Retinoblastoma is the third most common form of
cancer in infants, and metastatic
retinoblastoma is lethal in approximately 90% of cases. Early detection and aggressive
therapy has resulted in a 95% probability of survival for
retinoblastoma patients in the United States. However, the United States only represents 3-4% of the
retinoblastoma cases worldwide. The majority of children diagnosed with
retinoblastoma each year live in developing countries where the probability of survival is closer to 50%. This difference in survival rates reflects poor early detection rates and limited resources for the aggressive
therapy necessary to treat
retinoblastoma and manage the side effects associated with broad-spectrum systemic
chemotherapy in young children. In order to have the most significant impact on
retinoblastoma treatment in the United States and worldwide, current efforts have focused on local delivery of targeted
chemotherapy. In this review, we summarize recent data showing that the p53 pathway is inactivated in 75% of
retinoblastoma patients due to extra copies of the MDM2 and MDMX genes. A small molecule inhibitor of MDM2 called
nutlin-3 can induce p53-mediated cell death in
retinoblastoma cells. Subconjunctival delivery of
nutlin-3 in preclinical models of
retinoblastoma confirmed the efficacy of this approach in vivo. The advantage of local application of targeted chemotherapeutic agents such as
nutlin-3 is that greater intraocular
drug concentrations can be achieved without the side effects associated with systemic broad-spectrum
chemotherapy. We propose that subconjunctival administration of targeted
chemotherapy may be the best treatment option for children with
retinoblastoma in the United States and throughout the developing world because it provides greater
tumor response without the costs and complications associated with current treatment protocols.