Breakthroughs in the Quest to Cure Cancer
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Breakthroughs in the Breakthroughs in the Quest to Cure CancerQuest to Cure Cancer
Professor Gerry PotterProfessor Gerry Potter
Founder of the Founder of the
Cancer Drug Discovery GroupCancer Drug Discovery Group
Leicester School of PharmacyLeicester School of Pharmacy
De Montfort University, Leicester, De Montfort University, Leicester, UKUK
Early DaysEarly Days
University of ManchesterUniversity of Manchester1983-19861983-1986
““Mechanism of Action of Anticancer Agents”Mechanism of Action of Anticancer Agents”
- Most are generally toxic (cytotoxic)Most are generally toxic (cytotoxic)- Toxic to liver, kidneys, heart, white blood Toxic to liver, kidneys, heart, white blood
cellscells- Many are highly mutagenic & carcinogenicMany are highly mutagenic & carcinogenic- Key Issue is SelectivityKey Issue is Selectivity
Chemotherapy Agents Mutate DNA and are Highly Carcinogenic
Institute of Cancer Institute of Cancer ResearchResearch
1987 - 19941987 - 1994Drug Development Section, CRC Drug Development Section, CRC
LaboratoryLaboratory
developed new selective agents fordeveloped new selective agents for
Breast & Prostate CancerBreast & Prostate Cancer Tamandron (Antiandrogen)Tamandron (Antiandrogen) Idoxifene (An Improved Tamoxifen Idoxifene (An Improved Tamoxifen
Analogue)Analogue) Ribonucleotide Reductase InhibitorsRibonucleotide Reductase Inhibitors Abiraterone Acetate (ZytigaAbiraterone Acetate (ZytigaTMTM))
Selective Anticancer AgentsSelective Anticancer AgentsDeveloped by Prof Potter at Developed by Prof Potter at
thetheInstitute of Cancer ResearchInstitute of Cancer Research
OH
HO
I
ON
ONMe2
O
N
HO
ON
O
IdoxifeneStilbene AntiestrogenCancer Res., 55, 1070-1074 (1995).
TamandronStilbene AntiandrogenNew Scientist, 16, 23 May 1992
CB7653Non-steroidal CYP17 InhibitorJ. Med. Chem., 38, 4191-4197 (1995).
Abiraterone AcetateCYP17 InhibitorJ. Med. Chem., 38, 2463-2471 (1995).
Design of Abiraterone Design of Abiraterone AcetateAcetate
Zytiga (Abiraterone Acetate) Designed by the Steroid to Haeme Juxtaposition of the Lyase Transition State #3 of a Proposed
Catalytic Cycle for the Lyase/Hydroxlase Enzyme CYP 17 Derived by Professor Potter
Design & Synthesis of Design & Synthesis of AbirateroneAbiraterone
Journal of Medicinal Chemistry, 38, 2463, 1995
Potent Androgen AblationPotent Androgen Ablationby Abiraterone (CB7598)by Abiraterone (CB7598)
Journal of Steroid Biochemistry and Molecular Biology, 50, 267, 1994
Abiraterone (Zytiga)Abiraterone (Zytiga)•Successfully completed Clinical Trials
•Approved by NICE for use on the NHS in the UK
•Licensed to Johnson & Johnson marketed as “Zytiga”
•FDA and EMA Approved for the treatment of advanced Prostate Cancer after taxotere chemotherapy has failed
•Currently used worldwide by thousands of patients
Link Between Diet and Link Between Diet and CancerCancer
LowerLower incidence of cancer correlates incidence of cancer correlates withwith
HigherHigher consumption of fruits & consumption of fruits & vegetablesvegetables
(Western diet correlates to(Western diet correlates to
high incidence of cancer)high incidence of cancer)
Nobody really knows why !Nobody really knows why !
(many theories, antioxidants, (many theories, antioxidants, phytoestrogens, polyphenols etc)phytoestrogens, polyphenols etc)
Understanding this link would help•cancer prevention•cancer treatment
Discovery of a Tumour Discovery of a Tumour Specific Salvestrol Specific Salvestrol
Metabolising EnzymeMetabolising Enzyme(Salvestrol Activase)(Salvestrol Activase)
BreastBreast BrainBrain LungLung OvarianOvarian ProstateProstate
BladderBladder ColonColon KidneyKidney OesophagaelOesophagael StomachStomach
Cancer Research, 57, 3026, 1997
Stomach Oesophageal
Ovarian Myosarcoma
Normal Colon Colon Cancer Dysplasia
Salvestrol Activase is a Salvestrol Activase is a Tumour Suppressor EnzymeTumour Suppressor Enzyme Works as a cancer preventing enzyme acting via Works as a cancer preventing enzyme acting via
natural prodrug bioactivation, i.e. salvestrol natural prodrug bioactivation, i.e. salvestrol activationactivation
Expressed in a variety of tumoursExpressed in a variety of tumours Generic Rescue MechanismGeneric Rescue Mechanism Irrespective of tumour type or oncogenic originIrrespective of tumour type or oncogenic origin Cancers arise from many different mutagenic originsCancers arise from many different mutagenic origins
Induction tightly regulatedInduction tightly regulated Induced by various cellular damaging effectsInduced by various cellular damaging effects
G.A. Potter, British Journal of CancerG.A. Potter, British Journal of Cancer, , 8686 (Suppl 1), S12, (Suppl 1), S12, 20022002
Designed Prodrugs Designed Prodrugs Activated by a Tumour Activated by a Tumour
Specific EnzymeSpecific Enzyme Synthetic Prodrugs DesignedSynthetic Prodrugs Designed
Shows very exciting tumour selective activityShows very exciting tumour selective activity No toxic effectsNo toxic effects Development to clinical use taking many yearsDevelopment to clinical use taking many years
Realised molecular relationship to natural compoundsRealised molecular relationship to natural compoundsthat have cancer preventative propertiesthat have cancer preventative properties Could have a natural version of this drugCould have a natural version of this drug Could explain link between diet and cancerCould explain link between diet and cancer
Potter et al, British Journal of CancerPotter et al, British Journal of Cancer, , 8686 (Suppl 1), (Suppl 1), S117, 2002S117, 2002
Targeting Growth Factor Targeting Growth Factor PathwaysPathways
Designed Prodrugs Designed Prodrugs Activated by a Tumour Activated by a Tumour
Specific EnzymeSpecific Enzyme Synthetic Prodrugs DesignedSynthetic Prodrugs Designed
Shows very exciting tumour selective activityShows very exciting tumour selective activity(10,000-fold selective)(10,000-fold selective) No toxic effects observedNo toxic effects observed Currently Undergoing Pre-clinical development at the Currently Undergoing Pre-clinical development at the
Gray Cancer Institute, LondonGray Cancer Institute, London Phase I Clinical Studies being planned in the USPhase I Clinical Studies being planned in the US Results look very promisingResults look very promising Drug has real potential as a non-toxic tumour selective Drug has real potential as a non-toxic tumour selective
anticancer agentanticancer agent
Potter et al, British Journal of CancerPotter et al, British Journal of Cancer, , 8686 (Suppl 1), S117, (Suppl 1), S117, 20022002
Classic Chemotherapeutic Classic Chemotherapeutic AgentsAgents
Methotrexate
0
25
50
75
100
125
10 -3 10 -2 10 -1 100 101 102
control concentration (M)
Normal Breast
Breast Tumour
IC50 =0.06M
IC50 =0.04M
surv
ival
(%
)
sem
•Most are equally toxic to normal and tumour cells•Some are actually more toxic to normal cells than tumours
(e.g. Taxol, Doxorubicin, 5-FU)•Many are carcinogenic tumour promoters (Chlorambucil etc)
Tumour Selective Tumour Selective Activation of DMU-212 Activation of DMU-212
(Stilserene(StilsereneTMTM))DMU212 cytotoxicity
0
25
50
75
100
125
10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2
control
Normal breastIC50=4.3 M
Breast tumourIC50=0.001 M
concentration (M)
surv
ival
(%
)
sem
Tumour Selective Bioactivation of the Tumour Selective Bioactivation of the Prodrug DMU212 (Stilserene) by Human Prodrug DMU212 (Stilserene) by Human
Breast TissueBreast Tissue
0
1
2
3
4
5
6
7
8
9
10
HBM016 HBM017 HBM018 HBM019 HBM020 HBM021 HBM022 HBM023 HBM024 HBM025 HBM026 HBM027
DM
U21
2 m
etab
oli
te f
orm
atio
n [
pm
ol/
min
/mg
prt
]
DMU281
DMU214
DMU291
normal breast tissue samples
tumour breast tissue samples
Discovery of Natural Discovery of Natural Dietary Prodrugs Dietary Prodrugs
(Salvestrols)(Salvestrols) Realised molecular relationship to natural Realised molecular relationship to natural
compoundscompounds Some of these have known cancer preventative Some of these have known cancer preventative
propertiesproperties Explains the link between diet and cancer Explains the link between diet and cancer
preventionprevention Generic name for natural dietary prodrugs termed Generic name for natural dietary prodrugs termed
as salvestrolsas salvestrols
G.A. Potter, British Journal of CancerG.A. Potter, British Journal of Cancer, , 8686 (Suppl 1), (Suppl 1), S12, 2002S12, 2002
Tumour Selective Tumour Selective ActivationActivation
of Salvestrolsof Salvestrols
M
Ez
Normal Cell Cancer Cell
Tumour Selective Tumour Selective BioactivationBioactivation
Ez
Ez
Ez
EzEz
M
Salvestrol(Non-toxic)
Actived Salvestrol(Highly Toxic)
Ez
SalvestrolActivase
Cancer Cells
Cancer Cells
Normal Cells
ResveratrolResveratrolThe First Salvestrol to be The First Salvestrol to be
DiscoveredDiscovered Resveratrol is a natural molecule found in Resveratrol is a natural molecule found in
grapesgrapes
(a phytoestrogen, polyphenol, and antioxidant)(a phytoestrogen, polyphenol, and antioxidant) Cancer preventative (unknown mechanism)Cancer preventative (unknown mechanism)
Tumour CYP enzyme catalyses the Tumour CYP enzyme catalyses the bioactivation of resveratrol to generate bioactivation of resveratrol to generate piceatannolpiceatannol
PiceatannolPiceatannol Known anticancer activityKnown anticancer activity TK Inhibitor (src, MAPK, tubulin)TK Inhibitor (src, MAPK, tubulin)Potter et al, British Journal of Cancer, 86, 774, 2002
HO
OH
OH
Resveratrol
HO
OH
OH
OH
Piceatannol
CYP1B1
HO
HO
OH
OH
OH
HO
OH
HO
OH
Estradiol 4-Hydroxyestradiol
OH
a
b
c
CYP1B1
Bioactivation of Resveratrol by CYP1B1
SalvestrolsSalvestrols New class of molecule with very important New class of molecule with very important
activity in removing diseased cells from the activity in removing diseased cells from the human bodyhuman body((salvesalve = to save) = to save)
Defined as natural dietary prodrugs that are Defined as natural dietary prodrugs that are bioactivated in diseased cellsbioactivated in diseased cells
Present in cancer preventative foods and dietsPresent in cancer preventative foods and diets
Higher levels found in traditional medicinal Higher levels found in traditional medicinal plantsplants
Anti-salvestrols also identifiedAnti-salvestrols also identified- inhibit the positive action of salvestrols- inhibit the positive action of salvestrols
Relationship of Salvestrols to Relationship of Salvestrols to Antioxidants, Polyphenols & Antioxidants, Polyphenols &
PhytoestrogensPhytoestrogens
Antioxidants
PolyphenolsSalvestrols
Salvestrols are a new class of natural productSome are antioxidantsSome are polyphenolsSome are phyoestrogens
- others are not
However…Some Anti-salvestrols are alsoantioxidants, polyphenols and phytoestrogens
A model of CYP1B1 A model of CYP1B1 Activation Activation
of a Salvestrol in a of a Salvestrol in a Tumour Tumour
Classic Chemotherapeutic Classic Chemotherapeutic AgentsAgents
Methotrexate
0
25
50
75
100
125
10 -3 10 -2 10 -1 100 101 102
control concentration (M)
Normal Breast
Breast Tumour
IC50 =0.06M
IC50 =0.04M
surv
ival
(%
)
sem
•Most are equally toxic to normal and tumour cells•Some are actually more toxic to normal cells than tumours
(e.g. Taxol, Doxorubicin, 5-FU)•Many are carcinogenic tumour promoters (Chlorambucil etc)
Tumour Specific ActivationTumour Specific Activationof Salvestrol Q40of Salvestrol Q40
Salvestrols in Natural Salvestrols in Natural FoodsFoods
(Fruits & Vegetables)(Fruits & Vegetables)
Natures Way of Eliminating Cancer Cells as they form
– Disease Prevention
Hippocrates “Let food be your medicine
and medicine be your food”
- referring to foods rich in salvestrol Q40
Salvestrol Q40
0
25
50
75
100
125
10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2control
Breast cancerIC50=2 M
Normal breastIC50=21 M
concentration (M)
surv
ival
(%
)
sem
Resveratrol Bioactivation
0
25
50
75
100
125
10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2
control
Normal BreastIC50=60 MIC25=30 M
Breast TumourIC50=60 MIC25=0.003 M
concentration (M)
surv
ival
(%
)
sem
Salvestrols in Medicinal Salvestrols in Medicinal HerbsHerbs
Salvestrol P52
0
25
50
75
100
125
10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2control
Breast cancerIC50=0.5 M
Normal breastIC50=16 M
concentration (M)
surv
ival
(%
)
sem
Salvestrol P54
0
25
50
75
100
125
10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2control
Breast cancerIC50=0.08 M
Normal breastIC50>100 M
concentration (M)
surv
ival
(%
)
sem
Ancient Cancer Cures used herbs rich in Salvestrols
Culpeper (1653) - This herb is under the celestial sign of Cancer
“It healeth tough tumours of the breast, and for this I hold it inferior to but few herbs that grow”
Dioscorides – “this is marvellous good for the joints, and for Cancers which cannot be healed by any other meanes”
Depletion of SalvestrolsDepletion of Salvestrolsin the Modern Dietin the Modern Diet
Depleted by Modern Agricultural MethodsDepleted by Modern Agricultural Methods- Use of fungicides depletes plants - Use of fungicides depletes plants salvestrolssalvestrols- Much Higher levels in Organic produce- Much Higher levels in Organic produce
Removed by Food ProcessingRemoved by Food Processing- Fruit Juice Extraction- Fruit Juice Extraction- Filtering- Filtering
Only really present in wholefoodsOnly really present in wholefoods Modern processed foods have no Modern processed foods have no
salvestrolssalvestrols
P450 Salvestrol P450 Salvestrol ActivationActivation
Catalytic heme group
Need for a SalvestrolNeed for a SalvestrolFood SupplementFood Supplement
Specialist knowledge of SalvestrolsSpecialist knowledge of Salvestrols Modern diet seriously depleted in Modern diet seriously depleted in
SalvestrolsSalvestrols Dietary intake randomDietary intake random
-food source, growing conditions-food source, growing conditions No need for exotic foods or specialist dietNo need for exotic foods or specialist diet Guaranteed intake of essential SalvestrolsGuaranteed intake of essential Salvestrols Convenient source of SalvestrolsConvenient source of Salvestrols
Formation of Natures Formation of Natures Defence LtdDefence Ltd
Linked up with The Herbal ApothecaryBased in Syston, Leicestershire
Natures Defence Ltd Established January 2004
Salvestrol Natural Products Ltd
Produce Salvestrol Rich Food Supplements
Salvestrols in ActionSalvestrols in Action
Tumour Selective Action
Rich in the most potent salvestrols
Non-toxic even at high doses
www.IJOPT.org
Salvestrol SupportingSalvestrol SupportingVitamins & MineralsVitamins & Minerals
Biotin (Vitamin H)Biotin (Vitamin H) 0.2 – 1.0 0.2 – 1.0 mgmg
Niacin (Vitamin B3)Niacin (Vitamin B3) 50 mg50 mg MagnesiumMagnesium
IronIron OxygenOxygen
Cancer Cure Cases & Cancer Cure Cases & ResponsesResponses
using Salvestrol Therapyusing Salvestrol TherapyTerminally Ill people with Advanced Metastatic DiseaseTerminally Ill people with Advanced Metastatic Disease(relapsed after chemotherapy and radiotherapy failed)(relapsed after chemotherapy and radiotherapy failed)
Have made truly remarkable recoveries after taking salvestrol food Have made truly remarkable recoveries after taking salvestrol food supplementssupplements
Salvestrol supplements have exciting anticancer activity against:Salvestrol supplements have exciting anticancer activity against:
•Breast CancerBreast Cancer•Prostate CancerProstate Cancer•Ovarian CancerOvarian Cancer•Testicular CancerTesticular Cancer
•Bladder Bladder CancerCancer•Liver Liver CancerCancer•Lung CancerLung Cancer•Colon Colon CancerCancer
Google search on “Salvestrol Case Studies"Google search on “Salvestrol Case Studies"
* * experience since 2004 with practitioners & patients. experience since 2004 with practitioners & patients. max 120,000 pointsmax 120,000 points
Observer MagazineObserver MagazineBest & BrightestBest & Brightest
Innovation Award 2005Innovation Award 2005
AcknowledgementsAcknowledgements
Cancer Drug Discovery GroupCancer Drug Discovery Group
Danny BurkeDanny BurkePaul ButlerPaul ButlerNicola WilsherNicola WilsherElugba WanogoeElugba WanogoeKetan RupareliaKetan RupareliaHoon TanHoon TanAsma PatelAsma PatelDyan AnkrettDyan AnkrettSomchaiya SurichanSomchaiya SurichanVasilios AndroutsopoulosVasilios AndroutsopoulosSaba LodhiSaba LodhiKen BeresfordKen BeresfordEllen GaoEllen GaoRandolf ArrooRandolf ArrooMeng WangMeng WangToks TaiwoToks Taiwo
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