On May 9, 1:03*pm, help_save_ser...@yahoo.co.uk wrote:neuroplastoma <<
NeuroBlastoma ..
The treatment has been known for quite some time ..
Deferoxamine has been shown to reverse this.
It is an iron chelator ..
CANCERLIT®
AUTHOR: Fan L, Iyer J, Zhu S, Frick KK, Wada RK, Eskenazi
AE, Berg PE, Ikegaki N, Kennett RH, Frantz CN
TITLE:
Inhibition of N-myc expression and induction of apoptosis by iron
chelation in human neuroblastoma cells.
SOURCE:
Cancer Res; 61(3):1073-9 2001 UI: 21115842
ABSTRACT:
Neuroblastoma is the second most common solid malignancy of
childhood.
Enhanced expression of the amplified N-myc gene in the tumor cells
may be associated with poor patient prognosis and may contribute to
tumor
development and progression.
The use of deferoxamine mesylate (DFO), an iron chelator, to treat
neuroblastoma is being investigated in national clinical studies.
We show here by TUNEL assay and DNA laddering that DFO induces
apoptosis in cultured human neuroblastoma cells, which is preceded
by a
decrease in the expression of N-myc and the altered expression of
some other
oncogenes (up-regulating c-fos and down-regulating c-myb) but not
housekeeping genes.
The decrease in N-myc expression is iron-specific but does not
result from inhibition of ribonucleotide reductase, because specific
inhibition of this iron-containing enzyme by hydroxyurea does not
affect N-myc protein levels.
Nuclear run-on and transient reporter gene expression experiments show
that the decrease in N-myc expression occurs at the level of
initiation of transcription and by inhibiting N-myc promoter
activity.
Comparison across neuroblastoma cell lines of the amount of residual
cellular
N-myc protein with the extent of apoptosis measured as pan-caspase
activity
after 48 h of iron chelation reveals no correlation, suggesting that
the
decrease in N-myc expression is unlikely to mediate apoptosis.
In conclusion, chelation of cellular iron by DFO may alter the
expression of multiple genes affecting the malignant phenotype by
multiple pathways.
Given the clinical importance of N-myc overexpression in
neuroblastoma malignancy, decreasing N-myc expression by DFO might
be useful as an
adjunct to current
MESH TERMS: Aphidicolin/Pharmacology Apoptosis/*Drug Effects
Deferoxamine/*Pharmacology Gene Expression/Drug Effects Gene
Expression
Regulation, Neoplastic/Drug Effects Genes, Reporter/Drug Effects
Genes,
myc/*Drug Effects/Genetics Human Hydroxyurea/Pharmacology
Inhibitory
Concentration 50 Iron/Metabolism Iron Chelating Agents/
*Pharmacology
Neuroblastoma/Genetics/*Metabolism/*Pathology Promoter Regions
(Genetics)/Drug Effects Proto-Oncogene Proteins c-myc/Antagonists
and
Inhib/*Biosynthesis Proto-Oncogenes/Drug Effects RNA,
Messenger/Biosynthesis/Genetics Substrate Specificity Support, Non-
U.S.
Gov't Support, U.S. Gov't, P.H.S. Transcription, Genetic/Drug
Effects
Tumor Cells, Cultured LANGUAGE: ENG PUBLICATION TYPE: JOURNAL
ARTICLE
TITLE ABBREVIATION: Cancer Res YEAR: 2001 ADDRESS: Department of
Pediatrics
and the Greenebaum Cancer Center, University of Maryland School of
Medicine,
Baltimore 21201, USA. ENTRY MONTH: 200104 CAS NO.: 0 (Iron
Chelating
Agents) 0 (Proto-Oncogene Proteins c-myc) 0 (RNA, Messenger)
127-07-1
(Hydroxyurea) 38966-21-1 (Aphidicolin) 70-51-9 (Deferoxamine)
7439-89-6
(Iron) ID: NS34432\NS\NINDS
------------------------------
Biochim Biophys Acta 2002 Oct 2;1603(1):31 Related Articles, Links
The role of iron in cell cycle progression and the proliferation of
neoplastic
cells.
Le N, Richardson D.
The Iron Metabolism and Chelation Group, The Heart Research Institute,
145
Missenden Rd, Camperdown, New South Wales, 2050, Sydney, Australia
Iron (Fe) is an obligate requirement for life and it is well known
that Fe
depletion leads to G(1)/S arrest and apoptosis.
These facts, together with
studies showing that Fe chelators can inhibit the growth of aggressive
tumours
such as neuroblastoma, suggest that Fe-deprivation may be an
important
therapeutic strategy.
To optimise the anti-proliferative effects of Fe chelators, the role
of Fe in cell cycle control requires intense investigation.
For many years, Fe chelators were known to prevent the activity of the
R2
subunit of ribonucleotide reductase (RR) that catalyzes the conversion
of
ribonucleotides into deoxyribonucleotides (dNTPs) for DNA synthesis.
In addition, Fe depletion may also inhibit the newly identified p53-
inducible form
of this molecule called p53R2.
This protein has the same Fe-binding sites as found in R2, and its
activity is thought to supply dNTPs for the critical process of DNA
repair.
Iron chelation also causes hypophosphorylation of the retinoblastoma
protein (pRb) and decreases the expression of cyclins A, B and D,
which are vital for cell cycle progression.
Other regulatory molecules whose expression is affected by Fe
depletion include p53 and hypoxia inducible factor-1alpha
(HIF-1alpha).
The levels of p53 increase following Fe chelation via the ability of
HIF-1alpha to bind and stabilize p53.
The activity of HIF-1alpha is controlled by an Fe-dependent enzyme
known as HIF-alpha prolyl hydroxylase (PH).
Chelation of Fe from this enzyme inhibits its activity, leading to
stabilization of HIF-1alpha and the subsequent effects on downstream
targets critical for angiogenesis and tumour growth.
The levels of p53 may also increase after Fe chelation by
phosphorylation of this protein at serine-15 and -37.
This prevents the interaction of p53 with murine double minute-2
(mdm-2)
and its degradation. Iron chelation also markedly increases the mRNA
levels of
the p53-inducible cyclin-dependent kinase (cdk) inhibitor, p21(WAF1/
CIP1).
Surprisingly, the increase in p21(WAF1/CIP1) mRNA was not reciprocated
at the
protein level, and this may result in cell cycle dysregulation.
This review will focus on the molecular mechanisms induced following
Fe chelation and the role of Fe in cell cycle progression.
PMID: 12242109 [PubMed - in process]
--------------------------------------------------------------------------
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/a3cc3
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk
> I am writing to you today as A desperate father pleading for help to
> save my three-year-old daughter who is dying from a rare form of
> cancer. Serena has been suffering from neuroplastoma - a tumour in the
> adrenal glands - for the past 18 months.
>
> She has spent most of her life in hospital undergoing chemotherapy and
> radiotherapy, but in January this year we were told Serena was in
> remission.
>
> Serena spent the past few weeks at home living like a normal little
> girl for the first time. But two weeks ago she was readmitted to
> hospital, where doctors told her the cancer had returned.
>
> Medics say there is no more they can do, except offer treatments that
> can prolong her life. Her only apparent hope of beating the disease is
> to undergo revolutionary treatment in America
>
> If she does not have the treatment she may only have weeks or months
> to live.
>
> Please, Please help us save our baby.. You can see her story in two
> local newspapers online.
>
> http://www.croydonguardian.co.uk/new....var.2249915.0...
>
> http://www.croydonadvertiser.co.uk/d...Id=250080&comm...
>
> Please help us raise support for serena by reposting this message
> elsewhere or by emailing it to your contacts.
>
> Thankyou 
PLEASE HELP SAVE SERENA 
Linear Mode
