Combretastatin A-4 prodrug in the treatment of a murine model of retinoblastoma.
OBJECTIVE
To evaluate the effect of subconjunctival injections of combretastatin A-4 phosphate (CA-4P) prodrug treatment on tumor vasculature and growth in an animal model of hereditary retinoblastoma.


METHODS
Twenty-four, 12-week-old simian virus-40 T-antigen-positive mice received six subconjunctival CA-4P injections at doses of 0.5, 1.0, 1.5, and 2.0 mg delivered at 72-hour intervals to the right eye only. Six control animals received placebo treatment. All animals underwent serial ophthalmic evaluations and were euthanatized at 16 weeks of age, and eyes were obtained for histopathologic examination. Eyes were graded for presence or absence of tumor, delay of tumor growth, and intratumoral vascularity.


RESULTS
The use of subconjunctivally injected CA-4P prodrug induced an extensive, dose-dependent decrease in microvessel density and led to significant tumor reduction in treated eyes compared with the placebo control (P <0.001). No evidence of corneal, lenticular, choroidal, or retinal toxicity was observed by histopathologic evaluation.


CONCLUSIONS
Subconjunctival delivery of CA-4P is associated with extensive dose-dependent reduction in blood vessel count in this murine model of retinoblastoma. A combination treatment of retinoblastoma incorporating CA-4P may allow enhanced tumor reduction enabling a decrease in standard treatment doses of both chemotherapy and external beam radiotherapy.
Escalona-Benz
Erika
E
Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami, Miami, Florida 33101, USA.
Jockovich
Maria-Elena
ME
Murray
Timothy G
TG
Hayden
Brandy
B
Hernandez
Eleut
E
Feuer
William
W
Windle
Jolene J
JJ
D000818:Animals; D000952:Antigens, Polyomavirus Transforming; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003228:Conjunctiva; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007267:Injections; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D011355:Prodrugs / Q000627:therapeutic use*; D019572:Retinal Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D012175:Retinoblastoma / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D013267:Stilbenes / Q000627:therapeutic use*
D000952:Antigens, Polyomavirus Transforming; D000970:Antineoplastic Agents; D011355:Prodrugs; D013267:Stilbenes; C058728:fosbretabulin