Ferritin Iron Release by Anthracyclines: Investigations of the Basis for Cardiotoxicity and Implications for Drug Development
Publication Date
4-1999
Type of Culminating Activity
Thesis
Degree Title
Master of Science in Interdisciplinary Studies, Perspectives on Anti-Cancer Drug Developement
Department
Interdisciplinary Studies
Supervisory Committee Chair
Susan E. Shadle
Supervisory Committee Member
Robert W. Ellis
Supervisory Committee Member
Gary Shook
Supervisory Committee Member
Richard D. Olson
Abstract
Developing anti-tumor therapy utilizes basic and clinical research. A widely used family of anti-cancer drugs, anthracyclines, are beneficial in a broad spectrum of cancer treatment, however, their therapeutic potential is limited by a cardiotoxic side effect. The development of improved anthracycline drugs that exhibit reduced cardiotoxicity while retaining their anti-cancer properties would provide more effective and ethically sound treatment for cancer patients.
Studies have proposed several possible mechanisms by which anthracycline drug interaction at the molecular level may lead to the cardiotoxic side effects, yet the mechanistic details remain unclear. Free radical induced oxidative stress and the accumulation of the primary drug metabolite appear to play an important role in the molecular explanation of anthracycline cardiotoxicity. Toxicity to heart tissue has also been shown to involve disruption of iron homeostasis, possibly linked to the metabolite, and the release of iron from normal intracellular storage proteins.
Spectroscopic iron release studies indicate both doxorubicin (DOX) and its primary metabolite, doxorubicinol (DOXol), are capable of releasing ferritin iron. Moreover, the metabolite does so with greater efficiency. Dose dependence shows clear, but unusual trends that may indicate mechanisms for iron release are different for the parent and metabolite. Analysis of the chemical fate of DOX and DOXol indicates the two species likely cause iron release by different mechanisms.
Recommended Citation
Brown, Julie L., "Ferritin Iron Release by Anthracyclines: Investigations of the Basis for Cardiotoxicity and Implications for Drug Development" (1999). Boise State University Theses and Dissertations. 1206.
https://scholarworks.boisestate.edu/td/1206