The Effects of Imatinib Mesylate in an Animal Model of Uveal Melanoma

Abstract

Purpose: : Imatinib mesylate (Gleevec) is a FDA approved compound that inhibits tyrosine kinase receptors as well as c-kit. Phosphorylation by protein tyrosine kinases is important in cellular signalling and can mediate major cellular processes such as proliferation, differentiation, apoptosis, attachment, and migration of malignant cells. Previous work reports indicate that 78% of uveal melanomas (UM) express c-kit and Gleevec inhibits proliferation and invasion of UM cell lines. The objective of this study was to investigate the in vivo effect of Gleevec in an animal model of UM.

Methods: : Twenty-six albino rabbits were injected with 1x10⁶ human UM cells (92.1) into the suprachoroidal space of the right eye. Animals were immunosuppressed using cyclosporin A throughout the 12-week experiment. The animals were divided into two groups of 13 animals each. The experimental group received Gleevec once daily by gavage while the control group received a placebo. One animal per group was sacrificed every week after the 2^nd week. Upon necropsy, organs were saved for histopathological examination. Cells from the primary tumors were recultured and tested in proliferation and invasion assays. A PCR Array was also used to investigate the differences in expression of 84 genes related to tumor metastasis.

Results: : In the treated group, 4 rabbits developed intraocular tumors, average largest tumor dimension (LTD) was 2.5mm and metastatic disease was seen in 5 animals. Comparatively, in the control group, 6 rabbits developed intraocular tumors, average LTD was 5.8mm and metastatic disease was seen in 6 animals. The recultured cells from the treated group showed lower proliferation rates (p<0.001) and were less invasive (p<0.001) than those from the control group. The PCR array showed different expression of genes related to metastatic disease. Notably, there was a 10-fold higher expression of KISS-1, a metastasis suppressor gene, in the treated group.

Conclusions: : The treatment with Gleevec correlated with fewer and smaller primary tumors as well as less metastatic disease. The previously demonstrated in vitro effects of Gleevec were confirmed in this animal model; lower proliferation and invasion rates were seen with recultured cells from the treated group. Interestingly, Gleevec increased the expression of the metastasis suppressor gene KISS-1; an action not previously attributed to Gleevec. These results justify the need for a clinical trial to investigate the response of UM patients to Gleevec.

Keywords: uvea • tumors • pathology: experimental