Ozonioterapia em

Oncologia - Emilia Serra

- Dez 2010
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Ozonioterapia Em Oncologia - Emilia Serra - Dez 2010

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Visão Biológica das Neoplasias

Radicais Hipóxia Vírus
livres

Oferta de glicose

Inflamação crônica
Déficit imunológico
Célula normal Déficit mineral e vitaminas (Se, Mg,
Zn, Vitamina D) Célula tumoral
Metais pesados
Hiperproteinização / Hiperacidez
Disbiose intestinal
Alergia alimentar tardia (imunocomplexos)
Campos de interferência / Focos (dentes)
Geopatia

Visão Biológica das Neoplasias

• Produção de lactato
• Indução de HIF-1
• Avidez por glicose
• Manutenção de
hiperacidez
Glicólise anaeróbica
• Diminuição da
apoptose
• Destruição da MEC
• Fatores de
Célula tumoral crescimento
• Neoangiogênese
• Metástases

Silvia Menendez

Efeitos Biológicos da Ozonioterapia

Efeitos Biológicos da Ozonioterapia

Os efeitos biológicos da ozonioterapia incluem:
• o aumento do metabolismo e da liberação de oxigênio a nível
tecidual
• imunomodulação (indução de citocinas - interferons, interleucinas e
fatores de crescimento)
• manutenção do balanceamento redox celular (equilíbrio
antioxidantes/pró-oxidantes) induzindo um aumento do sistema anti-
oxidante intracelular
• influência na síntese e na liberação dos eicosanóides (metabólitos
do ácido aracdônico)
• propriedades virustáticas

A hormése (adaptação do organismo ao meio), levando a uma

sinalização celular com uma resposta de proteção celular e indução
de apoptose das células tumorais, parece ser um mecanismo
adicional de ação da ozonioterapia em Oncologia.

Mantainsthecellular
redoxbalance
IT
Antioxidants Prooxidants

Increases
OZONE Influencesinthe
oxygen synthesis/releaseof
metabolism eicosanoids
(Oincreasesoxigenationin
hypoxictumors).Tumorhypoxia
Immunological
increaseresistanceto
radiotherapyandchemotherapy).
regulator PGE2
Arachidonic.Acid

Cyclecaygenine-2

PGG,
COXIBS
Parezidas»

PGH,
PiSunthabas

TXA,PGD,PGE,PI,PEFa

Silvia Menendez Colar

Ozone selectively inhibits growth of human

cancer cells.
Sweet F, Kao MS, Lee SC, Hagar WL, Sweet WE.
Science. 1980 Aug 22;209(4459):931-3.]

The growth of human cancer cells from lung, breast, and uterine tumors
was selectively inhibited in a dose-dependent manner by ozone at 0.3
to 0.8 part per million of ozone in ambient air during 8 days of culture.
Human lung diploid fibroblasts served as noncancerous control cells.
The presence of ozone at 0.3 to 0.5 part per million inhibited cancer cell
growth 40 and 60 percent, respectively. The noncancerous lung cells
were unaffected at these levels. Exposure to ozone at 0.8 part per
million inhibited cancer cell growth more than 90 percent and control
cell growth less than 50 percent. Evidently, the mechanisms for
defense against ozone damage are impaired in human
cancer cells.
PMID: 7403859 [PubMed - indexed for MEDLINE]

Os protocolos de ozonioterapia utilizados na

prevenção e tratamento de tumores
incluem combinações variadas de:
!grande auto-hemoterapia (GAHT)

!pequena auto-hemoterapia (PAHT)

!insuflação retal

!ozonioterapia intraperitoneal (resultados

preliminares muito promissores no
controle e até mesmo erradicação de
tumores agressivos)
!infiltração local da mistura gasosa

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Oncogênese

Flora intestinal

Vírus

Déficit Hipóxia
Imunológico
Inflamação crônica Stress oxidativo

Hipóxia

Pesquisar
 

The Prime Cause and Prevention of Cancer

RevisedBaixar
Lindau Lecture
By Otto Warburg !
(Director, Max Planck Institute for Cell Physiology, Berlin-Dahlem, Germany)
English Edition by DEAN BURK*, National Cancer Institute, Bethesda, Maryland

• There are prime and secondary causes of diseases. For example, the prime
cause of the plaque is the plaque bacillus, but secondary causes of the
plaque are filth, rats, and the fleas that transfer the plaque bacillus from rats
to man. By a prime cause of a disease I mean one that is found in every 
case of the disease.
• Cancer, above all other diseases, has countless secondary causes. But,
even for cancer, there is only one prime cause. Summarized in a few
words, the prime cause of cancer is the replacement of
the respiration of oxygen in normal body cells by a
fermentation of sugar.
• All normal body cells meet their energy needs by respiration of oxygen,
whereas cancer cells meet their energy needs in great part by fermentation.
All normal body cells are thus obligate aerobes, whereas all cancer cells
are partial anaerobes. From the standpoint of the physics and chemistry of
life this difference between normal and cancer cells is so great that one can
scarcely picture a greater difference. Oxygen gas, the donor of energy in
plants and animals is dethroned in the cancer cells and replaced by an
energy yielding reaction of the lowest living forms, namely, a fermentation
of glucose.

Johannes Coy

German Biologist and researcher, who discovered the

metabolic pathway, which Prof.Otto Warburg already
postulated in 1924.
1996: First description of the TKTL1-
Gene (Transketolase like enzyme)
2005: Description of the enzyme and
metabolic pathway of TKTL1 and the
importance for cancer cells:
(fermentation of Glucose to R-lactic acid, which
turns the cancer cell metabolism into highly
malignant)

ParacelsusKlinik
Lustmühle

TKTL1-negativ TKTL1-positiv

 © Dr. med. Thomas Rau, Chefarzt, Paracelsus Klinik Lustmühle, Schweiz Juni 2008

Hipóxia
As células saudáveis obtém energia através da respiração
aeróbica, em contraste com as células tumorais que, em
presença de hipóxia, o fazem preferencialmente por
meio da fermentação anaeróbica.
! a hipóxia crônica leva à alteração do metabolismo
celular, liberação do fator induzível por hipóxia (HIF-1),
produção da citocina imunosupressora VEGF e de
angiopoetinas e neoangiogênese de vasos anormais.
! a hipóxia também pode induzir metástases e aumentar a
resistência à radioterapia (RXT) e à quimioterapia (QT),
favorecendo o crescimento tumoral e perpetuando o
processo neoplásico.
! na presença de hipóxia, as células tumorais reforçam a
conversão de glicose em lactato, através de oncogenes
e da expressão da enzima TKTL-1 (transketolase-1) que
ativam a via glicolítica anaeróbica, promovendo acidose
intracelular persistente.

Efeitos da Hipóxia
Alteração do metabolismo celular
Produção de angiopoetinas
Liberação de HIF-1 (Fator Induzível pela Hipóxia)
Neoangiogênese de vasos anormais
Crescimento tumoral
Metástases
Resistência à RXT e QT

Hipóxia tumoral : 2-10 mm Hg

Tecido normal: 45-50 mm Hg

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glucose

RAS

VHL
HIF1
glucose

PDK1 CAcvcle
AKT
MYC
pyruvate acetvl-CoA

PDH
-IV
p lexI
Com
lactate
mtDNAmutations

O2
p53
HaO
ROS

CancerResearchReviews

Figure1.MolecularunderpinningsoftheWarburgeffect.TheWarburgeffect(highlighteg)describestheenhancedconversionofglucosetolactatebytumor
cells,eveninthepresenceofadequateoxygenthatwouldordinarilybeusedforoxidativephosphorylation.ActivationoftheAKToncogeneresultsinincreased
glucosetransportationandstimulationofHK2activity,whichenhancesglycolyticrates.TheMYConcogeneisdepictedtoactivateglycolyticgenesand
mitochondrialbiogenesis,whichwhensustainedbyhighMYClevelscanresultinreactiveoxygenspecies(ROS)production.ROScould,inturn,causemtDNA
mutationsthatrendermitochondriadysfunctional.p53isshowtostimulaterespirationthroughactivationofacomponentoftherespiratorychain.Inaddition
tohypoxicstabilization,HIF-1isshowntobeincreasedbyRASandlossofVHL,whichmediatesitsdegradation.HIF-1transactivatesglycolyticgenesaswellas
directlyactivatesthePDK1gene,whichinturninhibitsPDHthatcatalyzestheconversionofpyruvatetoacety/-CoA.Acetyl-CoAisshowmtoantertheTCA
cydle,whichdonateselectronstothemitochondrialrespiratorychaincomplexesltoIV.InhibitionofPDHbyPDK1attenuatesmitochondrialfunction,resultingin
theshuntingofpyruvatetolactate.

Normoxia Hypoxia

lowpO2
highpO?
HIF-10)(HIF-1B HIF-10 HIF-1B
prateasame

HIF-1B
CBP/p300HIF-100 H
XIONUHRE10.00.0X
metabolism survival/death
{HIF-10 (HIF-13
angiogenesisinvasion/metastasis

Degradation Activation
Fig.3.Degradationandactivationofthehypoxia-induciblefactor-la(HIF-1)transcriptionfactorinnormoxiaandhypoxi,respectidy.The
transcriptionfactorHIFiscomposedofanalphaandbetasubunit.Underatmosphericlevelofoxygen(normoxia)theHIF-laandHIF-1ßsubunits
areconstitutivelyexpressod.WhiktHIF-laisrapidlydegradedbythe26Sproteasomalsystem,HIF-1Bremainsconstant.Incontrast,underlow
levesoloxygen(hypoxn)HIF-loescapesdegradation,associateswithHIF-1fandtogethertheybindtohypoxm-responseclements(HR.E)intarget
genes.Recruitmentofco-activatorssuchasCBP/p300thenresultsintranscriptionalactivationofmultipletargetgenesinvolvedinfunctionssuchas
mctabolism,angiognesk,invasion/metastasisandcellsurvival/death.

292 CancerMetastasisRev(2007)26:291-298

Fig1HIF-1-mediatedmeta-
bolealterations.Stabilized
Hifi-1etherbyhypoxinorby
glucose
non-hypoxieoneogenicevents
includinglossoftumorsup-
pressorsandactivationofonco-
genesandgrowthfactor
signalingstransactivatesgenes glut
thatareinvolvedinmetabolic
reprogrammingoftumorcells. COz
Inductionofgenesencoding glucose
glucosetransporters(glut)and
virtuallyallglycolyticenzymes 9 HCO;+H*
chancesglucoseuptakeand Hypoxia GLYCOLYSIS CA
glycolyticmetabolismintolac- Lossoftumor
tate.Toxieintracelularacidosis
suppressors
largelycausedbyexcessivelat- (VHL,TSC,SDH)
lategenerationisrelievedby pyruvate
carbonicanhydrase9(CA9), Activationof
whichgencratesextracellular oncogenes
(Src,Ras)
HIF
bicarbonatethatistranslocated
intocytosoltoalleviateintra-
Growthfactor
celularacidosis.Foruvatede-
signalings(IGF.
bydrogenasekinase1(PDK1) EGF,HER2,PI3S)
inactivatespyruvatedehydroge-
nase(PDH)complexinthe ROS lactate
mitochondriaresultinginsup-
pressionofconversionofpyru-
vatetoacetyl-CoA. ROS
Compositionofeytochromee
oxidusesubunits(00X4-1and
00X4-2)thatarecomponentsof IV PDK1
mitochondrialelectrontranster
E XH
complexIV,isregulatedby ATP PL PDH
HIF-I.TheinitialburstofROS
COM
frominefficienthypoxicmito-
chondriastabilizesHIF-1,which
inturnreducesROSproduction TCACYCLE
bydiminkshingmitochondrial
respirationthroughPDKiand acetyl-CoA
increasingelectrontransportef-
ficiencythroughCOX4-2

Cancer'sMolecularSweetToothandtheWarburgEffect
Jung-whanKim'andChiV.Dang
'DivisionofHematology,DepartmentofMedicine,TheSidneyKimmelCompreensiveCancerCenteratJohnsHoplins,
JohnsHopkinsUniversitySchoolofMedicine.Baltimore,Maryland

Abstract Recentadvancesingenomicsandproteomicshaveprovided
insightsintomolecularmechanismsthatcontributetothe
Morethan80yearsaço,therenownedbiochemist Outo
Warburgeffectandtumorigenesis.Inthisreview,molecular
Warburgdescribedhowcancercellsavidlyconsumeglucose
andproducelacticacidunderacrobieconditions.Recent
mechanismsthatprovidesignificantmolecularinsightsintomany
studiesarguingthatcancercellsbenefitfromthisphenom-
aspectsoftheWarburgeffect.suchasoncogenes(AKT,MYC,and
RAS),tumorsuppressors(succinatedehydrogenase(SDH)and
enon,termedtheWarburgeffect,havereneweddiscussions
aboulitsexactroleascause,correlate,orfacilitatorofcancer. fumaratehydratase(FIl)I,andthenovelHIFpathway(pyruvate
Molecularadvancesinthisareamayreveallactiestoexploit dehydrogenasekinase(PDK1)]willbediscussed.
thecancercell's"sweettooth"forcancertherapy.(CancerRes
2006:66(18):8927-30) Oncogenes,TumorSuppressors,andthe
WarburgEffect

Aerobicglucosemetabolism:
CHg0,+38ADP+38P+60,*600;*44H,0+38ATP
ose
c
glu

Glut
Glycolysis 我ATP
Bloodvessel **Pyruvate TCA
Cycle OXPHOS
2ATP
Lacticacid MitocondrialCO
,
respiration
Anaerobicglucosemetabolism:
C.H,O.+2ADP+2P,-*2lactate+2H*+2H,0+2ATP
Fig.S.Tumourcellaswitchtromacrobictoamacrobieglucosemetabolismdespitethelowerenergyyicld.Non-malignantandmalignantcellstake-up
glucosefromthebloodstreampimembraneglucosetransporters(Glut)andmetabolizeglucosethroughtheglycolyticpathwaytoformpyruvate.
Pyruvateinnon-malignantcellsentersthemitochondrialtricarboxyleacideycle(TCA)andoxygen-requiringoxidativephosphorylation(OXPHOS)
toproduceCOaand38moleculsofATP.IncontrastmalignantcellsconvertpyruvatetolacticacidtoproducetwomoleculesotATP.

ParacelsusKlinik
Lustmühle
TKTL-1 Cancer Metabolism

The scientific findings of Dr.Johannes Coy:

There are cancer cells with a special TKTL-1-metabolism, which are
specially malignant, infiltrativ and only fermentate glucose. They can be
blocked by total glucose-reduction.

The bad R-lactate can be inhibited by l-lactate.

With specific fatty acids you can „isolate“ these cells.

 © Dr. med. Thomas Rau, Chefarzt, Paracelsus Klinik Lustmühle, Schweiz Juni 2008

ACTIVEMITOCHONDRIA INACTIVEMITOCHONDRIA

Combustionprocesswithoxygen Fermentationprocesswithoutoxygen Legend

Nutrients Bloodsugar

ParacelsusKlinik
Lustmühle

Switch

TKTL1-Enzyme
CarbondioxadeandWater Lacticacid
Cellnucleus
Energygenerationofalessdangerous" Energygenerationofa„dangerous"
TKTL1-negativetumorcell TKTL1-positivetumorcell (NUMitochondrium

Different types of cancer cells

!
TKTL1- negative: !
TKTL1- positive:
!
Mitochondrias are active !
Mitochondrias are inactive
!
Glucose gets metabolized in
citric acid cycle !
Glucose gets fermentated

!
36 ATP !
2 ATP

!
Production of H2O and CO2 !
Production of lactic acid
!
Better Prognosis !
Prognosis much worse!

 © Dr. med. Thomas Rau, Chefarzt, Paracelsus Klinik Lustmühle, Schweiz Juni 2008

Metabolism of Cancer Cells,

the 2 different metabolic types

Glucose Glucose
or Fats

O2
O2
TKTL1-negative
TKTL1-positiv

CO2 + H2O Lactic

acid

 © Dr. med. Thomas Rau, Chefarzt, Paracelsus Klinik Lustmühle, Schweiz Juni 2008

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ParacelsusKlinik
Lustmühle
Clinical relevance and results

!
The more TKTL-1-positive cells are in a cancer, the
worse is the prognosis.

!
The more TKTL-1-positive cells are in a cancer, the less
the cancer responds to chemotherapy.

!
The more TKTL-1-positive cells are in a cancer, the
more the surroinding gets blocked and infiltrated.

 © Dr. med. Thomas Rau, Chefarzt, Paracelsus Klinik Lustmühle, Schweiz Juni 2008

ParacelsusKlinik
Lustmühle
TKTL1-cells even get selected by chemo !!

TKTL1-negative TKTL1-negative & positive

1000

1. Chemotherapie
Arei
0
0
0
10

2. Chemotherapie

Death of the der TKTL1- Selection of the TKTL1-

negative cells ! positive cells !

 © Dr. med. Thomas Rau, Chefarzt, Paracelsus Klinik Lustmühle, Schweiz Juni 2008

Prognosis: e.g. Colon- Cancer

Langbein S et al: Expression of transketolase TKTL1 predicts colon an urothelial cancer patient
survival: Warburg effect reinterpreted. British Journal of Cancer, 2006; 94(4): 578-585

 © Dr. med. Thomas Rau, Chefarzt, Paracelsus Klinik Lustmühle, Schweiz Juni 2008

aNormal bTumour

Blind
ends

Temporary
occuson Hypoxia

Breakin
veasewalls

Pedbloodcells
Avshunt

Figure1|Thevascularnetworkofnormaltissueversustumourtissue.Tumourscontainregionsofhypodaandnecrosis
becausetheirvasculaturecannotsupplyoxygenandothervitalnutrientstoallthecells.Whereasnormalvasculature(a)ls
hierarchicallyorganized,withvesselsthataresuficientlyclosetoensureadequatenutrentandoxygensupplytoallcells,tumour
vesgels(b)arechaotic,dilated,tortuousandareoftenfarapertandhavesluggishbloodflow.Asaconsequence,areasofhypoxia
andnecroslsoftendevelopdistantfrombloodvessels.Inadditiontotheseregionsofchroniofordifusion-limited)hypoxia,areasof
acuteforperfusion-limited)hypoxiacandevelopintumoursasaresultofthetemporaryclosureorreducedflowincertainvessels.
AdaptedtromREF.125.AV,arteriovenous.

Tumor Hypoxia and Ozone Therapy

• Author: Kornel Kusznieruk
• Affiliation: University of Western Ontario
• Date Published: Tuesday October 24th, 2006 @ 23:30:29
EST

Abstract
• This paper describes the importance of increasing oxygen
content in tumors and provides some possible ways of doing
this.

• The SCP Journal

Tumor Hypoxia
1. Stimulates angiogenesis

2. Suppresses immune function by:

- Blocking TNF-α toxicity
- Blocking systemic TNF-α activity by shed receptors
- Blocking lymphocyte proliferation
- Blocking LAK cell generation and activity
- Induces production of the immune-suppressive
cytokine VEGF

3. Stimulates resistance to radio- and chemotherapy.

Efeitos da Hipóxia
A ozonioterapia ativa o metabolismo das
hemácias e aumenta a flexibilidade de
suas membranas celulares, além de
promover o aumento da síntese de 2-3
DPG, que desloca a curva de dissociação
da oxihemoglobina para a direita e
estimula a liberação de oxigênio a nível
tecidual. Tal aumento da oxigenação inibe
o HIF-1, estimulando a apoptose e
diminuindo o crescimento tumoral.

Ozonioterapia e
Oxigenação Tissular
Buckley et al., 1975
Freeman et al., 1979
2.3D
PG Washüttl et al., 1977, 1986
Lell,Viebahn et al., 2001
Hoffmann, Viebahn, 2001

Oxygen saturation
100% Formação de peróxidos e
without DPG ativação do metabolismo das
hemácias, sistema da
with DPG
glutationa com melhora da
liberação de oxigênio nos
Oz-Sättigung

Oxygen partial pressure pO2 in mm Hg tecidos

20 40 60 80 100