Unit:
Department of PharmacyLibrary of the School of Science
Dissertation committee:
Μαράκος Παναγιώτης, Καθηγητής, Τομέας Φαρμακευτικής Χημείας, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Ταμβακόπουλος Κωνσταντίνος, Ερευνητής Α', Κέντρο Κλινικής, Πειραματικής Χειρουργικής & Μεταφραστικής Έρευνας, Ίδρυμα Ιατροβιολογικών Ερευνών Ακαδημίας Αθηνών
Σκαλτσούνης Αλέξιος-Λέανδρος, Καθηγητής, Τομέας Φαρμακογνωσίας και Χημείας Φυσικών Προϊόντων, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Μικρός Εμμανουήλ, Καθηγητής, Τομέας Φαρμακευτικής Χημείας, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Παπαπετρόπουλος Ανδρέας, Καθηγητής, Τομέας Φαρμακευτικής Χημείας, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Πολίτης Παναγιώτης, Ερευνητής Β', Κέντρο Βασικής Έρευνας, Ίδρυμα Ιατροβιολογικών Ερευνών Ακαδημίας Αθηνών
Ξάνθου-Τσιγκόγλου Γεωργία, Ερευνήτρια Β', Κέντρο Βασικής Έρευνας, Ίδρυμα Ιατροβιολογικών Ερευνών Ακαδημίας Αθηνών
Original Title:
Evaluation of novel nucleoside analogues for lung cancer treatment: an approach based on metronomic chemotherapy
Translated title:
Evaluation of novel nucleoside analogues for lung cancer treatment: an approach based on metronomic chemotherapy
Summary:
Lung cancer presents a contemporary global pandemic being responsible for a 18,4% of deaths for both sexes worldwide in 2018, as well as an estimated 13% of cancer related cases and 134,720 deaths in US in 2020. Non-Small Cell Lung Cancer (NSCLC), being the most prevalent form, represents 80% of the total reported cases. This high percentage is due to the late-stage diagnosis, limiting the median survival time up to 5 years. Staging lung cancer is based on whether the cancer is advanced locally or has spread from the lungs to the lymph nodes or other organs. Because of the size of the lungs, tumors can grow for a long time before they can be detected. Even when symptoms, like coughing and fatigue occur, people think they are caused by tuberculosis and chronic bronchitis. For this reason, early-stages of lung cancer (stages I and II) are difficult to detect. Most people with lung cancer are diagnosed at stages III (a and b) and IV.
No one can deny that in the last decade, encouraging progress has been reported with the development of personalized molecular screenings leading to more targeted therapies which if combined with immunotherapies could possibly lead to a more curative option. However, taking into account the urgent need for the restriction of tumor’s progression and metastasis, clinicians prefer to turn to traditional chemotherapy, as it focuses directly on the disruption of the uncontrolled and abnormal proliferation of cancer cells.
Maximum Tolerated Dose chemotherapy (MTD) is the most preferred treatment modality for NSCLC and it is based on the highest acceptable dose of a drug or treatment that does not cause side effects. Though effective at first, after several cycles of drug administration, this approach results in the appearance of cancer resistance to the drug, as well as increases in acute toxicity causing patients to ultimately experience unpleasant side effects. Gemcitabine is a commonly used nucleoside analogue for the chemotherapeutic treatment of NSCLC, which inhibits the cell cycle through DNA polymerase inhibition and effectively prevents tumor growth and expansion. Although gemcitabine is approved for the treatment of various cancer types including NSCLC, its efficacy is still limited. A major disadvantage is its lack of efficiency, which is caused by rapid metabolic inactivation, as well as the induction of cancer resistance. To overcome these drawbacks, metronomic chemotherapy (MTR) is presented to constitute an alternative approach to fight cancer. MTR, which relies on the frequent administration of the chosen drug, at low doses, with no prolonged drug-free breaks, is a multi-targeted therapy, as it inhibits tumor angiogenesis, modulates immunity pathways, effects tumor initiating cells and induces tumor dormancy exceeding the toxicity of traditional standard-dose chemotherapy. Our goal is to investigate the effect of MTR on NSCLC, both in vitro and in vivo, using an orally administered nucleoside analogue, OralGem, which is a prodrug of gemcitabine with ultimate goal to cover patients' needs as far as their compliance and quality of life are concerned.
Alterations in the angiogenic profile around the tumor site were detected, as well as the recruitment of immune populations limiting inflammation and boosting immune surveillance. This alternative chemotherapeutic strategy also favored OralGem revealing more promising pharmacokinetic properties, as well as minimized blood and thymus toxicity compared to traditional MTD gemcitabine. However, MTR OralGem alone could not reach the efficacy offered by MTD gemcitabine, whilst showing improvements compared to the untreated groups of animals. For this reason, MTR OralGem was co-dosed with anti-PD1, maintaining its effect on tumor microenvironment, but mainly leading to improved efficacy against lung cancer.
Main subject category:
Science
Other subject categories:
Health Sciences
Keywords:
Non-small cell lung cancer, nucleoside analogues, gemcitabine, metronomic chemotherapy, OralGem, immunotherapy, efficacy, toxicity, pharmacokinetics, animal models
Number of references:
107
File:
File access is restricted until 2025-07-14.
Skavatsou Eleni PhD.pdf
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File access is restricted until 2025-07-14.
