Current and future strategies for the treatment of malignant brain tumors

Castro, María G.; Cowen, Rachel L.; Williamson, Ian; David, Anne; Jiménez-Dalmaroni, Maximiliano J.; Yuan, Xiangpeng; Bigliari, A; Williams, Judith C.; Hu, Jinwei; Löwenstein, Pedro R.

doi:10.1016/s0163-7258(03)00014-7

Cited by 160 publications

(107 citation statements)

References 251 publications

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“…All animal procedures were performed according to the practices of the Swedish Board of Animal Research and were approved by the Committee of Animal Ethics in LundMalm€ o. The GL261 mouse glioma cell line (GL-wt) 19 of C57Bl/6 origin was a kind gift from Dr. G. Safrany. The GL261 cell line was induced by intracerebral implantation of methylcholanthrene (MCA) pellets and later established as a permanent cell line.…”

Section: Animals and Cell Linesmentioning

confidence: 99%

Synergism between GM–CSF and IFNγ: Enhanced immunotherapy in mice with glioma

Smith

Janelidze

Visse

et al. 2006

Intl Journal of Cancer

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Glioblastoma multiforme is the most common malignant primary brain tumor and also one of the most therapy-resistant tumors. Because of the dismal prognosis, various therapies modulating the immune system have been developed in experimental models. Previously, we have shown a 37-70% cure in a rat glioma model where rats were peripherally immunized with tumor cells producing IFNc. On the basis of these results, we wanted to investigate whether a combination of GM-CSF and IFNc could improve the therapeutic effect in a mouse glioma model, GL261 (GL-wt). Three biweekly intraperitoneal (i.p.) immunizations with irradiated GM-CSF-transduced GL261 cells (GL-GM) induced a 44% survival in mice with intracranial glioma. While treatment of GLwt and GL-GM with IFNc in vitro induced upregulation of MHC I and MHC II on the tumor cells, it could not enhance survival after immunization. However, immunizations with GL-GM combined with recombinant IFNc at the immunization site synergistically enhanced survival with a cure rate of 88%. Tumors from mice receiving only 1 immunization on Day 10 after tumor inoculation were sectioned on Day 20 for analysis of leukocyte infiltration. Tumor volume was reduced and the infiltration of macrophages was denser in mice immunized with GL-GM combined with IFNc compared with that of both wildtype and nonimmunized mice. To our knowledge, this is the first study to demonstrate a synergy between GM-CSF and IFNc in experimental immunotherapy of tumors, by substantially increasing survival as well as inducing a potent anti-tumor response after only 1 postponed immunization. ' 2006 Wiley-Liss, Inc.

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Section: Animals and Cell Linesmentioning

confidence: 99%

Synergism between GM–CSF and IFNγ: Enhanced immunotherapy in mice with glioma

Smith

Janelidze

Visse

et al. 2006

Intl Journal of Cancer

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“…Completely removing the tumor surgically is nearly impossible because of the diffusive growth pattern of gliomas. The mean survival time after initial diagnosis is approximately 6-12 months with current therapies being unable to improve the poor outcome (Castro et al, 2003). Previous research indicates that these tumors have a tendency to recur soon after resection of the initial tumor mass.…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-mediated transfer of siRNA against MMP-2 mRNA results in impaired invasion and tumor-induced angiogenesis, induces apoptosis in vitro and inhibits tumor growth in vivo in glioblastoma

et al. 2008

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Invasive tumors, including gliomas, utilize proteinases to degrade extracellular matrix components and diffuse into the adjacent tissues or migrate toward distant ones. In addition, proteinase activity is required for the formation of new blood vessels within the tumor. Levels of the proteinase matrix metalloproteinase-2 (MMP-2) are highly increased in gliomas. In this study, we examined the effect of the downregulation of MMP-2 via adenovirus-mediated siRNA in gliomas. Here, we show that siRNA delivery significantly decreased levels of MMP-2 in the glioblastoma cell lines U-87 and U-251. U-87 and U-251 cells showed impaired invasion through matrigel as well as decreased migration from tumor spheroids transfected with adenoviral vector expressing siRNA against MMP-2. Additionally, tumor-induced angiogenesis was decreased in in vitro experiments in cultured human microvascular endothelial cells (HMECs) in serum-free conditioned medium of glioblastoma cells transfected with these constructs and co-cultures of glioma cells with HMECs. We also observed decreased angiogenesis in the in vivo dorsal skin-fold chamber model. Moreover, MMP-2 inhibition induced apoptotic cell death in vitro, and suppressed tumor growth of preestablished U-251 intracranial xenografts in nude mice. Thus, specific targeting of MMP-2 may provide a novel, efficient approach for the treatment of gliomas and improve the poor outcomes of patients with these brain tumors.

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“…Glioblastomas are among the most difficult malignant neoplasms to treat with median survival after diagnosis of about 12 months (Castro et al, 2003). One reason for failure to achieve long-term survival in patients with glioblastoma is attributed to high resistance to apoptosis after treatment with radiation or chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy

et al. 2006

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Transglutaminase 2 (TG2, a.k.a. tissue transglutaminase) belongs to a family of transglutaminase enzymes that stabilize proteins by affecting covalent crosslinking via formation of amide bonds. Cell surface TG2 is directly involved as an adhesive receptor in cell-extracellular matrix (ECM) interactions. Here, we show that TG2 activity is elevated in glioblastomas compared with non-neoplastic brain. Immunofluorescent studies showed increased staining of fibronectin colocalized with TG2 in the ECM in glioblastomas. In addition, small clusters of invading human glioblastoma cells present in non-neoplastic brain parenchyma secrete high levels of TG2 and fibronectin that distinguish them from normal brain stroma. Downregulation of TG2 in U87MG glioblastoma cells with RNAi demonstrated decreased assembly of fibronectin in the ECM. Treatment with KCC009 blocked the remodeling of fibronectin in the ECM in glioblastomas in both in vitro and in vivo studies. KCC009 treatment in mice harboring orthotopic glioblastomas (DBT-FG) sensitized the tumors to N,N 0 -bis(2-chloroethyl)-N-nitrosourea chemotherapy, as measured by reduced bioluminescence, increased apoptosis and prolonged survival. The ability of KCC009 to interfere with the permissive remodeling of fibronectin in the ECM in glioblastomas suggests a novel target to enhance sensitivity to chemotherapy directed not only at the tumor mass, but also invading glioblastoma cells.

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Current and future strategies for the treatment of malignant brain tumors

Cited by 160 publications

References 251 publications

Synergism between GM–CSF and IFNγ: Enhanced immunotherapy in mice with glioma

Synergism between GM–CSF and IFNγ: Enhanced immunotherapy in mice with glioma

Adenovirus-mediated transfer of siRNA against MMP-2 mRNA results in impaired invasion and tumor-induced angiogenesis, induces apoptosis in vitro and inhibits tumor growth in vivo in glioblastoma

Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy

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