title: Topotecan combination chemotherapy in two new rodent models of retinoblastoma.
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-E(E1A)) encoding the E1A oncogene. Clonal, focal tumors arise from mouse retinal progenitor cells when LIA-E(E1A) 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.
authors.affiliation: Department of Developmental Neurobiology and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Nikia A
authors.initials: NA
authors.lastname: Laurie
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Gray
authors.forename: Jiakun
authors.initials: J
authors.lastname: Zhang
authors.forename: Mark
authors.initials: M
authors.lastname: Leggas
authors.forename: Mary
authors.initials: M
authors.lastname: Relling
authors.forename: Merrill
authors.initials: M
authors.lastname: Egorin
authors.forename: Clinton
authors.initials: C
authors.lastname: Stewart
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dyer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005047:Etoposide / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D005123:Eye / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D019572:Retinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012175:Retinoblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D019772:Topotecan / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D014750:Vincristine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014750:Vincristine; D005047:Etoposide; D019772:Topotecan; D016190:Carboplatin