Abstract
The ruthenium-based photosensitizer (PS) TLD1433 has completed a phase I clinical trial for photodynamic therapy (PDT) treatment of bladder cancer. Here, we investigated a possible repurposing of this drug for treatment of conjunctival melanoma (CM). CM is a rare but often deadly ocular cancer. The efficacy of TLD1433 was tested on several cell lines from CM (CRMM1, CRMM2 and CM2005), uveal melanoma (OMM1, OMM2.5, MEL270), epidermoid carcinoma (A431) and cutaneous melanoma (A375). Using 15 min green light irradiation (21 mW/cm2, 19 J.cm−2, 520 nm), the highest phototherapeutic index (PI) was reached in CM cells, with cell death occurring via apoptosis and necrosis. The therapeutic potential of TLD1433 was hence further validated in zebrafish ectopic and newly-developed orthotopic CM models. Fluorescent CRMM1 and CRMM2 cells were injected into the circulation of zebrafish (ectopic model) or behind the eye (orthotopic model) and 24 h later, the engrafted embryos were treated with the maximally-tolerated dose of TLD1433. The drug was administrated in three ways, either by (i) incubating the fish in drug-containing water (WA), or (ii) injecting the drug intravenously into the fish (IV), or (iii) injecting the drug retro-orbitally (RO) into the fish. Optimally, four consecutive PDT treatments were performed on engrafted embryos using 60 min drug-to-light intervals and 90 min green light irradiation (21 mW/cm2, 114 J.cm−2, 520 nm). This PDT protocol was not toxic to the fish. In the ectopic tumour model, both systemic administration by IV injection and RO injection of TLD1433 significantly inhibited growth of engrafted CRMM1 and CRMM2 cells. However, in the orthotopic model, tumour growth was only attenuated by localized RO injection of TLD1433. These data unequivocally prove that the zebrafish provides a fast vertebrate cancer model that can be used to test the administration regimen, host toxicity and anti-cancer efficacy of PDT drugs against CM. Based on our results, we suggest repurposing of TLD1433 for treatment of incurable CM and further testing in alternative pre-clinical models.
Highlights
Conjunctival melanoma (CM) is a rare but often deadly ocular disease that arises from mutated melanocytes, the melanin-producing cells in the conjunctiva [1]
We propose that TLD1433 remained longer in the interstitial fluid at the injection site after RO injection, reaching a higher effective concentration to inhibit conjunctival melanoma (CM) cells grown in the same area
The Ru-based photodynamic therapy (PDT) sensitizer TLD1433 is very active in eye melanoma cell lines, where green light activation provokes cell death via apoptosis and necrosis
Summary
Conjunctival melanoma (CM) is a rare but often deadly ocular disease that arises from mutated melanocytes, the melanin-producing cells in the conjunctiva [1]. Conjunctival melanoma is increasing [2]. Efficient treatment for this disease has not yet been developed and the side-effects caused by present treatments are severe [3]. Lymph node metastases often develop in spite of a seemingly effective treatment of the local tumor, and may lead to further spreading [4,5,6]. Mutations in BRAF and NRAS genes lead to constitutive activation of the MAPK/ERK signalling pathway, which promotes CM proliferation and survival [6,7,8,9]
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