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Metronomic administration of the drug GMX1777, a cellular NAD synthesis inhibitor, results in neuroblastoma regression and vessel maturation without inducing drug resistance
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (christian sundberg)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Barnkirurgi/Christoffersson)
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2010 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 126, no 12, 2772-2789 p.Article in journal (Refereed) Published
Abstract [en]

High-risk neuroblastoma is a rapidly growing tumor with a survival rate below 50%. A new treatment strategy is to administer chemotherapeutic drugs metronomically, i.e. at lower doses and frequent intervals. The aim of the study was to investigate the effects of GMX1777, a chemotherapeutic drug affecting cellular energy metabolism, in a mouse model for high-risk neuroblastoma.Female SCID mice were injected s.c. with MYCN-amplified human neuroblastoma cells and randomized to either treatment with GMX1777 or vehicle. In some animals, treatment was discontinued allowing tumor relapse. Treatment response was evaluated using the Pediatric Preclinical Testing Program (PPTP). Immunohistochemistry and qRT-PCR was performed on tumor cryosections to investigate the microscopic and molecular changes in tumors in response to GMX1777.Despite an increase in vessel density, tumor regression and a high group response score according to PPTP criteria was induced by GMX1777 without inducing drug resistance. Treatment resulted in inhibition of tumor cell proliferation, vessel maturation, reduced hypoxia, increased infiltration of MHC class II negative macrophages and expansion of the non-vascular stromal compartment. Decreased stromal VEGF-A and PDGF-B mRNA in response to treatment together with the structural data suggest a "deactivation" or "silencing" of the tumor stroma as a paracrine entity.In conclusion, GMX1777 was highly efficient against high-risk neuroblastoma xenografts through modulation of both the tumor cell and stromal compartment.

Place, publisher, year, edition, pages
2010. Vol. 126, no 12, 2772-2789 p.
Keyword [en]
Fibrosis, Tumor Stroma, Myofibroblast, Pericyte, Angiogenesis, Inflammation
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-120881DOI: 10.1002/ijc.25206ISI: 000277551100003PubMedID: 20112275OAI: oai:DiVA.org:uu-120881DiVA: diva2:304091
Note

De två sista författarna delar sistaförfattarskapet

Available from: 2010-03-17 Created: 2010-03-17 Last updated: 2013-04-08Bibliographically approved
In thesis
1. Studies of Stroma Formation and Regulation in Human Pathological Conditions and in Experimental in vivo Models
Open this publication in new window or tab >>Studies of Stroma Formation and Regulation in Human Pathological Conditions and in Experimental in vivo Models
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fibrosis is a sequel of chronic inflammation and is defined as an excessive deposition of collagen that ultimately leads to organ dysfunction. To date there are no effective treatments for fibrosis. The main cell type involved in collagen deposition and organization is the myofibroblast.

In the first study we examined how myofibroblasts differentiate in human fibrotic conditions and in experimental animal models. Human tissues were stained with antibodies that recognize integrin receptors and in addition we also stained for α-SMA, a myofibroblast marker. We found a co-localization between these two markers in stromal cells and hypothesized that integrin α1 is important for the acquisition of the myofibroblast phenotype. To tests this hypothesis we used knockout animals for this integrin subunit. These animals showed a reduction of α-SMA positive fibroblasts, indicating that the α1 integrin subunit is required for proper myofibroblast differentiation.

In the second study we used a neuroblastoma tumor model to study tumour growth when a drug targeting the synthesis of cellular NAD was administered. In treated animals an expansion of the nonvascular stroma was observed compared to controls. Normalization of the vasculature was observed in treated tumors together with a decrease in hypoxia. Moreover, this was followed by a decrease in stromal PDGF-B and VEGF expression, suggesting a deactivation of the stroma.

In the third study the effects of over-expression of the two pro-fibrotic growth factors TGF-β and PDGF-B in skin was evaluated. We observed that both growth factors induced fibrosis. Over time, a decrease in blood vessel density was observed in both treatment groups. Both factors also stimulated an expansion of the connective tissue cell population originating from the microvascular pericyte, but the phenotype of these cells differed in the different treatments with regards to expression of markers. Furthermore, in tissue over-expressing PDGF-B but not TGF-β, the fibrotic process was partially reversible.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 41 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 541
Keyword
Fibrosis, Tumor Stroma, Myofibroblast, Pericyte, Angiogenesis, Inflammation, adenovirus
National Category
Cell and Molecular Biology Cell and Molecular Biology
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:uu:diva-120688 (URN)978-91-554-7754-7 (ISBN)
Public defence
2010-04-28, B22, Uppsala biomedicinska centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
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Available from: 2010-04-07 Created: 2010-03-15 Last updated: 2010-04-07

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Rodriguez, AlejandroChristofferson, RolfSundberg, Christian

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Department of Medical Cell BiologyDepartment of Medical Biochemistry and MicrobiologyDepartment of Women's and Children's Health
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