Regression of orthotopic neuroblastoma in mice by targeting the endothelial and tumor cell compartments.
BACKGROUND
High-risk neuroblastoma has an overall five-year survival of less than 40%, indicating a need for new treatment strategies such as angiogenesis inhibition. Recent studies have shown that chemotherapeutic drugs can inhibit angiogenesis if administered in a continuous schedule. The aim of this study was primarily to characterize tumor spread in an orthotopic, metastatic model for aggressive, MYCN-amplified neuroblastoma and secondarily to study the effects of daily administration of the chemotherapeutic agent CHS 828 on tumor angiogenesis, tumor growth, and spread.


METHODS
MYCN-amplified human neuroblastoma cells (IMR-32, 2 x 10(6)) were injected into the left adrenal gland in SCID mice through a flank incision. Nine weeks later, a new laparotomy was performed to confirm tumor establishment and to estimate tumor volume. Animals were randomized to either treatment with CHS 828 (20 mg/kg/day; p.o.) or vehicle control. Differences between groups in tumor volume were analyzed by Mann-Whitney U test and in metastatic spread using Fisher's exact test. Differences with p < 0.05 were considered statistically significant.


RESULTS
The orthotopic model resembled clinical neuroblastoma in respect to tumor site, growth and spread. Treatment with CHS 828 resulted in tumor regression (p < 0.001) and reduction in viable tumor fraction (p < 0.001) and metastatic spread (p < 0.05) in correlation with reduced plasma levels of the putative tumor marker chromogranin A (p < 0.001). These effects were due to increased tumor cell death and reduced angiogenesis. No treatment-related toxicities were observed.


CONCLUSIONS
The metastatic animal model in this study resembled clinical neuroblastoma and is therefore clinically relevant for examining new treatment strategies for this malignancy. Our results indicate that daily scheduling of CHS 828 may be beneficial in treating patients with high-risk neuroblastoma.
Fuchs
Dieter
D
Department of Medical Cell Biology, Uppsala University, 75123 Uppsala, Sweden. dieter.fuchs@mcb.uu.se
Christofferson
Rolf
R
Stridsberg
Mats
M
Lindhagen
Elin
E
Azarbayjani
Faranak
F
D000818:Animals; D001344:Autopsy; D040501:Calgranulin A / Q000097:blood; D002451:Cell Compartmentation / Q000187:drug effects; D045744:Cell Line, Tumor; D003486:Cyanides / Q000633:toxicity; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology*; D005347:Fibroblasts / Q000187:drug effects; D006146:Guanidines / Q000633:toxicity; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009447:Neuroblastoma / Q000098:blood supply / Q000473:pathology* / Q000628:therapy*; D012074:Remission Induction; D012307:Risk Factors; D023041:Xenograft Model Antitumor Assays
D040501:Calgranulin A; D003486:Cyanides; D006146:Guanidines; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine