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 doselimiting 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;Rb lox/lox ;p107 Γ/Γ ;p53 lox/lox ). The effects of combined subconjunctival CBP (CBP subcon ) and systemic TPT (TPT syst ) were compared with the effects of combined TPT subcon and CBP syst. at clinically relevant dosages. RESULTS: Pharmacokinetic and tumor-response studies, including analyses of ocular and hematopoietic toxicity, revealed that CBP subcon /TPT syst was more effective and had fewer side effects than TPT subcon / CBP syst . 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.