylesterase protein exerted antiproliferative effects on human cancer cells. This recombinant enzyme is, therefore, a promising new tool in enzyme prodrug therapy for the treatment of carcinoma with CPT-11.
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Uchino
authors.forename: K
authors.initials: K
authors.lastname: Takayama
authors.forename: A
authors.initials: A
authors.lastname: Harada
authors.forename: T
authors.initials: T
authors.lastname: Sone
authors.forename: T
authors.initials: T
authors.lastname: Harada
authors.forename: D T
authors.initials: DT
authors.lastname: Curiel
authors.forename: M
authors.initials: M
authors.lastname: Kuroki
authors.forename: Y
authors.initials: Y
authors.lastname: Nakanishi
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D043182:Carboxylesterase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D018390:Gene Targeting; D006367:HeLa Cells; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics* / Q000502:physiology; D000077146:Irinotecan; D011993:Recombinant Fusion Proteins / Q000235:genetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002272:Carcinoembryonic Antigen; D007135:Immunoglobulin Variable Region; D011993:Recombinant Fusion Proteins; D000077146:Irinotecan; C517204:CES2 protein, human; D043182:Carboxylesterase; D002166:Camptothecin