Development, characterization and therapy of a disseminated model of childhood neuroblastoma in SCID mice

Purpose: To develop a highly reproducible model of disseminated childhood n euroblastoma 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 w ere detected by PCR for synaptophysin and tyrosine hydroxylase in periphera l blood, and bone marrow. Therapeutic studies evaluated topotecan and vincr istine as single agents or in combination. Topotecan was administered i.v. daily for 5 days on two consecutive weeks. Courses were repeated every 21 d ays for three cycles. Vincristine (1 mg/kg) was administered i.v. every 7 d ays for nine consecutive weeks. Treatment started 11-21 days after tumor ce ll inoculation. Results: Following injection of greater than or equal to 1x 10(5) cells 100% of mice developed disease. Mice inoculated with 10(7) cell s 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 organ s in particular liver, ovaries, kidneys and adrenals. NB-1691 cells were de tected by PCR in peripheral blood, and bone marrow. Immunohistochemical sta ining showed that lesions were strongly positive for synaptophysin, chromog ranin A and negative for leukocyte common antigen. Topotecan (0.6 mg/kg) al one extended median survival from 44 days (controls) to 95 days. When treat ment was started 21 days after inoculation of NB-1691 cells, topotecan exte nded median survival from 39 days (controls) to 91 and 99 days at dose leve ls of 0.3 and 0.6 mg/kg, respectively. Vincristine (1 mg/kg) extended survi val by a median of 9.5 days. In combination with vincristine (1 mg/kg), med ian 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 d isease it may be a valuable adjunct in developing new approaches to advance d stage, poor prognosis neuroblastoma.