Topotecan combination chemotherapy in two new rodent models of retinoblastoma

Nikia A. Laurie, Jonathan K. Gray, Jiakun Zhang, Mark Leggas, Mary Relling, Merrill Egorin, Clinton Stewart, Michael A. Dyer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

Chemotherapy combined with laser therapy and cryotherapy has improved the ocular salvage rate for children with bilateral retinoblastoma. However, children with late-stage disease often experience recurrence shortly after treatment. To improve the vision salvage rate in advanced bilateral retinoblastoma, we have developed and characterized two new rodent models of retinoblastoma for screening chemotherapeutic drug combinations. The first model is an orthotopic xenograft model in which green fluorescent protein - or luciferase-labeled human retinoblastoma cells are injected into the eyes of newborn rats. The second model uses a replication-incompetent retrovirus (LIA-EE1A) encoding the E1A oncogene. Clonal, focal tumors arise from mouse retinal progenitor cells when LIA-EE1A is injected into the eyes of newborn p53-/- mice. Using these two models combined with pharmacokinetic studies and cell culture experiments, we have tested the efficacy of topotecan combined with carboplatin and of topotecan combined with vincristine for the treatment of retinoblastoma. The combination of topotecan and carboplatin most effectively halted retinoblastoma progression in our rodent models and was superior to the current triple drug therapy using vincristine, carboplatin, and etoposide. Vincristine had the lowest LC50 in culture but did not reduce tumor growth in our preclinical retinoblastoma models. Taken together, these data suggest that topotecan may be a suitable replacement for etoposide in combination chemotherapy for the treatment of retinoblastoma.

Original languageEnglish (US)
Pages (from-to)7569-7578
Number of pages10
JournalClinical Cancer Research
Volume11
Issue number20
DOIs
StatePublished - Oct 15 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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