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The Polyamine Dependence of Cell Cycle Progression-Application in Breast Cancer Treatment

Myhre, Louise LU (2007)
Abstract (Swedish)
Popular Abstract in Swedish

I en normalt fungerande organism är det en balans mellan cellproliferation, celldifferentiering och celldöd. Olika typer av störningar av denna balansen resulterar i olika typer av sjukdomar. Denna avhandlingen handlar om när det är för lite celldöd och celldifferentiering och ökad cellproliferation. Detta leder till okontrollerad cell proliferering och resulterar i cancer. Polyaminer är en grupp molekyler som är livsnödvändiga för normal cellproliferation och polyaminnivåer är ofta förhöjda i cancerceller. Det generella syftet med avhandlingen var att öka förståelsen för polyaminernas roll i cellprogressionen och hur man kan tillämpa detta och manipulera bröstcancercellcykeln. I ett modellsystem... (More)
Popular Abstract in Swedish

I en normalt fungerande organism är det en balans mellan cellproliferation, celldifferentiering och celldöd. Olika typer av störningar av denna balansen resulterar i olika typer av sjukdomar. Denna avhandlingen handlar om när det är för lite celldöd och celldifferentiering och ökad cellproliferation. Detta leder till okontrollerad cell proliferering och resulterar i cancer. Polyaminer är en grupp molekyler som är livsnödvändiga för normal cellproliferation och polyaminnivåer är ofta förhöjda i cancerceller. Det generella syftet med avhandlingen var att öka förståelsen för polyaminernas roll i cellprogressionen och hur man kan tillämpa detta och manipulera bröstcancercellcykeln. I ett modellsystem undersökte vi cellcykelprogressionen i Chinese hamster ovary celler som uttrycker olika typer av ett enzym som är involverat i polyaminbiosyntesen och resulterar i olika polyaminnivåer. I det andra modellsystem tömde vi polyaminerna i fyra bröstcancercellinjer med olika genetisk bakgrund. Substanserna som vi använde för att tömma cellerna på polyaminer var: alfa-difluorometylornitin, 4-amidinoindan-1-one 2'-amidinohydrazon, and, N1, N11-dietylnorspermin. Cellcykelkinetiken var påverkad i båda modellsystemen av manipulering av polyaminpoolerna. De olika cellinjerna svarade olika för samma typ av behandling och inducerade olika signalvägar. Detta resulterade i olika svar i cellcykelkinetiken så som förlängning av S fasen och G1/S block. De cellcykelkinetiska effekterna kunde korreleras till förändringar i nivån av olika cellcykelregulatoriska proteiner. De olika svar hos de olika cellinjerna beror på deras genetiska bakgrund. Tillsammans visar dessa resultat hur viktigt det är att hitta biomarkörer för olika typer av substanser som påverkar polyaminpoolerna i behandling av bröstcancer. Resultaten visar att DENSPM behandling och troligtvis andra sperminanaloger är väldigt effektiv i vissa typer av den familjära formen av bröstcancer medan den är ineffektiv i andra typer av bröstcancer. (Less)
Abstract
In the normal functioning organism, there is a balance between cell proliferation, cell differentiation, and cell death. An imbalance in these processes results in different diseases. This thesis concerns the imbalance where there is too little cell death and cell differentiation with increased cell proliferation. The result is uncontrolled cell proliferation resulting in the development of cancer. Polyamines are essential for normal cell cycle proliferation and polyamine levels are often elevated in cancer cells. The general aim of my thesis was to achieve a better understanding of the role of the polyamines in cell cycle progression and how to apply this to manipulate the breast cancer cell cycle. In one model system we investigated cell... (More)
In the normal functioning organism, there is a balance between cell proliferation, cell differentiation, and cell death. An imbalance in these processes results in different diseases. This thesis concerns the imbalance where there is too little cell death and cell differentiation with increased cell proliferation. The result is uncontrolled cell proliferation resulting in the development of cancer. Polyamines are essential for normal cell cycle proliferation and polyamine levels are often elevated in cancer cells. The general aim of my thesis was to achieve a better understanding of the role of the polyamines in cell cycle progression and how to apply this to manipulate the breast cancer cell cycle. In one model system we investigated cell cycle progression in Chinese hamster ovary cells expressing different types of an enzyme involved in polyamine biosynthesis resulting in different polyamine pool levels. In the second model system we depleted the polyamines in four breast cancer cell lines with different genetic profiles to resemble the reality of breast cancer disease, and in one normal-like breast epithelial cell line. The substances we used to deplete the polyamines were: alpha-difluoromethylornithine, 4-amidinoindan-1-one 2'-amidinohydrazone, and, N1, N11-diethylnorspermine. Cell cycle kinetics was affected in both model systems by manipulation of the polyamine pools. The different cell lines responded differently to the same kind of treatment and different signaling pathways were induced. This resulted in different responses in cell cycle kinetics such as S phase prolongation and G1/S block. The cell cycle kinetic effects were correlated to changes in the levels of cell cycle regulatory proteins. The responses in the human cell lines can be reflected in their different genetic makeup. Altogether these data show the importance of finding biomarkers for the efficient use of compounds that affect the polyamine pools in the treatment of breast cancer. The result show that DENSPM treatment and almost certainly other spermine analogues may be effective in certain types of familial breast cancer sub groups while ineffective in other types of breast cancer. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Alhonen, Leena, University of Kuopio, Kuopio, Finland
organization
publishing date
type
Thesis
publication status
published
subject
keywords
tissue culture, histochemistry, Histology, cytochemistry, onkologi, cancer, Cytologi, oncology, cancerology, Cytology, cell cycle kinetics, cell cycle regulatory proteins, polyamine analogues, DENSPM, CGP48664, DFMO, cell cycle regulation, Polyamines, breast cancer, Djurfysiologi, Animal physiology, vävnadskultur, Histologi, cytokemi, histokemi
pages
151 pages
publisher
Department of Cell and Organism Biology, Lund University
defense location
Animal Physiology Building, Helgonavägen 3B, Lund
defense date
2007-05-18 09:00
ISBN
978-91-85067-30-5
language
English
LU publication?
yes
id
27dfe3c5-77d9-4080-a2e4-e27a3629a708 (old id 548551)
date added to LUP
2007-09-06 10:37:07
date last changed
2016-09-19 08:45:08
@phdthesis{27dfe3c5-77d9-4080-a2e4-e27a3629a708,
  abstract     = {In the normal functioning organism, there is a balance between cell proliferation, cell differentiation, and cell death. An imbalance in these processes results in different diseases. This thesis concerns the imbalance where there is too little cell death and cell differentiation with increased cell proliferation. The result is uncontrolled cell proliferation resulting in the development of cancer. Polyamines are essential for normal cell cycle proliferation and polyamine levels are often elevated in cancer cells. The general aim of my thesis was to achieve a better understanding of the role of the polyamines in cell cycle progression and how to apply this to manipulate the breast cancer cell cycle. In one model system we investigated cell cycle progression in Chinese hamster ovary cells expressing different types of an enzyme involved in polyamine biosynthesis resulting in different polyamine pool levels. In the second model system we depleted the polyamines in four breast cancer cell lines with different genetic profiles to resemble the reality of breast cancer disease, and in one normal-like breast epithelial cell line. The substances we used to deplete the polyamines were: alpha-difluoromethylornithine, 4-amidinoindan-1-one 2'-amidinohydrazone, and, N1, N11-diethylnorspermine. Cell cycle kinetics was affected in both model systems by manipulation of the polyamine pools. The different cell lines responded differently to the same kind of treatment and different signaling pathways were induced. This resulted in different responses in cell cycle kinetics such as S phase prolongation and G1/S block. The cell cycle kinetic effects were correlated to changes in the levels of cell cycle regulatory proteins. The responses in the human cell lines can be reflected in their different genetic makeup. Altogether these data show the importance of finding biomarkers for the efficient use of compounds that affect the polyamine pools in the treatment of breast cancer. The result show that DENSPM treatment and almost certainly other spermine analogues may be effective in certain types of familial breast cancer sub groups while ineffective in other types of breast cancer.},
  author       = {Myhre, Louise},
  isbn         = {978-91-85067-30-5},
  keyword      = {tissue culture,histochemistry,Histology,cytochemistry,onkologi,cancer,Cytologi,oncology,cancerology,Cytology,cell cycle kinetics,cell cycle regulatory proteins,polyamine analogues,DENSPM,CGP48664,DFMO,cell cycle regulation,Polyamines,breast cancer,Djurfysiologi,Animal physiology,vävnadskultur,Histologi,cytokemi,histokemi},
  language     = {eng},
  pages        = {151},
  publisher    = {Department of Cell and Organism Biology, Lund University},
  school       = {Lund University},
  title        = {The Polyamine Dependence of Cell Cycle Progression-Application in Breast Cancer Treatment},
  year         = {2007},
}