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Q. Zhang, H. Yang, E. G. Van Meir, H. E. Grossniklaus; Small Molecule Hif Inhibitor Kcn1 Reduces Primary Ocular Melanoma and Hepatic Micrometastases in a Murine Ocular Melanoma Model. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5768.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the effect of a hypoxia inducible factor (HIF) small molecule inhibitor KCN1 in reducing the size of primary ocular melanoma and the number of hepatic micrometastases in a murine model of ocular melanoma.
The posterior compartments of the right eyes of C57BL6 mice were inoculated with 5 x 105 B16LS9 melanoma cells. There were two experimental groups (n=15) as follows: group 1, intraperitoneal injection of 12 µg KCN1 in 300 µl (60 mg/kg) of a 1:1 cremophor /ethanol formulation, starting at the 1st day, once per day until sacrifice; group 2, intraperitoneal injection of an equal volume of cremophor and ethanol. The right eyes were enucleated at the 7 th day to examine primary tumor growth, and the mice were sacrificed at the 28th day after inoculation to examine metastases to the liver. The histologic sections of right eyes and livers were obtained, the volumes of primary ocular tumors were evaluated using Image J and the numbers of hepatic micrometastases were counted.
The average size of primary ocular melanoma in group 1 treated with KCN1 was 73715958.25 ± 27869753 pixel3, comparing with 326443070.2 ± 126256136 pixel3 in group 2 with the treatment of cremophor and ethanol (p = 0.01). The number of hepatic micrometastases in mice treated with KCN1 versus cremophor and ethanol was 177.12 ± 60.01 and 298.12 ± 67.79 (p = 0.001). The livers showed increased interstitial liquid accumulation.
This study suggests that the small molecule HIF inhibitor KCN1 reduces both of the size of primary ocular melanoma and the number of hepatic micrometastases in a murine ocular melanoma model. This therapeutic response was associated with some side effect in the liver that needs further examination.Supported in part by NCI R01 CA126557, CA116804, NEI P30 EY06360 and an unrestricted grant from Research to Prevent Blindness, Inc.
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