Abstract
Despite aggressive surgery and post-operative radiation and chemotherapy, the prognosis is poor for glioblastoma patients. Antiangiogenic therapy with compounds such as endostatin could delay the onset of relapse. However, the short systemic half-life of this proteins as well as the blood-brain barrier makes the use of this therapy difficult for brain cancer patients. The aim of this project is to develop and implant genetically engineered producer cells secreting endostatin that are encapsulated in calcium cross-linked alginate gel beads. Encapsulation of cells within alginate gels has a potential as a sustained release system in addition to the fact that the encapsulation technology protects the cells from rejection by the immune system. Human embryonal kidney 293 cells have been transfected with the gene for endostatin. These cells have been encapsulated in calcium cross-linked alginate gels and optimized for the secretion of endostatin. Alginate gel beads implanted into rat brain have shown only a moderate loss in cell viability but extended endostatin release for periods of up to 12 months. Visualization of the anti-angiogenic effect on C6 rat glioma growth, tumor vasculature and microhemodynamics has been demonstrated by using intravital video microscopy. The data indicates that endostatin greatly affects tumor-associated microcirculation but does not appear to affect normal microcirculation. The local delivery of endostatin seems to specifically affect tumor-associated microvessels by reduction of the vessel density, diameter and functionality. Tumor cell migration and invasion was greatly reduced in the endostatin treated animals.
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References
Bjerkvig R, Read TA, Vajkoczy P, Aebischer P, Pralong W, Platt S, Brearley M, Hagen A, Dornish M (2001) In situ delivery of anti-angiogenic proteins by genetically engineered producer cells encapsulated in alginate gels: An EU 5th Framework Quality of Life project. Proc AACR-NCI-EORTC Int Conf 2–3
Eder JP, Supko JG, Clark JW, Puchalski TA, Garcia-Carbonero R, Ryan DP, Shulman LN, Proper J, Kirvan M, Rattner B, Connors S, Keogan MT, Janicek MJ, Fogler WE, Schnipper L, Kinchla N, Sidor C, Phillips E, Folkman J, Kufe DW (2002) Phase I clinical trial of recombinant human endostatin administered as s short intravenous infusion repeated daily. J Clin Oncol 20: 3772–3784
Ferlay J, Bray F, Pisani P, Parkin DM (2001) GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence Worldwide. Version 1.0, IARC CancerBase No 5. Lyon, IARCPress
Hagen A, Melvik JE, Skaugrud Ø Dornish M (2001) Biostructures of Ultrapure alginate for Tissue Engineering, Directed Drug Delivery and Cell Encapsulation Applications. Proc Amer Assoc. Cancer Res 42: 375
Herbst RS, Hess KR, Tran HT, Tseng JE, Mullani NA, Charnsangavej C, Madden T, Davis DW, McConkey DJ, O’Reilly MS, Ellis LM, Pluda J, Hong WK, Abbruzzese JL (2002) Phase I study of recombinant human endostatin in patients with advanced solid tumors. J Clin Oncol 20: 3792–3803
Joki T, Machluf M, Atala A, Zhu J, Seyfried NT, Dunn IF, Abe T, Carroll RS, Black PM (2001) Continuous release of endostatin from microencapsulated engineered cells for tumor therapy. Nat Biotechnol 19: 35–39
Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nature Reviews 2: 727–739
Kisker O, Becker CM, Prox D, Fannon M, D’Amato R, Flynn E, Fogler WE, Sim BKL, Alfred EN, Pirie-Shepherd SR, Folk-man J (2001) Continuous administration of endostatin by intra-peritoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenograft tumor model. Cancer Res 61: 7669–7674
Klokk TI, Melvik JE (2002) Controlling the size of alginate gel beads by use of a high electrostatic potential. J Microencapsulatoin 19: 415–424
Levin VA, Sheline GE, Gutin PH (1989) Neoplasms of the central nervous system. In: DeVita VT, Hellman S, Rosenberg SA (eds) Cancer principles and practice of oncology. JP Lippincott Co, Philadelphia, pp 1557–1611
Levin V (1994) Present and future prospects for the chemotherapy of gliomas. In: Banzet P, Holland JF, Khayat D, Weil M (eds) Cancer treatment — an update. Springer, Paris, pp 66–69
Lim F, Sun AM (1980) Microencapsulated islets as bioartificial endocrine pancreas. Science 210: 908–910
Marshall E (2002) Setbacks for endostatin. Science 295: 2198–2199
O’Reilly MN, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 88: 277–285
Read TA, Stensvaag V, Videnes H, Ulvestad E, Bjerkvig R, Thorsen F (1999) Cells encapsulated in alginate: A potential system for delivery of recombinant proteins to malignant brain tumours. Int J Devel Neurosci 17: 653–663
Read TA, Farhadi M, Holtan S, Olsen BR, Hurthy P, Bjerkvig R, Vajkoczy P (2001) Intravital microscopy reveals novel anti-vascular and anti-tumour effects of endostatin delivered locally by alginate encapsulated cells. Cancer Res 61: 6830–6837
Read TA, Sorensen DR, Mahesparan R, Enger PO, Timpl R, Olsen BR, Hjelstuen MHB, Haraldseth O, Bjerkvig R (2001) Local endostatin treatment of gliomas administered by micro-encapsulated producer cells. Nature Biotech 19: 29–34
Rokstad AM, Holtan S, Strand B, Steinkjer B, Ryan L, Kulseng B, Skjak-Braek G, Espevik T (2002) Microencapsulation of cells producing therapeutic proteins optimizing cell growth and secretion. Cell Transplant 11: 313–324
Smidsrod O, Skják-Bræk G (1990) Alginate as immobilization matrix for cells. Trends in Biotechnology 8: 71–78
Visted T, Westphal HR, MacDonald NJ, Sim KL, Bjerkvig R (2000) Release of angiostatin from alginate-encapsulated producer cells; a new approach for the treatment of malignant brain tumors. Proc Amer Assoc Cancer Res 41: 258
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Bjerkvig, R. et al. (2003). Cell therapy using encapsulated cells producing endostatin. In: Westphal, M., Tonn, JC., Ram, Z. (eds) Local Therapies for Glioma Present Status and Future Developments. Acta Neurochirurgica Supplements, vol 88. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6090-9_19
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DOI: https://doi.org/10.1007/978-3-7091-6090-9_19
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