Terapia antiangiogênica de tumores utilizando células produtoras de endostatina encapsuladas em dispositivos de imunoisolamento / ANTIANGIOGENIC THERAPY USING ENDOSTATIN PRODUCER CELLS ENCAPSULATED IN IMMUNOISOLATION DEVICES.

AUTOR(ES)
DATA DE PUBLICAÇÃO

2008

RESUMO

Endostatin is a specific inhibitor of endothelial cell proliferation, migration and a potent angiogenesis inhibitor. It has been shown that continuous administration of endostatin is more effective in tumor suppression than the same dose administered s.c. daily. Achieving concentration of endostatin to combat tumor growth is complicated by the short life of the protein. Transplantation of encapsulated cells in immunoisolation devices is a promising approach for many diseases since it allows a long-term delivery of the therapeutic protein and the semi-permeable membrane can protect cell from host’s immune rejection, to circumvent the problem of toxicity, limited half life and variation in circulating levels. The Theracyte® device is a semi-permeable membrane macroencapsulation system for implantation of genetically engineered cells for therapeutic proteins delivery in vivo and which does not require host immunosuppression. It was shown in this study that encapsulated recombinant murine fibroblasts (LM) expressing 0.4µg of murine endostatina/106 cells in 24 hours presents a feasible approach to tumor therapy. The delivery system was composed of recombinant endostatin-producing LM murine cells encapsulated into Theracyte macrocapsule for immunoisolation of cells. To demonstrate the usefulness of this system, experimental mice models with Ehrlich and Melanoma tumors were treated with 107 encapsulated endostatin-expressing cells. Two protocols were used for the implant of the devices: 1) The devices were implanted in the animals and after 14 days (wound healing), the cells expressing endostatin were implanted into the device and 2) the devices were implanted in the animals containing the cells. Melanoma tumor growth was reduced by 42% using the first implant protocol and by 54% when the second protocol was used. Ehrlich tumor growth was reduced by 25% using the first device implant protocol. As revealed by anti-endostatin immunostaining, there was a release of endostatin to the tissue outside the devices, demonstrating that endostatin, secreted by the confined recombinant cells, permeated trough the membrane, reaching the surrounding tissues. The effectiveness of endostatin delivery on the neovascularization of melanoma (B16-F10) was determined by analysis of the number of vascular structures, accessed by immunohistochemistry using anti-CD-34 antibody. It was shown that there was a decrease of 41.5% in the number of vascular structures, 35.9% in the number of viable vessels and 33.5% in the extension of vascular area in the treated group. The results described are quite promising and may offer an alternative for the treatment of a variety of tumor types. LISTA

ASSUNTO(S)

dispositivo theracyte endostatina imunoisolamento tumor dispositivo melanoma ehrlich imunoisolamento angiogênese tumor endostatina ehrlich angiogênese theracyte melanoma

ACESSO AO ARTIGO

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