Metronomic administration of the drug GMX1777, a cellular NAD synthesis inhibitor, results in neuroblastoma regression and vessel maturation without inducing drug resistance
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
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.
Fibrosis, Tumor Stroma, Myofibroblast, Pericyte, Angiogenesis, Inflammation
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-120881DOI: 10.1002/ijc.25206ISI: 000277551100003PubMedID: 20112275OAI: oai:DiVA.org:uu-120881DiVA: diva2:304091
De två sista författarna delar sistaförfattarskapet2010-03-172010-03-172013-04-08Bibliographically approved