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Veluchamy A Barathi, Lakshminarayanan Rajamani, Sai Bo Bo Tun, Mathew Suresh Francis, Navin Kumar Varma, Arkasubhra Ghosh; Synergistic Effect of AMPK modulation and chemotherapy in a Rabbit Model of Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1395.
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Retinoblastoma (Rb) is the most common childhood intraocular tumor in the retina, driven by the loss-of-function of the RB1 tumor suppressor gene. Targeted therapy for Rb has gained popularity worldwide including intra- arterial chemotherapy and intravitreal chemotherapy. Treatment modalities for intraocular Rb include chemotherapy with drugs of choice being the DNA topoisomerase inhibitor Topotecan or Melphalan, whereas enucleation has to be performed in very advanced cases. Purpose of this study was to enhance the chemotherapeutic effect of currently available drugs at lower doses and devoid of systemic toxicity, which remains an unmet clinical need.
New Zealand rabbits (n= 24; 4 eyes per condition) with a mean initial weight around 3 kg was used in this study. Immunosuppression was attained with daily subcutaneous injections of cyclosporine A (CsA; 15mg/kg/day for week 1 till week 6, followed by 10mg/kg/day for week 7 till week 10). All the animals were received subretinal injection (30μl) of cultured WERI-Rb (Rb-/-) cells (1.5x10e6) in each eye. After development of vitreous seeds, the animals were grouped into Group A, B, C, D, E and F, those receiving HK1 or E2F2 (genes regulated by Rb) over expression, Topotecan at IC100 (chemotherapeutic drug), AICAR (AMPK modulator) at IC50, combined AICAR/topotecan at IC50 and vehicle via intra-vitreal injection.
In the rabbit xenograft model, tumors developed in all eyes injected with E2F2 over expressed and control WERI-Rb1 cells at week 06 and week08 after orthotopic transplantation. HK1 over expression did not show any tumor formation in rabbit retina at week 08 and were analysed using OCT and fundus imaging. E2F2 over expressed cells formed large tumors and vitreous seeds extending to the anterior chamber, compared to the control cells at week 8 and the mean tumor area across E2F2 over expression (p=0.1600), HK1 over expression (p=0.0016). Topotecon at IC100 alone reduced 22% of tumor whereas combination of Topotecon/AICAR at IC50 (for each drug) reduced 32% of tumor growth (p = 0.0076).
This study results show that the synergistic effect of AMPK modulation and Topotecon at IC50 is better than Topotecon at IC100. Thus, targeting the altered metabolism in Rb tumors using drugs such as AICAR can serve as a therapeutic option to manage retinoblastoma.
This is a 2020 ARVO Annual Meeting abstract.
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