In vivo efficacy of melanoma internal radionuclide therapy with a 131I-labelled melanin-targeting heteroarylcarboxamide molecule.

The development of alternative therapies for melanoma treatment is of great interest as long-term tumour regression is not achieved with new targeted chemotherapies on selected patients. We previously demonstrated that radioiodinated heteroarylcarboxamide ([131I]ICF01012) induced a strong anti-tumoural effect by inhibiting both primary tumour growth and dissemination process in a B16BL6 melanoma model. In our study, we show that a single injection of [131I]ICF01012 (ranging from 14.8 to 22.2 MBq) was effective and associated with low and transient haematological toxicity. Concerning pigmented organs, cutaneous melanocytes and skin were undamaged. In 30% of treated animals, no histological alteration of retina was observed, and in the remaining 70%, damages were restricted to the optic nerve area. Using the Medical Internal Radiation Dose methodology, we determined that the absorbed dose in major organs is very low (<4 Gy) and that a delivery of 30 Gy to the tumour is sufficient for an effective anti-tumoural response. Molecular analyses of treated tumours showed a strong radiobiological effect with a decrease in proliferation, survival and pro-angiogenic-related markers and an increase in tumour suppressor gene expression, melanogenesis and anti-angiogenic markers. All these features are in accordance with a tumour cell death mechanism that mainly occurs by mitotic catastrophe and provide a better understanding of in vivo anti-tumoural effects of [131I] radionuclide. Our findings raise [131I]ICF01012 a good candidate for disseminated melanoma treatment and strongly support transfer of [131I]ICF01012 to clinical trial.

Effects of bevacizumab (Avastin®) on the electroretinogram of isolated rat retina.

AIM: To evaluate the in vitro effects of bevacizumab (Avastin®) on the electroretinogram (ERG) in rats using a model of isolated perfused retina ERG recording. METHODS: Retinas were isolated from rat eyes and placed in a chamber continuously perfused with a nutrient solution. The ERG was recorded every 3 min. Once the ERG b-wave amplitude was at a steady state, bevacizumab was added at concentrations of 0.25 and 0.5 mg/ml to the perfusion medium for 3 h. RESULTS: We observed no effect on ERG amplitudes or kinetics when bevacizumab was added to the perfusion medium. In addition, we found no significant differences in the survival curves of the b-wave and PIII wave during the application of bevacizumab between bevacizumab-exposed retinas and control retinas. CONCLUSIONS: We demonstrate that bevacizumab has no in vitro toxic effects on the ERG of isolated perfused rat retina. Our study supports the retinal safety of bevacizumab with respect to retinal function.

Uptake and esterification of vitamin A by RCS rat retinal pigment epithelial cells in primary culture.

We investigated the capacity of Royal College of Surgeons (RCS) rat retinal pigment epithelial (RPE) cells to take up all-trans-retinol (ROL) (vitamin A) and to metabolize it into retinyl esters (RE). Cultures of RPE cells were established from RCS and control newborn rats. All-trans-ROL was delivered to the apical surface of the RPE monolayer. Retinoids were analyzed by high-performance liquid chromatography. The cellular retinol-binding protein type I (CRBP-I) was assessed by Western blotting. Before supplementation with ROL, RE were lower in RCS rats. After ROL supplementation, esters increased and reached values that were similar in the two strains, but the increase, expressed relative to the initial value, was higher in RCS rats. The uptake of ROL and the level of CRBP-I were greater in RCS rats. Our results provide evidence of a functional retinol esterifying enzyme in cultured RCS RPE cells and suggest that CRBP-I could play a role in the uptake and esterification of ROL in the RPE cells.