Human alpha-lactalbumin made lethal to tumor cells (HAMLET) kills human glioblastoma cells in brain xenografts by an apoptosis-like mechanism and prolongs survival.
Fischer, Walter ; Gustafsson, Lotta LU
; Mossberg, Anki
LU
; Gronli, Janne
; Mork, Sverre
; Bjerkvig, Rolf
and Svanborg, Catharina
LU
(2004)
In Cancer Research
64(6).
p.2105-2112
- Abstract
Malignant brain tumors present a major therapeutic challenge because no selective or efficient treatment is available. Here, we demonstrate that intratumoral administration of human α-lactalbumin made lethal to tumor cells (HAMLET) prolongs survival in a human glioblastoma (GBM) xenograft model, by selective induction of tumor cell apoptosis. HAMLET is a protein-lipid complex that is formed from α-lactalbumin when the protein changes its tertiary conformation and binds oleic acid as a cofactor. HAMLET induces apoptosis in a wide range of tumor cells in vitro, but the therapeutic effect in vivo has not been examined. In this study, invasively growing human GBM tumors were established in nude rats (Han:rnu/rnu Rowett, n = 20) by... (More)
Malignant brain tumors present a major therapeutic challenge because no selective or efficient treatment is available. Here, we demonstrate that intratumoral administration of human α-lactalbumin made lethal to tumor cells (HAMLET) prolongs survival in a human glioblastoma (GBM) xenograft model, by selective induction of tumor cell apoptosis. HAMLET is a protein-lipid complex that is formed from α-lactalbumin when the protein changes its tertiary conformation and binds oleic acid as a cofactor. HAMLET induces apoptosis in a wide range of tumor cells in vitro, but the therapeutic effect in vivo has not been examined. In this study, invasively growing human GBM tumors were established in nude rats (Han:rnu/rnu Rowett, n = 20) by transplantation of human GBM biopsy spheroids. After 7 days, HAMLET was administered by intracerebral convection-enhanced delivery for 24 h into the tumor area; and α-lactalbumin, the native, folded variant of the same protein, was used as a control. HAMLET reduced the intracranial tumor volume and delayed the onset of pressure symptoms in the tumor-bearing rats. After 8 weeks, all α-lactalbumin-treated rats had developed pressure symptoms, but the HAMLET-treated rats remained asymptomatic. Magnetic resonance imaging scans revealed large differences in tumor volume (456 versus 63 mm3). HAMLET caused apoptosis in vivo in the tumor but not in adjacent intact brain tissue or in nontransformed human astrocytes, and no toxic side effects were observed. The results identify HAMLET as a new candidate in cancer therapy and suggest that HAMLET should be additionally explored as a novel approach to controlling GBM progression.
(Less)
- author
- Fischer, Walter
; Gustafsson, Lotta
LU
; Mossberg, Anki
LU
; Gronli, Janne
; Mork, Sverre
; Bjerkvig, Rolf
and Svanborg, Catharina
LU
- organization
- publishing date
- 2004
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cancer Research
- volume
- 64
- issue
- 6
- pages
- 8 pages
- publisher
- American Association for Cancer Research Inc.
- external identifiers
-
- pmid:15026350
- wos:000220249100032
- scopus:1542405871
- pmid:15026350
- ISSN
- 1538-7445
- DOI
- 10.1158/0008-5472.CAN-03-2661
- project
- HAMLET- In vivo effects and mechanisms of tumor cells death
- language
- English
- LU publication?
- yes
- additional info
- W. Fischer and L. Gustafsson contributed equally to this work
- id
- 813ec170-4659-469a-9853-b1f1c3ed69ed (old id 121164)
- alternative location
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15026350&dopt=Abstract
- http://cancerres.aacrjournals.org/cgi/content/full/64/6/2105
- date added to LUP
- 2016-04-01 16:39:16
- date last changed
- 2022-04-22 23:34:20
@article{813ec170-4659-469a-9853-b1f1c3ed69ed,
abstract = {{<p>Malignant brain tumors present a major therapeutic challenge because no selective or efficient treatment is available. Here, we demonstrate that intratumoral administration of human α-lactalbumin made lethal to tumor cells (HAMLET) prolongs survival in a human glioblastoma (GBM) xenograft model, by selective induction of tumor cell apoptosis. HAMLET is a protein-lipid complex that is formed from α-lactalbumin when the protein changes its tertiary conformation and binds oleic acid as a cofactor. HAMLET induces apoptosis in a wide range of tumor cells in vitro, but the therapeutic effect in vivo has not been examined. In this study, invasively growing human GBM tumors were established in nude rats (Han:rnu/rnu Rowett, n = 20) by transplantation of human GBM biopsy spheroids. After 7 days, HAMLET was administered by intracerebral convection-enhanced delivery for 24 h into the tumor area; and α-lactalbumin, the native, folded variant of the same protein, was used as a control. HAMLET reduced the intracranial tumor volume and delayed the onset of pressure symptoms in the tumor-bearing rats. After 8 weeks, all α-lactalbumin-treated rats had developed pressure symptoms, but the HAMLET-treated rats remained asymptomatic. Magnetic resonance imaging scans revealed large differences in tumor volume (456 versus 63 mm<sup>3</sup>). HAMLET caused apoptosis in vivo in the tumor but not in adjacent intact brain tissue or in nontransformed human astrocytes, and no toxic side effects were observed. The results identify HAMLET as a new candidate in cancer therapy and suggest that HAMLET should be additionally explored as a novel approach to controlling GBM progression.</p>}},
author = {{Fischer, Walter and Gustafsson, Lotta and Mossberg, Anki and Gronli, Janne and Mork, Sverre and Bjerkvig, Rolf and Svanborg, Catharina}},
issn = {{1538-7445}},
language = {{eng}},
number = {{6}},
pages = {{2105--2112}},
publisher = {{American Association for Cancer Research Inc.}},
series = {{Cancer Research}},
title = {{Human alpha-lactalbumin made lethal to tumor cells (HAMLET) kills human glioblastoma cells in brain xenografts by an apoptosis-like mechanism and prolongs survival.}},
url = {{http://dx.doi.org/10.1158/0008-5472.CAN-03-2661}},
doi = {{10.1158/0008-5472.CAN-03-2661}},
volume = {{64}},
year = {{2004}},
}