Subconjunctival carboplatin and systemic topotecan treatment in preclinical models of retinoblastoma

Katie M. Nemeth, Sara Federico, Angel M. Carcaboso, Ying Shen, Paula Schaiquevich, Jiakun Zhang, Merrill Egorin, Clinton Stewart, Michael A. Dyer

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Background: The authors demonstrated previously that the combination of topotecan (TPT) and carboplatin (CBP) was more effective than current chemotherapeutic combinations used to treat retinoblastoma in an orthotopic xenograft model. However, systemic coadministration of these agents is not ideal, because both agents cause dose-limiting myelosuppression in children. Methods: To overcome the toxicity associated with systemic TPT and CBP, the authors explored subconjunctival delivery of TPT or CBP in an orthotopic xenograft model and in a genetic mouse model of retinoblastoma (Chx10-Cre;Rblox/lox;p107-/-;p53lox/lox). The effects of combined subconjunctival CBP (CBPsubcon) and systemic TPT (TPTsyst) were compared with the effects of combined TPT subcon and CBPsyst. at clinically relevant dosages. Results: Pharmacokinetic and tumor-response studies, including analyses of ocular and hematopoietic toxicity, revealed that CBPsubcon/ TPTsyst was more effective and had fewer side effects than TPT subcon/CBPsyst. Conclusions: For the first time, retinoblastoma was ablated and long-term vision was preserved in a mouse model by using a clinically relevant chemotherapy regimen. These results eventually may be translated into a clinical trial for children with this debilitating cancer.

Original languageEnglish (US)
Pages (from-to)421-434
Number of pages14
JournalCancer
Volume117
Issue number2
DOIs
StatePublished - Jan 15 2011

Keywords

  • carboplatin
  • retinoblastoma
  • topotecan
  • translational research

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    Nemeth, K. M., Federico, S., Carcaboso, A. M., Shen, Y., Schaiquevich, P., Zhang, J., Egorin, M., Stewart, C., & Dyer, M. A. (2011). Subconjunctival carboplatin and systemic topotecan treatment in preclinical models of retinoblastoma. Cancer, 117(2), 421-434. https://doi.org/10.1002/cncr.25574