Folie 1 - Praxis Dr. Ursula Jacob

Report
Dr. Ursula Jacob
Medical director
USA 2012
Freitag, 17. Juli 2015
• The clinic has 17 rooms
• Over 7,000 patients treated,
from Europe, Australia and
North America.
• Staff of 4 doctors,
12 nurses, nutritionist and
psychologist
Indications
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preventive diagnostics and treatments
regenerative treatments
hematological diseases
metabolic disorders
chronic neurological diseases
chronic viral diseases
oncological diseases
Diagnostic spectrum:
• electrocardiogram at rest
• sonography
• bone marrow cytology with possibility of
fast diagnosis
• biopsies under appropriate control
Diagnostic spectrum in cooperation:
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CST chemo sensitivity test (testing of chemotherapeutics, natural
substances, antibodies and tumor genes)
CTC test (checking for circulating tumor cells)
CFS test (checking for autoimmune-/viral disease)
X-ray, CT and MRT
pulmonary function test
exercise electrocardiogram
bronchoscopy
gastroscopy
coloscopy
rectoscopy
PET (positron-emission-tomography)
scintigraphy
laboratory diagnostics
pathology
Therapeutic spectrum:
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hyperthermia
immunological treatment
naturopathic treatments
psycho-oncology
nutritional therapies
individually tested chemotherapy / immune therapy
individual preventive therapy (based on gene
analysis)
• vaccination
Therapeutic spectrum in cooperation:
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surgical interventions
radiation therapy
venous port implantations
embolisation
perfusion therapy
laser therapy
cyberknife
Micro tumor testing (CTC)chemosensitivity Assays and
R&D
CFS -Testings
AUTHOR-PRESENTER: DR. Ursula Jacob
R.G.C.C s Services
• Clinical Services
1.
2.
Chemosensitivity testing
Detection , quantification and immunophenotyping CTCs (MRD test)
• Research activities
1.
2.
3.
Evaluation of substances candidates for drugs “whanabe”.
Detection of new targets for new therapeutic approaches
Basic research in molecular Oncology
Cancer Hallmarks
CARCINOGENESIS STEPS
INITIATION
•Viral interference
•Chemical interference
•Radiation influence
PROMOTION
•Cell cycle instability
•DNA repair aberration
•Apoptosis instabiliity
PROGRESS
•Invasion
•Neo-angiogenesis
•EMT and MET
VOGELSTEIN MODEL OF DEVELOPING COLON CANCER
Cancer Hallmarks
Novel techniques
•
FEATURES OF NOVEL ASSAYS-METHODS
1.
2.
3.
4.
5.
6.
7.
8.
TECHNIQUES
Accuracy
•Flow Cytometry
Sensitivity
Specificity
•Quantitative PCR
Cellular profile
•Micro-arrays
Cellular abilities and potentials
•Protein arrays
Detection of heterogeneity
Detection of subpopulation
Detection and isolation of MRD cells
Flow cytometry
1.
2.
3.
4.
5.
METHODOLOGY
Single cell analysis.
Information about size and granularity
for each cell.
Information through fluorescence
about any antigen we wish to analyze
(in theory).
Information about DNA quantity and
quality.
Viability and apoptosis detection.
THE MORE PARAMETERS YOU CAN
ANALYZE THE MORE INFORMATION
YOU RECEIVE AND THE
DISCRIMINATION ABILITY RISES.
Quantitative PCR
•
THE METHODOLODY OF qPCR
1.
2.
3.
ISOLATION OF mRNA FROM ALL CELLS
PRODUCTION OF cDNA FROM mRNA USING RT-PCR.
USING SPECIFIC PROBE FOR EACH GENE THAT WE
ARE INTERESTED IN (WITH FLUOROPHORE AND
QUENCER)
IN EACH CYCLE THE PROBE IS RELEASED AND THE
QUENCER IS SEPARATED FROM THE FLUOROPHORE
AND ITS BLEACHES.
VISUALISATION
AND
QUANTIFICATION
OF
FLUORESCENCE
4.
5.
•
DATA ANALYSIS
1.
THE CYCLE THRESHOLD REFLECT THE PRIMARY
ORIGINAL AMOUNT OF TEMPLATE mRNA .
THE LEVEL OF FLUORESCENCE REFLECT THE NUMBER
OF AMPLIFICATIONS THAT cDNA HAS RECEIVED
IT IS POSSIBLE EITHER TO PERFORM RELATIVE
QUANTIFICATION OF A GENE IN COMPARE WITH AN
ENDOGENOUS ONE (HOUSEKEEPING OR ABSOLUT
QUNATIFICATION BASED ON
2.
3.
Micro-Arrays analysis
•
THE METHODOLODY OF MICRO-ARRAY
1.
2.
5.
ISOLATION OF mRNA FROM CANCER CELLS
PRODUCTION OF cDNA FROM mRNA USING cDNA
SYNTHESIS (first and second strand).
MODIFICATION OF cDNA WITH BIOTIN-STREPTAVIDIN OR
FLUORESCENT DYES.
HYBRIDIZATION OF cDNA WITH SPECIFIC PROBES FOR
GENES
VISUALISATION OF HYBRIDIZED PROBES
•
GENES THAT ARE ANALYSED
1.
GENES THAT BECOME TARGETS FOR CYTOSTATICS
(DHFR,TS, TOPOI, TOPOII etc)
GENES THAT PRODUCE GROWTH FACTORS OR GROWTH
FACTOR RECEPTORS (EGF, IGF , TGF etc)
GENES THAT ARE INVOLVED TO METASTASIS (VEGF, EGF,
PDGF ETC)
GENES THAT REGULATE CELL CYCLE (p53, p27, p16 etc)
GENES THAT ARE INVOLVED TO RESISTANCE PHENOTYPE
(MDR1, DNMT1,BCL, NP, NFK, HTERT etc)
3.
4.
2.
3.
4.
5.
The role of SNPs in drug metabolism
•
The majority of drugs need to transformed into active formulations by
several enzymatic transformations
•
Most of the active substances needed to deactivated in order to be
removed from the organism.
•
SNPs can cause either accumulate toxicities due slow removal of an active
drug (accumulators) or
•
By specific SNPs drugs will never sustain their active forms in order to act
(rapid metabolizers)
Chemosensitivity molecular assays may proved powerful tool of prediction
of adverse reaction and drug side effects
Chemosensitivity and targeted therapy
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Recently monoclonal antobodies or biomolecules used as inhibitors or
modifiers of a target antigen (CD20, Her/neu 2, CD33, CD52, EGF-r,
VEGFRII, Bcr-Abl etc).
Only molecular techniques can detect and quantify such molecules (flow
cytometry, IHC, qPCR, hybridization assay).
Mutation of such target molecules may induce resistant phenotype of
cancer cells.
Down regulation of those antigens may also induce resistance
Antigen depletion may stress and promote more resistant subclones if
there is no control.
Flip-flop of membrane antigen may hide targets for biological drugs
Molecular techniques may control and personalize the therapy
Chemo-sensitivity / resistance
Testing
and
targeted treatments in cancer
Our clinical experience
ONCOTRACE
ONCOTRAIL
ONCOCOUNT
TU profile
+
What is Artemisinin?
• Artemisinin is a sesquiterpene lactone
isolated from the plant Artemesia annua
L. (has been used for the treatment of
malaria).
• Dr. Zhenxing Wei was first to isolate
artemisinin in 1970.
• The artemisinin molecule contains an
endoperoxide bridge that reacts with a
ferrous iron to form free radicals
• There are several analogs of artemisinin
including artesunate and artemether.
How does Artemisinin work?
• Artemisinin causes the cancer cell to commit
suicide.
• The artemisinin molecule contains an
endoperoxide bridge that reacts with a
ferrous iron atom to form free radicals
• Generation of free radicals leads to
macromolecular damages and cell death.
• Cancer cells have a very high iron uptake
and thus they are more susceptible.
Research on Artemisinin:
MOLT-4 (Leukemia Cell Line) Studies
• First study on artemisinin (1995) was
done in cell culture (MOLT-4
lymphoblastoid leukemia cell line).
• Results show all MOLT-4 cells were
killed in 8 hours by 200 micromolar of
dihydroartemisinin.
• The drug is 100 times less toxic to
human lymphocytes in culture.
Research on Artemisinin: Leukemia Cell Line
APOPTOSIS IN MOLT-4 LEUKEMIA CELLS
(dihydro) Artemisinin (8 hours only)
0%
Control
100 %
200 M
Hyperthermia (24 hr incubation)
3.26 %
Control
5.01 %
44C for 1 hr
Hydrogen Peroxide (24 hr incubation)
3.52 %
Control
40.09 %
176 M
Mitoxantrone (24 hr incubation)
3.51 %
Control
55.02 %
0.5 M
Novobiocin (24 hr incubation)
3.75 %
Control
22.68 %
800 M
Sodium Ascorbate (24 hr incubation)
3.47 %
Control
62.59 %
2000 M
X-ray (24 hr incubation)
3.2 %
Control
9.5 %
100 rads
Research on Artemisinin: Trials in Dogs
• Dog trials were begun soon after encouraging
results in MOLT-4 experiments (1994-1995).
• Dogs of different breeds (male and female)
having various types of cancers
(lymphosarcoma, breast adenocarcinoma,
osteosarcoma, ETC) were treated.
• Results: Specific results varied with dogs, but
generally positive. Tumor sizes were drastically
reduced. No reoccurrence of cancer in 5 dogs
operated and given artemisinin.
Research on Artemisinin:
Human Breast Cancer Cells
in vitro
• Most recent research was published
(2001) on a breast cancer cell line (HB
27) in vitro.
• Breast cancer cells treated with
dihydroartemisinin and holotransferrin
were almost completely eliminated
(after 16 hrs of treatment cell count was
only 2% of that at time zero).
Research on Artemisinin:
Human Breast Cancer Cells
in vitro
• A morphological examination of breast
cancer cells treated with
dihydroartemisinin and holotransferrin
showed that they were undergoing
apoptosis and necrosis.
• Drug had no effect on normal breast
cells.
FI GU R E 1
Breast Cancer Cells in vitro
undergo rapid and almost
complete cell death (98%)
after treatment with
dihydro-artemisinin and
holotransferrin.
100
50
0
0
4
8
12
16
Ti me (hr)
N ormal breas t cells (HTB 125)
Percent of cell count from time zero
Research on Artemisinin:
Percent of cell count from time zero
B reast cancer cel ls (HTB 27)
150
150
100
50
0
0
4
8
12
Ti me (hr)
C ontrol
holotransf errin
dihydroartem isini n
dihydroartem isini n + holotransf errin
16
FIGURE 2
Research on Artemisinin:
150
24 hrs after
replating
8 hrs and
replating
200
time zero
Perecnt of cell count from time zero
Breast cancer cells were
completely non-viable after 8
hours of treatment with
holotransferrin and
dihydroartemisinin, as proved
by replating.
BREAST CANCER CELLS (HTB 27)
holotransferrin
100
dihydroartemisinin +
holotransferrin
50
0
24 hrs after
replating
8 hrs and
replating
150
time zero
Normal breast cell counts
slightly decreased with the
same treatment, suggesting
some damage to cells.
Percent of cell count from time zero
NORMAL BREAST CELLS (HTB 125)
100
holotransferrin
50
0
dihydroartemisinin +
holotransferrin
Principles of Artemisinin Therapy: How to
kill cancer cells
• Starvation by depletion of nutrients
• Exercise by generating H2O2
• Drugs including vitamin C, vitamin D and
artemisinin and analogs
• Alkaline pH in body
Benefits of Exercise
For killing of Cancer Cells:
•
•
•
•
Generates Hydrogen Peroxide.
Results in high concentrations of oxygen in the body.
With the help of vitamin D, puts calcium in bones.
Increases circulation allowing immune cells to reach
cancer
General Benefits:
• Feeling of well-being (increased appetite)
• Increased excretory processes
• Raises Pain Threshold
Conclusion
• Artemisinin can be used to treat
various types of cancer.
• Side effects are minimal and it can
be taken orally.
Catumaxomab
Mode of Action
Trifunctional antibodies:
Proof of principle
1. Activation of T cells
•
Methods:
–
–
•
Co-culture of tumour cell lines (EpCAM-positive and EpCAM-negative) with
peripheral blood mononuclear cells (PBMCs)
Incubated with trifunctional antibody (trAb; catumaxomab) for up to 10 days prior to
immunohistochemical analysis
Results:
–
–
–
–
–
–
–
After addition of trAb, EpCAM-positive cells had altered morphology and were
surrounded by PBMCs
After 72 hours no EpCAM-positive tumour cells could be detected
Clustering of PBMCs occurred in all cultures containing trAb
In cultures without trAb, no clusters of PBMCs were seen
Clusters consisted predominantly of CD3+ T cells
EpCAM-negative tumour cells were unaffected, however clustering of
PBMCs was seen
No difference in cell behaviour between PBMCs from healthy donors or those with
prostate cancer
EpCAM=Epithelial Adhesion Molecule; PBMC=peripheral blood mononuclear cell; trAb=trifunctional
antibody.
Riesenberg, et al. J Histochem Cytochem 2001; 49:911.
Trifunctional antibodies:
Proof of principle
1. Activation of T cells
• Activation of immune effector cells
(CD3+ T cells)
• Results:
– Increased proliferation of
lymphocytes
– Cluster consisted predominantly of
CD3+ T cells
Trifunctional antibodies:
Proof of principle
1. Activation of T cells
• Expression of lytic proteins specific
for cytotoxic T lymphocytes (CTLs)
– trAb-mediated release of perforine
• Results:
– Lymphocytes released perforine
• Cytotoxic T cell
– Evidence that tumour cells are killed
by cytotoxic T cells via necrotic
mode (via osmotic lysis) rather than
apoptosis
Trifunctional antibodies:
Proof of principle
1. Activation of T cells (cont’d)
• Activation of T cells and expression
of lytic proteins
ELISPOT (IFNg)
• Methods:
– Coculture of the tumour cell line BHY with
CD8+ cytotoxic T lymphocytes (CTLs)
– Incubated with or without trAb
BHY
CD8+
– ELISPOT analysis
CD8+
trAb
CD8+
BHY
CD8+
BHY
trAb
ELISPOT (Granzyme B)
• Results:
– CTL activation indicated by IFNg
– Cytotoxic activity mediated by
granzyme B
– Full induction of IFNg and granzyme B
depends on the presence of
EpCAM+ tumour cells
IFNγ=interferon-γ.
Schmitt M, et al. Int J Oncol 2004; 25:841–848.
BHY
CD8+
CD8+
trAb
CD8+
BHY
CD8+
BHY
trAb
Trifunctional antibodies:
Proof of principle
2. Activation of dendritic cells
• Tumour-cell killing mediated by
monocytes/dendritic cells
• Methods:
– Coculture of PCI-1 (EpCAM+ squamous-cell
carcinoma) cells with CD64+ monocytes and
DCs, in the absence of T cells
– Incubation with +/ - BiUII (anti-EpCAM x antiCD3)*
– Lysis measured by cell viability assay (MTT)
• Results
– In co-culture with monocytes and DCs,
tumour cell lysis depends on presence of
trAb
– Tumour cell lysis is most likely due to
trAb-mediated ADCC
*BiUII and catumaxomab originate from different parental
anti-EpCAM antibodies, but recognize the same epitope region
on human EpCAM.
Zeidler R et al. J Immunol 1999;163:1246–1252.
Trifunctional antibodies:
Proof of principle
3. Lytic capacity
• Tumour cell killing with BiUII compared
with the parental antibodies (Abs)
• Methods:
– PBMCs were incubated with PCI-1
– Incubation with +/- BiUII
(anti-EpCAM x anti-CD3) trAb or the
monoclonal parental Abs
(αCD3 and αEpCAM)
– Lysis measured by cell viability assay
(MTT)
• Results
– BiUII displays a much higher lytic
activity compared with parental Abs
Zeidler R et al. J Immunol 1999;163:1246–1252.
Tumour cell lysis
Trifunctional antibodies:
Proof of principle
4. Activation of monocytes/macrophages
• Tumour cell killing by monocytes/macrophages
(phagocytosis)
• Methods
– Coculture of FITC-labelled PCI-1 cells with
CD64+ monocytes
– Incubation with +/- BiUII
(anti-EpCAM x anti-CD3) trAb for 15h
– Monocytes analysed by flow cytometry
– Presence of FITC+ monocytes indicates phagocytosis
of PCI cells
• Results
– Phagocytosis induced by BiUII
– Activation of macrophages indicated by expression of
neopterin and biopterin (not shown)
– Activation of DCs indicated by upregulation of DC-CK1, CD83
and CD86 (co-stimulatory molecules)
Zeidler R, et al. Br J Cancer 2000;83:261–266.
Trifunctional antibodies:
Proof of principle
5. Activation of natural killer cells
• Binding and activation of NK cells resulting in tumour cell lysis by
NK cells (ADCC)
• Methods:
– Highly purified CD56+/CD3– NK-cells were incubated with
+/- BiUII (anti-EpCAM x anti-CD3)
– Antibody binding assessed by flow cytometry
• Results:
Binding of trAb to
highly purified NK
cells
Expression of CD95
(activation marker)
after binding of trAb
Tumor cell lysis by NKcells after binding of
trAb
Trifunctional antibodies:
Proof of principle
6. Antitumour efficacy in vivo
• Mouse model
– Methods:
• Antibody (BiLu = anti-human EpCAM x anti-mouse CD3) was
administered
on days 0, 2, 4 and 7
• Mice were injected intraperitoneally with a lethal dose of B16
(EpCAM+ melanoma) or A20 (EpCAM+ B-cell lymphoma) cells on day
2
Survival after challenge
– Results:
Survival after challenge
with B16-EpCAM cells
with A20-EpCAM cells
100
100
75
% survivors
% survivors
• Anti-mouse EpCAM x anti-CD3 monoclonal antibody kills tumour
Bs(Fab)² = without
cells in vivo
Fc-part
50
75
50
Par Abs =parental
antibodies
• No additional co-stimulation like IL-2 needed
25
25
0
0
0
24
48
72
96
120
days after tumor challenge
bsAb
bsAbW
par.Abs
Ruf and Lindhofer Blood 2001; 98(8):2526–34
contr.
0
30
60
90
120
150
days after tumor challenge
bsAb
par.Abs
bs(Fab´)2
Trifunctional antibodies:
Proof of principle
6. Antitumour efficacy in vivo
(cont’d)
• Long-lasting antitumour protection in
vivo (mouse model)
• Results
– 14 of 18 BiLu treated mice survived the
primary B16-EpCAM tumour challenge
– Rechallenge with B16-EpCAM tumour cells
without additional antibody treatment
– Long-lasting protective immunity: tumorreactive antibodies are not restricted to
EpCAM
– Correlation between humoral (dominant
IgG2a) immune response and survival of
mice
Ruf and Lindhofer. Blood 2001;98(8):2526–34.
Survival after rechallenge with B16EpCAM cells without additional BiLu
treatment
T cells
CD3
• CD3 is a pan T-cell marker expressed exclusively on
all T cells
• CD3 and T-cell receptor form the functional
T-cell receptor complex
• Binding of CD3 leads to an activation of T cells.
MHC=major histocompatibility complex
T cells
CD3
• 2x CD3e
• 1x CD3d
• 1x CD3g
TCR=T-cell receptor.
Source: Holmes N. 2000. Available at: http://wwwimmuno.path.cam.ac.uk/~immuno/part1/lec14/lec15_00.html [Accessed 25 August 2008].
Case Report
Patient with heavily
pretreated pancreatic
cancer
Patient J14: Cytokine measurements (Luminex) I
IL-2
50
Cytokines in pg/ml
45
40
35
30
25
20
15
10
5
0
18.9.2009 (5µg)
23.9.2009 (10µg)
before infusion
29.9.2009 (10µg)
end of infusion
13.10.2009 (10µg)
20.10.2009 (10µg)
24h after infusion
IL-6
2000
Cytokines in pg/ml
1800
1600
1400
1200
1000
800
600
400
200
0
18.9.2009 (5µg)
23.9.2009 (10µg)
before infusion
29.9.2009 (10µg)
end of infusion
13.10.2009 (10µg)
24h after infusion
20.10.2009 (10µg)
Patient J14: Human anti mouse antibody measurements (HAMA)
Plasma; Mean value of six measurements, < 40 ng/ml = negative
18.9.2009 (5µg)
23.9.2009 (10µg)
29.9.2009 (10µg)
13.10.2009 (10µg)
20.10.2009 (10µg)
Before therapy
Negative (< 40 ng/ml)
End of therapy
Negative (< 40 ng/ml)
24h after therapy
Not done
Before therapy
Negative (< 40 ng/ml)
End of therapy
Negative (< 40 ng/ml)
24h after therapy
Negative (< 40 ng/ml)
Before therapy
Negative (< 40 ng/ml)
End of therapy
Negative (< 40 ng/ml)
24h after therapy
Negative (< 40 ng/ml)
Before therapy
Negative (< 40 ng/ml)
End of therapy
Negative (< 40 ng/ml)
24h after therapy
Negative (< 40 ng/ml)
Before therapy
Negative (< 40 ng/ml)
End of therapy
Negative (< 40 ng/ml)
24h after therapy
Negative (< 40 ng/ml)
Immun Plus +++++
a new form of
HAELAN 951 immun plus
Introduction
Asian countries
Western
industrialized
countries
20mg – 80mg Isoflavones
amount per day
Less hormone-dependent
tumors ¹ ² ³
Less coronary disease
Fewer menopausal
symptoms
1 mg - 3 mg isoflavones
amount per day
Higher rate of hormonedependent tumors
High rate of coronary
disease
Common menopausal
symptoms
Genetic differences have been excluded by studies ④. Through Westernization a sharp increase in
breast cancer rate was observed
1.Lee HP, Gourley L, Duffy SW, Esteve J, Lee J und Day NE (1991). Dietary effects on breast-cancer risk in Singapore. Lancet 337(8751):1197-1200.
2. Wu AH, Ziegler RG, Horn-Ross PL, Nomura AM, West DW, Kolonel LN, Rosenthal JF, Hoover RN und Pike MC (1996). Tofu and risk of breast cancer in Asian-Americans.
Cancer Epidemiol Biomarkers Prev 5(11):901-906.
3. Messina M und Wu AH (2009). Perspectives on the soy-breast cancer relation. Am J Clin Nutr 89(5):1673S-1679S.
4. Korde LA, Wu AH, Fears T, Nomura AM, West DW, Kolonel LN, Pike MC, Hoover RN und Ziegler RG (2009). Childhood Soy Intake and Breast Cancer Risk in Asian American
Women. Cancer Epidemiol Biomarkers Prev 18(4):1050-1059.
The History
1992 the National Cancer Institute (NCI) invests 23,7 Mio USD to research
soy. The NCI Journal publishes the study and latest findings about the newly
discovered active substances :
The content of isoflavones in soyfoods was the main objective in studies on far more than 400 000
women.
Soy is one of the best researched food plants, with more than 10,000 relevant publications and 700 to
800 new articles per year (Messina et al. 2009a).
Messina M, Watanabe S und Setchell KD (2009a). Report on the 8th International Symposium on the Role of Soy in Health Promotion and Chronic Disease Prevention and
Treatment. J Nutr 139(4):796S-802S.
Bioavailability und Fermentation
In the plant, isoflavones are bound to sugars as glycosides from
Genistin
Daidzin
Glycitin
In the fermentation (as in immune plus ™ ®) and also partly in the gastrointestinal tract, the
glycosides are split by enzymes in the aglycones:
Genistein
Daidzein
Glycitein
also in other forms such as equol (from daidzein) for example converted
z.B. Equol
However, only about 30% of Europeans
are capable to produce equol in their
own body.
Aglycones are absorbed much better, so
that the bioavailability is increased
significantly .
The amount of Aglykons represents
60% of the total weight of the
glycoside: 100mg Isoflavonglykoside
therefore correspond to about 60 mg of
isoflavone aglycones
Mechanisms of the Phytooestrogene from Soy
•
Anti-estrogen effect: Isoflavones have a weak estrogen effect (1: 1,000 to 1: 10,000). They
bind to estrogen receptors (ER-alpha), without making an impact. They block the body's
“strong” own estrogen. In this mechanism isoflavones act as anti-estrogens.
•
Stimulating the synthesis of SHBG (sex-hormone-binding globulin) in the liver, thus are
more endogenous estrogens in bound (biologically inactive) form
•
Conversion of 17 beta-estradiol through 4- hydroxyestradiol into the „good“ 2hydroxyestradiol indole-3-carbino contained in soy derivative modulates the estrogen
metabolism in such a manner that 4 - Hydroxöstradiol is turned into good 2 OH-estradiol.
•
Natural selective ER-beta agonist isoflavones dock selectively on to the ER-ß receptor and
thus lead to an expression
The Testosterone Metabolism
ER-ß
Anti-proliferation
and anti - inflammatory
Isoflavones
are selective
ER-ß agonists
ER-α
Proliferation and
inflammatory
3ß-Adiol
Estradiol
3ß-HSD*
metabolised 3ß-Adiol
5 α-DHT
Aromatase
5 α-Reductase
Testosterone
With increasing age less 3ß adiol is formed from testosterone, so an imbalance of
ER-ß in favor of ER.α will be created .
Age-related drop in estrogene and testosterone
Inflammation
+
Inflammation plays an important role in tumor development
1)Huang, Y., Cao, S., Nagamani, M., Anderson, K. E., Grady, J. J., und Lu, L. J. (2005). Decreased circulating levels of tumor necrosis factor-alpha in postmenopausal women
during consumption of soy-containing isoflavones. J. Clin Endocrinol. Metab 90 (7): 3956-3962.
2)Dijsselbloem, N., Vanden Berghe, W., De Naeyer, A., und Haegeman, G. (2004). Soy isoflavone phyto-pharmaceuticals in interleukin-6 affections. Multi-purpose
nutraceuticals at the crossroad of hormone replacement, anti-cancer and anti-inflammatory therapy. Biochem. Pharmacol. 68 (6): 1171-1185.
3)Vanden Berghe, W., Dijsselbloem, N., Vermeulen, L., Ndlovu, N., Boone, E., und Haegeman, G. (2006). Attenuation of mitogen- and stress-activated protein kinase-1-driven
nuclear factor-kappaB gene expression by soy isoflavones does not require estrogenic activity. Cancer Res. 66 (9): 4852-4862.
4)Vafeiadou, K., Hall, W. L., und Williams, C. M. (2006). Does genotype and equol-production status affect response to isoflavones? Data from a pan-European study on the
effects of isoflavones on cardiovascular risk markers in post-menopausal women. Proc Nutr. Soc. 65 (1): 106-115.
Two ways to inhibit the vascular endothelial growth factor VEGF
(Vascular Endothelial Growth Factor)
Genistein inhibits the
transcription factor 1
alpha ①
Genistein inhibits the
transmission of signals
from angiotensin II type 1
receptor for VEGF ②
Inhibition of angiogenesis by genistein in human breast cancer cells and glioma cells was confirmed ③
Inhibition of VEGF effects → probably one of the main mechanisms of cancer protective effects, as
observed in epidemiological and clinical studies on isoflavones.
①Guo, Y., Wang, S., Hoot, D. R., und Clinton, S. K. (2007). Suppression of VEGF-mediated autocrine and paracrine interactions between prostate cancer
ells and vascular endothelial cells by soy isoflavones. J. Nutr. Biochem. 18 (6): 408-417.
②Anandanadesan, R., Gong, Q., Chipitsyna, G., Witkiewicz, A., Yeo, C. J., und Arafat, H. A. (2007). Angiotensin II Induces Vascular Endothelial Growth
Factor in Pancreatic Cancer Cells Through an Angiotensin II Type 1 Receptor and ERK1/2 Signaling. J. Gastrointest. Surg. 12: 57-66.
③Schindler, R. und Mentlein, R. (2006). Flavonoids and vitamin E reduce the release of the angiogenic peptide vascular endothelial growth factor from
human tumor cells. J. Nutr. 136 (6): 1477-1482.
Immunological Studies of Supplement ZhenHua 851
Japan Health Management Center,
Osaka University of Foreigner Studies and Japan Institut of General Medical Sciences
Design: Double-bind placebo Crossover (13 control
group und 13 Placebogroup)
Investigator:Weimu Xisuhen // Gaoqiao Li
Control drug: 2400 mg Zhenhua 851 fermented
Sojaextract
Duration: 2 Weeks
Date: March 2000
•
Results: The substance Zhenhua 851
increases the activity of killer cells (NK
*) cells after a few hours and increases
the number of leukocytes (white blood
cells, WBC) significantly. The cellular
immune response was greatly
increased and the sIL-2R (soluble
interleukin 2 receptor) was improved.
•
Sojaextract in Immun plus® shows a positive Effect on NK cells and Interleukins
Study of fermented Soy extract ZhenHua 851
Therapeutic effect of adjuvant treatment
for cancer with ZhenHua 851 fermented soy
Karnofsky performance scale
70
Karnofsky performance scale KPS Index
Life quality index
68
66
67.31
65.31
65.64
Therapiebeginn
64.2
64
Therapieende nach 2
Monaten
62
60
Chemo 101 Pat. +
ZhenHua
Kontrollgruppe 103 Pat.
nur Chemo
Quality of life has improved significantly in the Zhenhua group
while deteriorating the control group accordingly
Sojaextract in Immun plus® has a positive effect on the quality of life
Investigator:Prof. ZenHua Zang (Alle andern nicht aufgeführt)
Studienort: Department of Radiotherapy and Department of Internal Medicine in Fujian Oncology Hospital, Fuzhou First Hospital, Division of Oncology Surgery, Department of Oncology, Fujian
Provincial HospitalChemo Treatment 136//Control 131
Radiotherapy Treatment 34//Control 32
Period: April – Oktober 1992
Publikation:Oktober 1992 Chinese Medical Journal
Study of fermented Soy extract ZhenHua 851
Therapeutic effect of adjuvant treatment
for cancer with ZhenHua 851 fermented soy
The serum protein, a protein for the authoritative malnutrition has improved
significantly during the chemotherapy in the Zhenhua group while
deteriorating the control group accordingly
Sojaextract in immune plus ® has a positive effect on malnutrition during chemotherapy
Studienleitung:Prof. ZenHua Zang (Alle andern nicht aufgeführt)
Studienort: Department of Radiotherapy and Department of Internal Medicine in Fujian Oncology Hospital, Fuzhou First Hospital, Division of Oncology Surgery, Department of
Oncology, Fujian Provincial Hospital
Chemo Treatment 136//Control 131 Bestrahlung Treatment 34//Control 32
Zeitraum: April – Oktober 1992 Publikation:Oktober 1992 Chinese Medical Journal
Study of fermented SojaextractZhenHua 851
Therapeutic effect of adjuvant treatment
for cancer with ZhenHua 851 fermented soy
The white blood cell count has improved significantly in the
Zhenhua group while deteriorating the control group accordingly
Soy extract in immune plus ® increases leukocytes
Studienleitung:Prof. ZenHua Zang (Alle andern nicht aufgeführt)
Studienort: Department of Radiotherapy and Department of Internal Medicine in Fujian Oncology Hospital, Fuzhou First Hospital, Division of Oncology Surgery, Department of
Oncology, Fujian Provincial Hospital
Chemo Treatment 136//Control 131 Bestrahlung Treatment 34//Control 32
Zeitraum: April – Oktober 1992 Publikation:Oktober 1992 Chinese Medical Journal
Study update
positive effects with soy
„Shanghai Breast Cancer Survival Study“
Prof. Dr. Xiao Ou Shu - Vanderbilt University (Nashvill, USA)
• 5043 women after breastcancer therapy
• Ongoing study since 5 years
•
First preliminary results of this largest
ongoing study of breast cancer patients show
a more favorable course of the disease under
the influence of soy isoflavones, with a
relative risk of 0.67 (p = 0.01, 95% CI 0.50 to
0.88) for disease-specific mortality in the
highest compared to the lowest
quartile. These for isoflavones safety
questions most relevant results were
published recently (Shu et al. 2009)
Prof. Shu has been able to use clinical data to show life-prolonging effects with isoflavones in breast
cancer patients
and the benefits of the combination of tamoxifen with isoflavones (Shu 2009)
① Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W und Lu W (2009). Soy intake and breast cancer survival. JAMA 302(22):2437-244
J Nutr. 2009 Apr;139(4):796S-802S. Epub 2009 Feb 18.
Report on the 8th International Symposium on the Role of Soy in Health Promotion and Chronic Disease Prevention and Treatment.
Messina M, Watanabe S, Setchell KD.
Study update
Randomized trials in women with breastcancer can be found in the published literature where 32- 132 mg isoflavones a day over a
period after 3 years were despensed and had no adverse effects on cancer development
Randomized trials in women with breast cancer show: 36-100
mg isoflavones per day over a period of up to three years, no
adverse effects on cancer development was detected
(Burke et al. 2003; Cheng et al. 2007; Hargreaves et al.
1999; Kaari et al. 2006; Marini et al. 2008; Maskarinec et
al. 2009; Nahas et al. 2007; Powles et al. 2008; Qin et al.
2009; Verheus et al. 2008).
A cohort study of 1954 breast cancer patients showed a
lower relapse rate and no adverse interaction with
tamoxifen.
There have been explicitly stated positive effects against
estrogen-receptor-positive breast cancer
(Guha et al. 2009).
Data points to protection against endometrial cancer with
increased intake of isoflavones
Goodman et al. 1997; Horn-Ross et al. 2003; Xu et al. 2004
Meta-analysis of 20 studies * with a duration of up to three
years with a daily dose of 35-132 mg isoflavones. Not one
case led to an influence on the structure of the
endometrium.
*Albertazzi et al. 2005; Baber et al. 1999; Balk et al. 2002; Burke et al. 2003;
Caserta et al. 2005; Cheng et al. 2007; Crisafulli et al. 2004; D'Anna et al.
2007; Duncan et al. 1999b; Duncan et al. 1999a; Han et al. 2002; Kaari et al.
2006; Marini et al. 2008; Nahas et al. 2007; Nikander et al. 2005; Penotti et al.
2003; Petri Nahas et al. 2004; Powles et al. 2008; Sammartino et al. 2003;
Scambia et al. 2000; Upmalis et al. 2000).
Study update
Phytoestrogenes wrongfully denunciated
The risk of Breastcancer rises with syntetic
gestagene
(Conner et al. 2008)②
WHI „Womens Health Initiative“
(Rossouw et al. 2002)①
HET in der Menopause
16 000 postmenopausal women between the
ages of 50 -79
•
Duration 5.2 years
•
Terminated early because of
41% more strokes, 29% more heart attacks
50% thrombosis 26 %more breastcancer
It seems that The development of
complications (….)is not due by estrogene
itself, but by the combination of synthetic
gestagene and estrogenes.
Increase in breast tissue density and cell
division was only detected in women
treated with high doses of estrogene and
progestin combined (2 mg estradiol + 1
mg norethisterone acetate).(Söderqvist
2009) ③
∙ Estrogen hypothesis = phytoestrogen = breast cancer → can no longer accurate
∙ Interplay of the estrogen receptor alpha / beta was not taken into account
∙ Phytoestrogens are ER-ß agonist
∙ Isoflavones no steroids but heterocyclic phenols
① Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM und Ockene J (2002). Risks and benefits of
estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288(3):321-333.
② Conner P, Lundström E und von Schoultz B (2008). Breast cancer and hormonal therapy. Clin Obstet Gynecol 51(3):592-606.
③ Söderqvist G (2009). Effects of conventional hormone therapy (HT) on breast tissue density and cell proliferation. Symposium on Evaluating the Efficacy and Safety of Isoflavones for
Postmenopausal Women, 13-14 May. Milan (Italy): Council for Responsible Nutrition.
I hope you didn’t fall asleep…
Thank you very much for your kind attention!
Thank you for your attention
Privat Hospital Dr. Ursula Jacob
Silberwaldstrasse 34
D 72280 Dornstetten –
Hallwangen Germany
Tel: +49 7443 964 240
Fax.: +49 7443 964 24 99
[email protected]
www.ursula-jacob.de
[email protected]
www.rgcc-genlab.com
privat clinic
Dr. Ursula Jacob
Silberwaldstraße 34
72280 Dornstetten-Hallwangen
Tel.: +49 (0) 7443 – 964 24 – 0
Fax: +49 (0) 7443 – 964 24 – 99
[email protected]
www.ursula-jacob.de
Freitag, 17. Juli 2015

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