BackgroundTheracyte is a polytetrafluoroethylene membrane macroencapsulation system designed to induce neovascularization at the tissue interface, protecting the cells from host's immune rejection, thereby circumventing the problem of limited half-life and variation in circulating levels. Endostatin is a potent inhibitor of angiogenesis and tumor growth. Continuous delivery of endostatin improves the efficacy and potency of the antitumoral therapy. The purpose of this study was to determine whether recombinant fibroblasts expressing endostatin encapsulated in Theracyte immunoisolation devices can be used for delivery of this therapeutic protein for treatment of mice bearing B16F10 melanoma and Ehrlich tumors.ResultsMice were inoculated subcutaneously with melanoma (B16F10 cells) or Ehrlich tumor cells at the foot pads. Treatment began when tumor thickness had reached 0.5 mm, by subcutaneous implantation of 107 recombinant encapsulated or non-encapsulated endostatin producer cells. Similar melanoma growth inhibition was obtained for mice treated with encapsulated or non-encapsulated endostatin-expressing cells. The treatment of mice bearing melanoma tumor with encapsulated endostatin-expressing cells was decreased by 50.0%, whereas a decrease of 56.7% in tumor thickness was obtained for mice treated with non-encapsulated cells. Treatment of Ehrlich tumor-bearing mice with non-encapsulated endostatin-expressing cells reduced tumor thickness by 52.4%, whereas lower tumor growth inhibition was obtained for mice treated with encapsulated endostatin-expressing cells: 24.2%. Encapsulated endostatin-secreting fibroblasts failed to survive until the end of the treatment. However, endostatin release from the devices to the surrounding tissues was confirmed by immunostaining. Decrease in vascular structures, functional vessels and extension of the vascular area were observed in melanoma microenvironments.ConclusionsThis study indicates that immunoisolation devices containing endostatin-expressing cells are effective for the inhibition of the growth of melanoma and Ehrlich tumors.Macroencapsulation of engineered cells is therefore a reliable platform for the refinement of innovative therapeutic strategies against tumors.

À orientadora Dra. Lígia Ely Morganti Ferreira Dias pelo voto de confiança, incentivo, pela fundamental contribuição no desenvolvimento deste trabalho e pelos ensinamentos. Ao professor Dr. Roger Chammas pelos ensinamentos, pela ampla ajuda e colaboração, auxiliando enormemente na execução deste trabalho. À Patrícia Luiza Nunes da Costa pela grande ajuda e apoio na execução dos experimentos realizados na Faculdade de Medicina, da qual surgiu uma grande amizade. A todos os amigos da FMUSP que também estiveram presentes na execução deste. À Natália, Keli e Rosa, grandes amigas e colegas de bancada, pela imensa ajuda, pelos incentivos, lamentações, risadas e pela companhia no dia a dia ao longo de toda esta etapa. À Juliana e Camila pela presença, dicas, ajudas e grande amizade. Ao Daniel Perez e Elier Cristo pelas valiosas dicas. À "Neidinha" pelo auxílio e por todos os cuidados com os animais do biotério no IPEN e à Cláudia do biotério da Faculdade de Veterinária da Universidade de São Paulo. A todos os orientadores do Centro de Biotecnologia do IPEN que de alguma maneira contribuíram neste trabalho. Aos animais que contribuem para o avanço dos conhecimentos.