PO-444 Evaluation of novel nucleoside analogues for lung cancer treatment: an approach based on metronomic chemotherapy

Abstract

IntroductionLung cancer presents a global pandemic responsible for an estimated 20% of cancer cases with Non-Small Cell Lung Cancer (NSCLC) being the most prevalent form. Chemotherapy is the preferred treatment modality for NSCLC, focusing on the disruption of the abnormal proliferation of cancer cells. Nevertheless, this approach causes patients to experience unpleasant side effects and more importantly, results in cancer recurrence. Gemcitabine (Gemc) is a nucleoside analogue used against NSCLC, which inhibits cell cycle and prevents tumour growth. Although gemc is approved for the treatment of various cancer types, its efficacy is still limited due to its lack of efficiency, which is caused by rapid metabolic inactivation. Metronomic chemotherapy (MTR), relying on the daily oral administration of a drug, at low doses, is a multi-targeted therapy, as it inhibits tumour angiogenesis, modulates immunity pathways and effects tumour initiating cells reducing the toxicity of traditional maximal tolerated dose chemotherapy (MTD). Our goal is to provide a new angle in the MTR approach, by administering an oral prodrug of gemc, Oral Gem, to improve gemc’s therapeutic properties, but also cover patients‘ quality of life.Material and methodsThe A549 lung cancer cell line was used to establish an in vitro model that simulated the MTD versus the MTR conditions. Cells were cultured either in presence of a high concentration of gemc or in medium in which lower concentrations were added daily in order to study alterations in the expression of various angiogenic factors. Additionally, an in vivo xenografted animal model was set up to study the effects of MTR chemotherapy on tumour’s expansion, toxicity of the drug and angiogenesis.Results and discussionsDaily addition of gemc in A549 cells led to a decreased expression of VEGFA, a well-established angiogenic factor, compared to the high dose incubation. In NOD/SCID xenografted mice, the MTR administration of Oral Gem led to a decreased expression of VEGFA and CD31, a marker found on endothelial cells, suggesting a suppressed angiogenic profile. Finally, MTR administration of Oral Gem led to an increase in the expression levels of Thrombospondin-1, an anti-angiogenic factor, compared to MTD chemotherapy.ConclusionMTR administration of Oral Gem limits the formed vessels around the tumour combining restriction of angiogenesis and vessel normalisation. In contrast, MTD chemotherapy seems to enhance the angiogenic potential around the tumour site, serving tumour’s establishment and expansion.