HAMLET - In vivo effects and mechanisms of tumor-cell death
Research output: Thesis › Doctoral Thesis (compilation)
Abstract
HAMLET (human alpha-lactalbumin made lethal to tumor cells), a molecular complex derived from human milk, is an interesting new tool in cancer research since it induces programmed cell death in tumor cells while leaving normal, differentiated cells unharmed.
The in vivo effects of HAMLET were studied in a rat xenograft model of human glioblastoma. HAMLET reduced the tumor volume and delayed the onset of pressure symptoms. Programmed cell death was induced in the tumor, but not in the adjacent normal brain tissue. In non-grafted rats, HAMLET spread throughout the infused brain hemisphere and no significant toxic side-effects were recorded.
The therapeutic effects of HAMLET were investigated further in a placebo-controlled study of patients with skin papillomas. Local application of HAMLET for a three-week period reduced the volume of the papillomas by >75% in all the patients and in 96% of the papillomas as compared with 21% in the placebo-control group. No adverse reactions were reported and there was no difference in outcome for immunosuppressed patients.
A mechanism of tumor-cell death was suggested, one that relates to the partially unfolded state of HAMLET. Massive amounts of HAMLET gained entry into the tumor cells, it interacted with the proteasomes and caused a stress response due to the overload of partially unfolded protein. HAMLET activated the proteasomes in the cytoplasm, but degradation was delayed and fragmentation of the proteasomes was triggered instead. HAMLET and proteasomes translocated to the tumor cell nuclei, where chromatin homeostasis was disrupted. HAMLET-induced tumor-cell death was partially prevented by blocking proteasome activity, supporting the role of proteasomes in cell death.
HAMLET represents a new approach to cancer therapy, having therapeutic effects in vivo and targeting cell death pathways that are susceptible for activation in tumor cells, thus circumventing the roadblocks that prevent cell death in many tumor cells.
The in vivo effects of HAMLET were studied in a rat xenograft model of human glioblastoma. HAMLET reduced the tumor volume and delayed the onset of pressure symptoms. Programmed cell death was induced in the tumor, but not in the adjacent normal brain tissue. In non-grafted rats, HAMLET spread throughout the infused brain hemisphere and no significant toxic side-effects were recorded.
The therapeutic effects of HAMLET were investigated further in a placebo-controlled study of patients with skin papillomas. Local application of HAMLET for a three-week period reduced the volume of the papillomas by >75% in all the patients and in 96% of the papillomas as compared with 21% in the placebo-control group. No adverse reactions were reported and there was no difference in outcome for immunosuppressed patients.
A mechanism of tumor-cell death was suggested, one that relates to the partially unfolded state of HAMLET. Massive amounts of HAMLET gained entry into the tumor cells, it interacted with the proteasomes and caused a stress response due to the overload of partially unfolded protein. HAMLET activated the proteasomes in the cytoplasm, but degradation was delayed and fragmentation of the proteasomes was triggered instead. HAMLET and proteasomes translocated to the tumor cell nuclei, where chromatin homeostasis was disrupted. HAMLET-induced tumor-cell death was partially prevented by blocking proteasome activity, supporting the role of proteasomes in cell death.
HAMLET represents a new approach to cancer therapy, having therapeutic effects in vivo and targeting cell death pathways that are susceptible for activation in tumor cells, thus circumventing the roadblocks that prevent cell death in many tumor cells.
Details
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| Research areas and keywords | Subject classification (UKÄ) – MANDATORY
Keywords
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| Original language | English |
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| Qualification | Doctor |
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| Award date | 2005 May 20 |
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| Print ISBNs | 91-85439-50-9 |
| Publication status | Published - 2005 |
| Publication category | Research |
Bibliographic note
Defence details
Date: 2005-05-20
Time: 13:00
Place: The GK lecture hall, Biomedical Center, Lund, Sweden.
External reviewer(s)
Name: Heldin, Carl-Henrik
Title: Professor
Affiliation: Ludwig Institute for Cancer Research, Uppsala, Sweden
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W Fischer, L Gustafsson, A.K. Mossberg, J Gronli, S Mork, R Bjerkvig and C Svanborg. 2004. Human Alpha-Lactalbumin Made Lethal to Tumor Cells (HAMLET) Kills Human Glioblastoma Cells in Brain Xenografts by an Apoptosis-Like Mechanism and Prolongs Survival. Cancer Res, vol 64 pp 2105-2112.
L Gustafsson, I Leijonhufvud, A Aronsson, A.K. Mossberg and C Svanborg. 2004. Treatment of Skin Papillomas with Topical Alpha-Lactalbumin-Oleic Acid. N Engl J Med, vol 350 pp 2663-2672. acc edit 2639-2642.
L Gustafsson, O Hallgren and C Svanborg. . Unfolded Protein Overload, Proteasome Activation and Death in HAMLET-Treated Tumor Cells. (submitted)
Related projects
2000/09/01 → 2008/09/01
Project: Dissertation › International collaboration, National collaboration, Teaching, Collaboration with industry
