Experimental therapies of pigmented ocular tumors in transgenic mice

Purpose. The Tyr-Tag line of transgenic mice express SV40-Tag oncoprotein under control of the mouse tyrosinase gene 5′ flanking region. These mice develop pigmented intraocular tumors which arise in the posterior pole. In order to characterize these tumors based on response to therapy, the mice were treated with the chemotherapeutic agent dacarbazine (DTIC) and external beam irradiation in separate treatment protocols. Methods. Mice in the DTIC treatment protocol were randomized into 2 groups and treated with parenteral DTIC (100mg/kg/day) or saline control at age 8 weeks. The mice received 2 5-day cycles of therapy and were sacrificed 9 days post-treatment. Eye tumors were examined by light microscopy and tumor size was measured using digital image analysis. For the radiation protocol, the mice were randomized into 5 groups with 4 mice in each. Groups were treated with 0, 6, 12, 18 and 24 Gy of radiation which was administered in twice daily doses of 3 Gy each. The energy setting was 250kV and the field of radiation included the eyes, oropharynx and anterior margin of the frontal lobes. Mice were periodically monitored for signs of radiation toxicity and age at mortality was recorded for all animals. All eyes were fixed within 12 hours of death and examined by light microscopy. Results. The mice treated with DTIC were noted to have a 71% reduction in tumor size compared with controls which was highly significant (p = 0.008, two tailed t-Test). In the radiation protocol, relative risks were calculated using Cox proportional hazards and a dose dependent increase in survival was noted using Kaplan-Meier survival curves. A 60% decrease in risk of mortality was noted for each 10 Gy increase in radiation dose (p = 0.013). Conclusion: Pigmented intraocular tumors in Tyr-Tag transgenic mice are sensitive to treatment with parenteral dacarbazine. A dose-dependent increase in survival is noted when the eyes are irradiated.