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Regression of orthotopic neuroblastoma in mice by targeting the endothelial and tumor cell compartments.

Fuchs D, Christofferson R, Stridsberg M, Lindhagen E, Azarbayjani F - J Transl Med (2009)

Bottom Line: Differences with p < 0.05 were considered statistically significant.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Cell Biology, Uppsala University, 75123 Uppsala, Sweden. dieter.fuchs@mcb.uu.se

ABSTRACT

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.

Conclusion: 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.

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Representative morphology and vessel profile in orthotopic NB xenografts. Vehicle-treated tumors (control) contained a larger number of small vessels (stained in brown) (A, C) compared to CHS 828 (20 mg/kg/day; p.o.) treated tumors (B, D-E) already 10 days after randomization. Vessels of control tumors had a thin endothelial cell lining (brown) (A, C). CHS 828 treated tumors revealed vessels only partly surrounded by endothelial cells (arrowheads) (B, D-E) or endothelial cells detaching from the basement membrane (arrows) (E). C and D are magnifications of A and B, respectively. Bandeiraea simplicifolia-1 (BS-1) lectin staining (brown); bar = 40 μm.
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Figure 5: Representative morphology and vessel profile in orthotopic NB xenografts. Vehicle-treated tumors (control) contained a larger number of small vessels (stained in brown) (A, C) compared to CHS 828 (20 mg/kg/day; p.o.) treated tumors (B, D-E) already 10 days after randomization. Vessels of control tumors had a thin endothelial cell lining (brown) (A, C). CHS 828 treated tumors revealed vessels only partly surrounded by endothelial cells (arrowheads) (B, D-E) or endothelial cells detaching from the basement membrane (arrows) (E). C and D are magnifications of A and B, respectively. Bandeiraea simplicifolia-1 (BS-1) lectin staining (brown); bar = 40 μm.

Mentions: Daily administration of CHS 828 altered vascular parameters as determined by stereology (Table 4). Vessel density, vessel length density (Lv), and surface density (Sv) were significantly reduced in these tumors compared to vehicle-treated controls. The vessel volumetric density (Vv) was reduced in CHS 828-treated tumors but the reduction was not significant (p = 0.09) (Table 4). A single layer of endothelial cells encircled the lumen of vessels in untreated tumors (Figure 5A and Figure 5C) whereas in CHS 828 treated tumors, endothelial cells were frequently not entirely surrounding the lumen (Figure 5B, D, E) or detaching from the basement membrane (Figure 5E). Despite the incomplete endothelial cell lining, only 1/13 (8%) of the animals treated with CHS 828 for 10 days showed intra-tumor hemorrhage, defined as erythrocytes outside vessel lumen, whereas 9/9 (100%) of the tumors in control animals had erythrocytes in the tumor tissue.


Regression of orthotopic neuroblastoma in mice by targeting the endothelial and tumor cell compartments.

Fuchs D, Christofferson R, Stridsberg M, Lindhagen E, Azarbayjani F - J Transl Med (2009)

Representative morphology and vessel profile in orthotopic NB xenografts. Vehicle-treated tumors (control) contained a larger number of small vessels (stained in brown) (A, C) compared to CHS 828 (20 mg/kg/day; p.o.) treated tumors (B, D-E) already 10 days after randomization. Vessels of control tumors had a thin endothelial cell lining (brown) (A, C). CHS 828 treated tumors revealed vessels only partly surrounded by endothelial cells (arrowheads) (B, D-E) or endothelial cells detaching from the basement membrane (arrows) (E). C and D are magnifications of A and B, respectively. Bandeiraea simplicifolia-1 (BS-1) lectin staining (brown); bar = 40 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2667491&req=5

Figure 5: Representative morphology and vessel profile in orthotopic NB xenografts. Vehicle-treated tumors (control) contained a larger number of small vessels (stained in brown) (A, C) compared to CHS 828 (20 mg/kg/day; p.o.) treated tumors (B, D-E) already 10 days after randomization. Vessels of control tumors had a thin endothelial cell lining (brown) (A, C). CHS 828 treated tumors revealed vessels only partly surrounded by endothelial cells (arrowheads) (B, D-E) or endothelial cells detaching from the basement membrane (arrows) (E). C and D are magnifications of A and B, respectively. Bandeiraea simplicifolia-1 (BS-1) lectin staining (brown); bar = 40 μm.
Mentions: Daily administration of CHS 828 altered vascular parameters as determined by stereology (Table 4). Vessel density, vessel length density (Lv), and surface density (Sv) were significantly reduced in these tumors compared to vehicle-treated controls. The vessel volumetric density (Vv) was reduced in CHS 828-treated tumors but the reduction was not significant (p = 0.09) (Table 4). A single layer of endothelial cells encircled the lumen of vessels in untreated tumors (Figure 5A and Figure 5C) whereas in CHS 828 treated tumors, endothelial cells were frequently not entirely surrounding the lumen (Figure 5B, D, E) or detaching from the basement membrane (Figure 5E). Despite the incomplete endothelial cell lining, only 1/13 (8%) of the animals treated with CHS 828 for 10 days showed intra-tumor hemorrhage, defined as erythrocytes outside vessel lumen, whereas 9/9 (100%) of the tumors in control animals had erythrocytes in the tumor tissue.

Bottom Line: Differences with p < 0.05 were considered statistically significant.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Cell Biology, Uppsala University, 75123 Uppsala, Sweden. dieter.fuchs@mcb.uu.se

ABSTRACT

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus