title: hTERT-promoter-based tumor-specific expression of MCP-1 effectively sensitizes cervical cancer cells to a low dose of cisplatin.
abstract: Cervical cancers at advanced stages or with recurrent status are mainly treated by platinum-based chemotherapy, such as cisplatin. However, a novel strategy to reduce the minimally effective dose is required to prevent severe adverse effects that limit the effectiveness of the treatment. Monocyte chemoattractant protein-1 (MCP-1) is a subtype of chemokines that can promote monocyte/macrophage infiltration and enhance their phagocytosis at not only sites of inflammatory lesions but also of tumors. The present study applies MCP-1-based gene therapy to treat cervical cancers. To achieve tumor-specific expression of MCP-1, retroviral expression vector was constructed using the human telomerase reverse transcriptase gene (hTERT) promoter. Retroviral expression of MCP-1 into cervical cancer ME180 cells did not affect their proliferation either in vitro or in vivo. However, when combined with a suboptimal low dose of cisplatin, tumor formation was obviously reduced in clones transduced with MCP-1, but not in control clones. Histological examination revealed that a substantial number of macrophages infiltrated the tumor sites of MCP-1-transduced cells, but not of controls. These findings suggest that MCP-1 expression sensitizes cervical cancer cells to an otherwise ineffective low dose of cisplatin, possibly by inducing the migration of macrophages to eradicate tumor cells. This system may be a novel strategy for chemotherapy combined with immunogene therapy against otherwise intractable cervical cancers.
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Nakamura
authors.forename: Satoru
authors.initials: S
authors.lastname: Kyo
authors.forename: Taro
authors.initials: T
authors.lastname: Kanaya
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yatabe
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Maida
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tanaka
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ishida
authors.forename: Chifumi
authors.initials: C
authors.lastname: Fujii
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Kondo
authors.forename: Masaki
authors.initials: M
authors.lastname: Inoue
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D004268:DNA-Binding Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D019098:Telomerase; D002945:Cisplatin