Target therapy is a type of treatment that use drugs to target specific molecules and interfere the progression of disease. Target therapy is expected to be more effective and specific than older treatment modalities and less harmful to normal cells. Target therapy has been applied in ophthalmology and also well-known for its ocular side effect due to systemic target therapy in other fields. In the following we will brief on the mechanisms of target therapy in ocular diseases and the ocular side effects due to systemic target therapy.
I. Target therapy in ocular diseases: mechanism
◎ Anti-vascular endothelial growth factor (anti-VEGF): VEGF increases vascular permeability and vasodilation required in physiological processes like lesion healing, but is also involved in pathological neovascularization found in ocular diseases. Ocular application includes retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration
◎Calcineurin inhibitors (cyclosporine and tacrolimus): The drug binds to cyclophilin, and this complex inhibits calcineurin, ultimately preventing it from activating the transcription product of interleukin-2 (IL-2). Since IL-2 is necessary for T-cell replication, cyclosporine is a potent inhibitor of T-cell proliferation and inhibits T-cell-mediated immune responses. It has been used to treat ocular inflammation.
II. Ocular side effect due to systemic target therapy:
◎ Epidermal growth factor receptor (EGFR) inhibitors: Agents targeting this pathway include EGFR tyrosine kinase inhibitors (erlotinib and gefitinib), and the EGFR monoclonal antibodies (cetuximab and panitumumab), which are used to treat colorectal and head and neck cancers. The most common ocular adverse events noted were conjunctivitis, blepharitis, dry eye, and visual disturbances (blurred vision, hemianopia, and photophobia). In addition, corneal erosions, superficial punctate keratopathy and trichomegaly have also been reported.
◎BCR-ABL and C-KIT inhibitors: Imatinib mesylate, a selective inhibitor of the Bcr-Abl, c-Kit, and platelet-derived growth factor receptor tyrosine kinases, is used for the treatment of chronic myelogenous leukemia and GI stromal tumors. Periorbital edema, epiphoria, optic neuritis, and cystoid macular edema have been described as ocular toxicities.
◎Tamoxifen: Tamoxifen is an oral selective estrogen receptor modulator used in hormone receptor–positive early and advanced breast cancer. The most common toxicities related to tamoxifen are white to yellow intraretinal crystalline deposits associated with macular edema and clinical symptoms of central visual field loss. Tamoxifen is thought to penetrate the choriocapillary barrier, triggering glycosaminoglycan deposition between the nerve fiber and inner plexiform layers of the retina. In addition, tamoxifen may inhibit lysosomal proteases required for phagocytosis by the retinal pigment epithelium.
◎Bisphosphonates: Bisphosphonates inhibit the differentiation of osteoclast precursors and are used to prevent skeletal-related events in patients with multiple myeloma, breast cancer, and prostate cancer. Ophthalmologic toxicities reported include conjunctivitis, uveitis, scleritis, episcleritis, eyelid edema, optic neuritis, and periorbital edema. Pamidronate and zoledronic acid share similar structure to several T-cell ligands that activate antigen receptors and induce cytokine release. This suggests a possible immune-mediated mechanism for bisphosphonate-induced ophthalmologic toxicities.
◎Anti-cytotoxic T cell lymphocyte antigen-4 antibody: Cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) regulates T-cell–mediated adaptive immunity. Ipilimumab is a humanized monoclonal antibody against CTLA-4 that overcomes CTLA-4– mediated T-cell suppression to enhance the immune response against tumors. Ocular toxicity reported included uveitis, iritis, and papillitis. Considering its mechanism of action, the ocular adverse effects of ipilimumab may be mediated by loss of immune tolerance.