Understanding anthracycline action: molecular insights to improve cancer therapy

Gelder, M.A. van (2025)

Doctoral Thesis

Anthracyclines have been in clinical use for decades, and their effectiveness against many tumor types has outweighed their limitations. However, it remains crucial to address these limitations because of significant impact on the quality of life for cancer patients. The use of anthracyclines is hindered by severe side effects and toxicities that occur during or after treatment. Additionally, the development of resistance poses a major barrier to successful anthracycline treatment. Various approaches have been explored to improve the efficacy and reduce the toxicity of anthracyclines, but none have established a permanent position in cancer treatment.
In this thesis, we focus on one strategy to improve the efficacy of anthracyclines and overcome resistance. We report the design, synthesis and biological evaluation of structural variations of the archetypical anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin and aclarubicin). The aim of this work is to gain a better understanding of the structure-activity relationships of anthracyclines, with the ultimate goals of identifying anthracycline variants that may elicit fewer adverse events and circumvent the molecular mechanisms underlying drug resistance.

• Cancer
• Chemotherapy
• Anti-cancer drugs
• Anthracyclines
• Drug resistance
• ABCB1
• Doxorubicin
• Chromatin damage
• DNA damage

• All authors: Gelder, M.A. van
• Supervisor: Neefjes, J.J.C.; Overkleeft, H.S.
• Co-supervisor: Zanden, S.Y. van der
• Committee: Stelt, M. van der; Ingen, H. van; Goumans, M.J.T.H.; Rijt, C.C.D. van der; Wezel, G.P. van
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2025-05-21
• ISBN (print): 9789465106182