title: Combination of Caspy2 and IP-10 gene therapy significantly improves therapeutic efficacy against murine malignant neoplasm growth and metastasis.
abstract: It has been shown that Caspy2, a zebrafish active caspase, can efficiently suppress the growth of malignant tumor. The present study was designed to test whether combined gene therapy with IP-10, a potent antitumor chemokine, and Caspy2 would improve therapy efficacy. Recombinant plasmid expressing both Caspy2 and IP-10 genes was mixed with DOTAP-cholesterol nanoparticles. Immunocompetent mice bearing CT26 colon carcinoma, B16-F10 melanoma, and 4T1 breast carcinoma were treated with the complex. We found that the combined gene therapy more efficiently inhibited tumor growth, while efficiently prolonging the survival of tumor-bearing animals, compared with monotherapy. Moreover, a significant reduction in spontaneous lung metastasis could be observed in the 4T1 breast carcinoma model. Infiltration of CD8(+) T lymphocytes was also observed. In addition, apoptotic cells were widely detected by TUNEL assay and caspase-3 immunostaining in coadministered tumor tissues. The combination treatment also successfully inhibited angiogenesis and tumor cell proliferation as assessed by CD31 and Ki-67 immunostaining, respectively. Furthermore, depletion of CD8(+) T lymphocytes could significantly abrogate the antitumor activity, whereas the depletion of CD4(+) cells or natural killer cells showed partial abrogation. Rechallenged CT26 tumors were rejected in all of the surviving mice treated by combination therapy. Our results suggest that combined therapy with Caspy2 and IP-10 can significantly enhance antitumor activity by acting as an immune response initiator, apoptosis inducer, and angiogenesis inhibitor, which may be important for further applications in clinical cancer therapy.
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Lin
authors.initials: L
authors.lastname: Cheng
authors.forename: Xiao-mei
authors.initials: XM
authors.lastname: Zhang
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Sheng-yong
authors.initials: SY
authors.lastname: Liu
authors.forename: Shu-ya
authors.initials: SY
authors.lastname: Wang
authors.forename: Rui-bo
authors.initials: RB
authors.lastname: Wang
authors.forename: Wen-jing
authors.initials: WJ
authors.lastname: Xu
authors.forename: Lei
authors.initials: L
authors.lastname: Dai
authors.forename: Nv
authors.initials: N
authors.lastname: Yan
authors.forename: Ping
authors.initials: P
authors.lastname: Fan
authors.forename: Li-xia
authors.initials: LX
authors.lastname: Dai
authors.forename: Hong-wei
authors.initials: HW
authors.lastname: Tian
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Hong-xin
authors.initials: HX
authors.lastname: Deng
mesh_terms: D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D020169:Caspases / Q000235:genetics*; D054357:Chemokine CXCL10 / Q000235:genetics*; D003110:Colonic Neoplasms / Q000473:pathology / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D008081:Liposomes; D008175:Lung Neoplasms / Q000556:secondary* / Q000628:therapy; D008546:Melanoma, Experimental / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000628:therapy; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D054357:Chemokine CXCL10; D008081:Liposomes; D029961:Zebrafish Proteins; D020169:Caspases; C582578:caspb protein, zebrafish