title: Combination of poly-gamma-glutamate and cyclophosphamide enhanced antitumor efficacy against tumor growth and metastasis in a murine melanoma model.
abstract: Conventional chemotherapeutic regimens often accompany severe side effects and fail to induce complete regression of chemoresistant or relapsing metastatic cancers. The need for establishing more efficacious anticancer strategies led to the development of a combined modality treatment of chemotherapy in conjunction with immunotherapy or radiotherapy. It has been reported that poly-gamma-glutamate (γ-PGA), a natural polymer composed of glutamic acids, increases antitumor activity by activating antigen-presenting cells and natural killer (NK) cells. Here, we investigated the antitumor effect of γ-PGA in combination with cyclophosphamide in a murine melanoma model. Whereas cyclophosphamide alone directly triggered apoptosis of tumor cells in vitro, γ-PGA did not show cytotoxicity in tumor cells. Instead, it activated macrophages, as reflected by the upregulation of surface activation markers and the secretion of proinflammatory factors, such as nitric oxide and tumor necrosis factor α. When the antitumor effects were examined in a mouse model, combined treatment with cyclophosphamide and γ-PGA markedly suppressed tumor growth and metastasis. Notably, γ-PGA treatment dramatically increased the NK cell population in lung tissues, coinciding with decreased metastasis and increased survival. These data collectively suggest that γ-PGA can act as an immunotherapeutic agent that exhibits a synergistic antitumor effect in combination with conventional chemotherapy.
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 306-809, Republic of Korea.
authors.forename: Doo-Jin
authors.initials: DJ
authors.lastname: Kim
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Kim
authors.forename: Tae-Young
authors.initials: TY
authors.lastname: Lee
authors.forename: Ji-Na
authors.initials: JN
authors.lastname: Won
authors.forename: Moon-Hee
authors.initials: MH
authors.lastname: Sung
authors.forename: Haryoung
authors.initials: H
authors.lastname: Poo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D011099:Polyglutamic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; C511775:poly(gamma-glutamic acid); D011099:Polyglutamic Acid; D003520:Cyclophosphamide