Abstract

Objectives: To tests the sensitivity of Y79 retinoblastoma cell lines to high doses of ascorbate, in vitro, and compare its effects with those of some chemotherapeutic agents routinely employed in the treatment of retinoblastoma.Methods: Y79 retinoblastoma cells have been exposed to increasing doses of either sodium ascorbate (SA) or Melphalan (MEL), to define a dose-response curve around the peak plasma concentrations reached by both chemicals when administered according to the existing therapeutic procedures and protocols. The assessment of cell number and viability was performed, before and after exposure, with both the manual (Trypan Blue Exclusion Test) and automated (flow cytometry) methods. Fluorescence microscopy and direct observation of cells in culture, with inverted microscope, were also performed.Results: Y79 cells are highly sensitive to the cytotoxic effect of SA, with cell viability reduced of over 90% in some experiments. As reported in the literature, this effect is directly cytotoxic and most probably mediated by acute oxidative stress on different cellular components. The same does not apply to Melphalan which, at the doses commonly used for therapeutic purposes, did not show any significant effect on cell viability, in vitro.Conclusion: To our knowledge, this is the first report showing that high doses of SA can actively kill retinoblastoma cells in vitro. While it is not surprising for SA, to show direct cytotoxic effect on tumor cells, the data reported herein represent the first evidence in favor of the possible clinical use of high doses of intravenous SA, to treat children affected by retinoblastoma. Given the many advantages of SA over the chemotherapeutic agents commonly employed to treat cancer (including its almost total absence of toxic or side effects, and its exclusive specificity for cancer cells), it is reasonable to assume, from the data reported herein, that the high doses of intravenous ascorbate, have the potential to represent a real revolution in the treatment of retinoblastoma.

Highlights

  • Retinoblastoma is a rare intraocular tumor affecting the retina of young children and infants [1]

  • Even if the dose of Melphalan (MEL) used in each therapeutic procedure is relatively low, doses greater than 0.48 mg/kg, such as those given for bilateral tandem infusion, are still associated with an increased risk of neutropenia, and some authors suggest that Superselective Ophthalmic Artery Infusion (SOAI) combination chemotherapy be used rather than MEL alone [13,14,20]

  • It is very well known that Trypan Blue Exclusion Test, is a robust direct test to measure cell viability, in which dead cells can be detected, because, by incorporating the blue dye, their cytoplasm stains blue, when observed under microscopy

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Summary

Introduction

Retinoblastoma is a rare intraocular tumor affecting the retina of young children and infants [1]. In an effort to improve drug delivery to the tumor, and simultaneously reduce systemic toxicity, Superselective Ophthalmic Artery Infusion (SOAI) of chemotherapeutic agents [8], has been more recently developed and become a well established, though still controversial [9,10] treatment for more advanced retinoblastoma, leading to a dramatic increase in the preservation rate of affected eyes [11,12,13,14,15]. Even if the dose of Melphalan (MEL) used in each therapeutic procedure is relatively low, doses greater than 0.48 mg/kg, such as those given for bilateral tandem infusion, are still associated with an increased risk of neutropenia, and some authors suggest that SOAI combination chemotherapy be used rather than MEL alone [13,14,20] The SOAI of Melphalan (SOAIM) has become one of the preferred therapeutic procedures in the local treatment of advanced retinoblastoma, given its low systemic toxicity and good tolerability [16,17,18,19], SOAI can be used to deliver other chemotherapeutic and non chemotherapeutic agents to the tumor.

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