# Diabetic Retinopathy and Ocular Melanoma: How Far We Are?
## 4 Uveal Melanoma, Angiogenesis and Anti-Angiogenic Therapy
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**Drug** & **Studies/Observations** \\ \hline Bevacizumab & [PERSON] et al. proved that in ocular melanoma bevacizumab allows suppression of primary tumour growth, reduction of liver micrometastases and decreased VEGF levels [162]. \\ [PERSON] et al. observed that in vitro uveal melanoma cell proliferation did not occur, but in vivo, the use of bevacizumab caused greater intraocular tumour growth, especially under hypoxic conditions. With treatment, anterior chamber and tumour bleeding were observed in the eyes, increasing microvascular permeability due to induced VEGF expression. It is thought to be a consequence of an adaptive or evasive tumour response [40]. \\ Sorafenib & Sorafenib inhibits VEGFR. [PERSON] et al. proved that after sorafenib therapy there is an inhibition of tumour growth and metastasis [223]. In patients with metastatic cutaneous melanoma, sorafenib monotherapy has not shown significant antitumor activity [224]. \\ [PERSON] et al. compared the treatment of patients with metastatic melanoma (not including uvea) with carboplatin, paclitaxel and sorafenib or placebo, where the results of the phase 3 study showed no relevance to overall survival [40]. \\ \hline Sunitinib & Sunitinib also inhibits VEGFR [225]. A preclinical phase 2 study demonstrated the benefit of sunitinib monotherapy in patients with advanced metastatic melanoma [40]. \\ \hline \hline \end{tabular}
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Table 1: Summary of anti-angiogenic agents and their effect on tumour growth and metastases in the ocular melanoma. There are studies based on cutaneous metastatic melanoma, uveal melanoma and some only with patients with developing ocular melanoma-related metastasis to investigate bevacizumabb, sorafenibb and sunitinibb as a single agent or in combination with other regimes. Another point contributing to uveal melanoma development is the concept of immune privilege. First described in animal eyes, this mechanism of immunoregulation can be modulated by the tumour microenvironment as an escape to the immune system [226]. tryptophan, one of the essential amino acids obtained from diet, seems to have a particular relation with the evolution of various tumour types, among which is uveal melanoma. Initially, it was stated that in normal conditions, tryptophan could be converted into serotonin and melatonin and, in pathological conditions, to kynureines, a group of tryptophan metabolites. Unlike melatonin, and some of its derivatives, which has been shown to possess anti-proliferative activity in a uveal melanoma cell line, serotonin and kynureines did not possess that activity, and thus did not control tumoural growth [227]. It is now known that kynureine and other tryptophan metabolites possess anti-micrbial activity but also show immunosuppressive potential, the point of interest in uveal melanoma progression. These metabolites are produced by the kynureine pathway, which is deeply involved in the immune privilege. This pathway starts with tryptophan and is limited by tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase 1/2 (IDO1 or IDO2) [226], enzymes that are expressed in various tumours. The first aspect concerning these enzymes and kynureine pathway is their activity and consequent tryptophan depletion. This amino acid is required for T cell function, growth and proliferation, and therefore, the lack of tryptophan limits the action of T cells, as for example natural killer T cells, preventing tumour rejection by specific T cells. In the case of IDO, its immunosuppressive and regulatory activity allow the organism to control infections. It is also involved in the survival of transplanted allografts and, in pregnancy, prevents maternal T cells from rejecting the fetus in response to IDO produced by fetal trophoblast cells. Concerning the eye, IDO has been found in various locations (iris, lens, retina, cornea, ciliary body) and intervened in the protection against UV radiation, through the formation of UV filters based on tryptophan and antioxidant defence [228].