Subconjunctival carboplatin and systemic topotecan treatment in preclinical models of retinoblastoma.
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;Rb(lox/lox);p107(-/-);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.
Nemeth
Katie M
KM
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
Federico
Sara
S
Carcaboso
Angel M
AM
Shen
Ying
Y
Schaiquevich
Paula
P
Zhang
Jiakun
J
Egorin
Merrill
M
Stewart
Clinton
C
Dyer
Michael A
MA
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D003228:Conjunctiva; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D019572:Retinal Neoplasms / Q000188:drug therapy*; D012175:Retinoblastoma / Q000188:drug therapy*; D019772:Topotecan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014792:Visual Acuity; D023041:Xenograft Model Antitumor Assays
D019772:Topotecan; D016190:Carboplatin
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