Subconjunctival carboplatin and systemic topotecan treatment in preclinical models of retinoblastoma

Abstract

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. 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 geneticmouse model of retinoblastoma ( ). The effects of combined subconjunctival CBP(CBPsubcon) and systemic TPT (TPTsyst) were compared with the effects of combined TPTsubcon and CBPsyst.at clinically relevant dosages. Pharmacokinetic and tumor-response studies, including analyses of ocular and hematopoietic toxicity, revealed that BPsubcon/TPTsyst was more effective and had fewer side effects than TPTsubcon/CBPsyst. 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 aclinical trial for children with this debilitating cancer.