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Updated: Aug 1, 2026
Using the BLT Humanized Mouse as a Stem Cell based Gene Therapy Tumor Model
Published on: December 18, 2012
Development, characterization and therapy of a disseminated model of childhood neuroblastoma in SCID mice
J Thompson1, S M Guichard, P J Cheshire
1Department of Molecular Pharmacology, St Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794, USA.
Purpose:
To develop a highly reproducible model of disseminated childhood neuroblastoma in mice to allow secondary evaluation of therapeutics against microscopic disseminated disease.
Methods:
CB17/Icr SCID were injected i.v. with 10(3) to 5 x 10(6) human NB-1691 neuroblastoma cells. NB-1691 cells were detected by PCR for synaptophysin and tyrosine hydroxylase in peripheral blood, and bone marrow. Therapeutic studies evaluated topotecan and vincristine as single agents or in combination. Topotecan was administered i.v. daily for 5 days on two consecutive weeks. Courses were repeated every 21 days for three cycles. Vincristine (1 mg/kg) was administered i.v. every 7 days for nine consecutive weeks. Treatment started 11-21 days after tumor cell inoculation.
Results:
Following injection of > or = 1 x 10(5) cells 100% of mice developed disease. Mice inoculated with 10(7) cells survived a median of 42 days. Survival time was a linear function of the cell inoculum. At autopsy, gross tumor was routinely detected in many organs in particular liver, ovaries, kidneys and adrenals. NB-1691 cells were detected by PCR in peripheral blood, and bone marrow. Immunohistochemical staining showed that lesions were strongly positive for synaptophysin, chromogranin A and negative for leukocyte common antigen. Topotecan (0.6 mg/kg) alone extended median survival from 44 days (controls) to 95 days. When treatment was started 21 days after inoculation of NB-1691 cells, topotecan extended median survival from 39 days (controls) to 91 and 99 days at dose levels of 0.3 and 0.6 mg/kg, respectively. Vincristine (1 mg/kg) extended survival by a median of 9.5 days. In combination with vincristine (1 mg/kg), median survival was increased to 141 days (topotecan 0.6 mg/kg) and 159 days (topotecan 1.0 mg/kg).
Conclusion:
This model of disseminated neuroblastoma is highly reproducible. As this model may more closely simulate childhood disease it may be a valuable adjunct in developing new approaches to advanced stage, poor prognosis neuroblastoma.
Insights
A reproducible mouse model for disseminated neuroblastoma was developed to test therapeutics. This model showed that topotecan and vincristine combination therapy significantly improved survival in mice with advanced neuroblastoma.
Area of Science:
- Oncology
- Preclinical Research
- Animal Models
Background:
- Neuroblastoma is a common childhood cancer.
- Disseminated neuroblastoma presents a significant therapeutic challenge.
- Evaluating novel therapeutics requires robust preclinical models.
Purpose of the Study:
- To create a highly reproducible mouse model of disseminated childhood neuroblastoma.
- To enable secondary evaluation of therapeutics against microscopic disseminated disease.
- To simulate advanced-stage, poor-prognosis neuroblastoma.
Main Methods:
- Intravenous injection of human NB-1691 neuroblastoma cells into CB17/Icr SCID mice.
- Detection of NB-1691 cells in peripheral blood and bone marrow using PCR.
- Therapeutic evaluation of topotecan and vincristine as single agents and in combination.
Main Results:
- 100% disease development with >= 1 x 10^5 cells; survival inversely correlated with cell inoculum.
- Gross tumors detected in multiple organs (liver, ovaries, kidneys, adrenals).
- Topotecan and vincristine combination therapy significantly extended median survival (up to 159 days).
Conclusions:
- The developed neuroblastoma model is highly reproducible.
- This model closely simulates childhood disseminated neuroblastoma.
- It serves as a valuable tool for developing new therapeutic strategies for advanced neuroblastoma.
