RESUMO
Retinoblastoma (Rb), the most frequent malignant intraocular tumor in childhood, is caused by mutations in the retinoblastoma gene (RB1) situated on chromosome 13q14.2. The incidence of retinoblastoma is approximately 1 in 17,000 live births with approximately 8,000 new cases diagnosed each year worldwide. Rb is the prototypical hereditary cancer in humans. Autosomal dominant inheritance is seen in 30-40% of cases whereas the non-inherited sporadic type accounts for the remaining 60-70%. Rb arises due to inactivation of both alleles of the Rb tumor suppressor gene, which results in a defective Rb protein (pRB) with subsequent cell cycle impairment and uncontrolled cell proliferation. Patients with Rb have survival rates higher than 95-98% in industrialized countries but mortality remains high in developing countries. For example, the mortality rate in Africa is 70%. In all cases of intraocular and extraocular retinoblastoma, there is a need for new therapies that are more effective and carry less risk of toxicity. The Bruckner test is a practical and easy test for the detection of Rb, this test consists of assessing the fundus reflex through the pupil (red reflex) in both eyes simultaneously with a bright coaxial light produced with the direct ophthalmoscope. Rb can be detected by the Bruckner test showing a pupil that shines white or "Leukocoria". Although the diagnosis of Rb remains essentially clinical, the newly identified biomarkers could contribute to early molecular detection, timely detection of micrometastases and establish new therapeutic options for Rb.
RESUMO
BACKGROUND/AIM: Retinoblastoma (RB) is the most common primary intraocular malignancy. Carboplatin (CPt) is a DNA damage-inducing agent that is widely used for the treatment of RB. Unfortunately, this drug also activates the transcription factor nuclear factor-kappa B (NF-ĸB), leading to promotion of tumor survival. Pentoxifylline (PTX) is a drug that inhibits the phosphorylation of I kappa B-alpha (IĸBα) in serines 32 and 36, and this disrupts NF-ĸB activity that promotes tumor survival. The goal of this study was to evaluate the effect of the PTX on the antitumor activity of CPt. MATERIALS AND METHODS: Y79 RB cells were treated with CPt, PTX, or both. Cell viability, apoptosis, loss of mitochondrial membrane potential, the activity of caspase-9, -8, and -3, cytochrome c release, cell-cycle progression, p53, and phosphorylation of IĸBα, and pro- and anti-apoptotic genes were evaluated. RESULTS: Both drugs significantly affected the viability of the Y79 RB cells in a time- and dose-dependent manner. The PTX+CPt combination exhibited the highest rate of apoptosis, a decrease in cell viability and significant caspase activation, as well as loss of mitochondrial membrane potential, release of cytochrome c, and increased p53 protein levels. Cells treated with PTX alone displayed decreased I kappa B-alpha phosphorylation, compared to the CPt treated group. In addition, the PTX+CPt combination treatment induced up-regulation of the proapoptotic genes Bax, Bad, Bak, and caspases- 3, -8, and -9, compared to the CPt and PTX individual treated groups. CONCLUSION: PTX induces apoptosis per se and increases the CPt-induced apoptosis, augmenting its antitumor effectiveness.