The breakthroughs in cancer research that have led to the discovery of new drugs for the treatment of cancer including Zytiga and Salvestrols

1. Breakthroughs in the
Quest to Cure Cancer
Professor Gerry Potter
Founder of the
Cancer Drug Discovery Group
Leicester School of Pharmacy
De Montfort University, Leicester, UK

2. Early Days

3. University of Manchester
1983-1986
“Mechanism of Action of Anticancer Agents”
- Most are generally toxic (cytotoxic)
- Toxic to liver, kidneys, heart, white blood cells
- Many are highly mutagenic & carcinogenic
- Key Issue is Selectivity

4. Chemotherapy Agents Mutate DNA and are Highly Carcinogenic

5. Institute of Cancer Research
1987 - 1994
Drug Development Section, CRC Laboratory
developed new selective agents for
Breast & Prostate Cancer
 Tamandron (Antiandrogen)
 Idoxifene (An Improved Tamoxifen Analogue)
 Ribonucleotide Reductase Inhibitors
 Abiraterone Acetate (ZytigaTM)

6. Selective Anticancer Agents
Developed by Prof Potter at the
Institute of Cancer Research
N
O
N
I HO
Idoxifene
Stilbene Antiestrogen Abiraterone Acetate
Cancer Res., 55, 1070-1074 (1995). CYP17 Inhibitor
OH J. Med. Chem., 38,
2463-2471 (1995).
HO NMe2
O
O
N
O
O
CB7653 Tamandron
Stilbene Antiandrogen
Non-steroidal CYP17 Inhibitor
New Scientist, 16, 23 May 1992
J. Med. Chem., 38, 4191-4197 (1995).

7. Design of Abiraterone Acetate
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

8. Design & Synthesis of Abiraterone
Journal of Medicinal Chemistry, 38, 2463, 1995

9. Potent Androgen Ablation
by Abiraterone (CB7598)
Journal of Steroid Biochemistry and Molecular Biology, 50, 267, 1994

10. 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

11. Link Between Diet and Cancer
 Lower incidence of cancer correlates with
Higher consumption of fruits & vegetables
(Western diet correlates to
high incidence of cancer)
Understanding this
 Nobody really knows why ! link would help
•cancer prevention
(many theories, antioxidants, phytoestrogens, •cancer treatment
polyphenols etc)

12. Discovery of a Tumour Specific
Salvestrol Metabolising Enzyme
(Salvestrol Activase)
 Breast  Bladder
 Brain  Colon
 Lung  Kidney
 Ovarian  Oesophagael
 Prostate  Stomach
Cancer Research, 57, 3026, 1997

13. Stomach Oesophageal
Ovarian Myosarcoma

14. Normal Colon Colon Cancer Dysplasia

15. Salvestrol Activase is a
Tumour Suppressor Enzyme
 Works as a cancer preventing enzyme acting via natural
prodrug bioactivation, i.e. salvestrol activation
 Expressed in a variety of tumours
 Generic Rescue Mechanism
 Irrespective of tumour type or oncogenic origin
 Cancers arise from many different mutagenic origins
 Induction tightly regulated
 Induced by various cellular damaging effects
G.A. Potter, British Journal of Cancer, 86 (Suppl 1), S12, 2002

16. Designed Prodrugs Activated
by a Tumour Specific Enzyme
 Synthetic Prodrugs Designed
 Shows very exciting tumour selective activity
 No toxic effects
 Development to clinical use taking many years
 Realised molecular relationship to natural compounds
that have cancer preventative properties
 Could have a natural version of this drug
 Could explain link between diet and cancer
Potter et al, British Journal of Cancer, 86 (Suppl 1), S117, 2002

17. Targeting Growth Factor Pathways

18. Designed Prodrugs Activated
by a Tumour Specific Enzyme
 Synthetic Prodrugs Designed
 Shows very exciting tumour selective activity
(10,000-fold selective)
 No toxic effects observed
 Currently Undergoing Pre-clinical development at the Gray Cancer
Institute, London
 Phase I Clinical Studies being planned in the US
 Results look very promising
 Drug has real potential as a non-toxic tumour selective anticancer agent
Potter et al, British Journal of Cancer, 86 (Suppl 1), S117, 2002

19. Classic Chemotherapeutic Agents
Methotrexate
survival (%) ± sem 125
100 Normal Breast
IC50 =0.06µM
75
50 Breast Tumour
IC50 =0.04µM
25
0
10 -3 10 -2 10 -1 10 0 10 1 10 2
control concentration (µM)
•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)

20. Tumour Selective Activation of
DMU-212 (StilsereneTM)
125
DMU212 cytotoxicity
survival (%) ± sem
100
Normal breast
75 IC50=4.3 µM
50 Breast tumour
IC50=0.001 µM
25
0
10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2
control concentration (µM)

21. Tumour Selective Bioactivation of the Prodrug
DMU212 (Stilserene) by Human Breast Tissue
DMU212 metabolite formation [pmol/min/mg prt]
10
9
8
7
6
DMU281
5
DMU214
DMU291
4
3
2
1
0
HBM016 HBM017 HBM018 HBM019 HBM020 HBM021 HBM022 HBM023 HBM024 HBM025 HBM026 HBM027
normal breast tumour breast tissue samples
tissue samples

22. Discovery of Natural Dietary
Prodrugs (Salvestrols)
 Realised molecular relationship to natural compounds
 Some of these have known cancer preventative
properties
 Explains the link between diet and cancer prevention
 Generic name for natural dietary prodrugs termed as
salvestrols
G.A. Potter, British Journal of Cancer, 86 (Suppl 1), S12, 2002

23. Tumour Selective Activation
of Salvestrols
Ez
M
Normal Cell Cancer Cell

24. Tumour Selective Bioactivation
Normal Cells
Ez
Ez
Ez
Ez
Ez
Cancer Cells
Cancer Cells
Ez
M
Salvestrol
Activase
Salvestrol Actived Salvestrol
(Non-toxic) (Highly Toxic)

25. Resveratrol
The First Salvestrol to be Discovered
 Resveratrol is a natural molecule found in grapes
(a phytoestrogen, polyphenol, and antioxidant)
 Cancer preventative (unknown mechanism)
 Tumour CYP enzyme catalyses the bioactivation of
resveratrol to generate piceatannol
 Piceatannol
 Known anticancer activity
 TK Inhibitor (src, MAPK, tubulin)
Potter et al, British Journal of Cancer, 86, 774, 2002

26. Bioactivation of Resveratrol by CYP1B1
a OH OH
OH CYP1B1 OH
HO HO
OH
Resveratrol Piceatannol
b
OH
OH
HO
OH
HO
c
OH OH
CYP1B1
HO HO
OH
Estradiol 4-Hydroxyestradiol

28. Salvestrols
 New class of molecule with very important activity
in removing diseased cells from the human body
(salve = to save)
 Defined as natural dietary prodrugs that are
bioactivated in diseased cells
 Present in cancer preventative foods and diets
 Higher levels found in traditional medicinal plants
 Anti-salvestrols also identified
- inhibit the positive action of salvestrols

29. Relationship of Salvestrols to Antioxidants,
Polyphenols & Phytoestrogens
Salvestrols are a new class
of natural product
Antioxidants Some are antioxidants
Some are polyphenols
Some are phyoestrogens
Polyphenols - others are not
Salvestrols
However…Some Anti-salvestrols are also
antioxidants, polyphenols and phytoestrogens

30. A model of CYP1B1 Activation
of a Salvestrol in a Tumour

31. Classic Chemotherapeutic Agents
Methotrexate
survival (%) ± sem 125
100 Normal Breast
IC50 =0.06µM
75
50 Breast Tumour
IC50 =0.04µM
25
0
10 -3 10 -2 10 -1 10 0 10 1 10 2
control concentration (µM)
•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)

32. Tumour Specific Activation
of Salvestrol Q40

33. Salvestrols in Natural Foods
(Fruits & Vegetables)
125
125
Resveratrol Bioactivation Salvestrol Q40
survival (%) ± sem
Normal Breast Normal breast
100
IC50=60 µM
survival (%) ± sem
100 IC50=21 µM
IC25=30 µM
75
75
Breast Tumour
IC50=60 µM
50
IC25=0.003 µM 50
25
25
Breast cancer
0
10 -4
10 -3
10 -2
10 -1
10 0
10 1
10 2
0 IC50=2 µM
control concentration (µM) control 10 -4
10 -3
10 -2
10 -1
10 0
10 1
10 2
concentration (µM)
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

34. Salvestrols in Medicinal Herbs
125 125
Salvestrol P52 Salvestrol P54
survival (%) ± sem
survival (%) ± sem
100 Normal breast 100 Normal breast
IC50=16 µM IC50>100 µM
75 75
50 50
25 25
Breast cancer
Breast cancer
IC50=0.08 µM
0 IC50=0.5 µM 0
control 10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2 control 10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2
concentration (µM) concentration (µM)
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”

35. Depletion of Salvestrols
in the Modern Diet
 Depleted by Modern Agricultural Methods
- Use of fungicides depletes plants salvestrols
- Much Higher levels in Organic produce
 Removed by Food Processing
- Fruit Juice Extraction
- Filtering
 Only really present in wholefoods
 Modern processed foods have no salvestrols

36. P450 Salvestrol Activation
Catalytic heme group

37. Need for a Salvestrol
Food Supplement
 Specialist knowledge of Salvestrols
 Modern diet seriously depleted in Salvestrols
 Dietary intake random
-food source, growing conditions
 No need for exotic foods or specialist diet
 Guaranteed intake of essential Salvestrols
 Convenient source of Salvestrols

38. Formation of Natures Defence Ltd
Linked up with The Herbal Apothecary
Based in Syston, Leicestershire
Natures Defence Ltd Established January 2004
Salvestrol Natural Products Ltd
Produce Salvestrol Rich Food Supplements

39. Salvestrols in Action
Tumour Selective Action
Rich in the most potent salvestrols
Non-toxic even at high doses
www.IJOPT.org

40. Salvestrol Supporting
Vitamins & Minerals
 Biotin (Vitamin H) 0.2 – 1.0 mg
 Niacin (Vitamin B3) 50 mg
 Magnesium
 Iron
 Oxygen

41. Cancer Cure Cases & Responses
using Salvestrol Therapy
Terminally Ill people with Advanced Metastatic Disease
(relapsed after chemotherapy and radiotherapy failed)
Have made truly remarkable recoveries after taking salvestrol food supplements
Salvestrol supplements have exciting anticancer activity against:
•Breast Cancer •Bladder Cancer
•Prostate Cancer •Liver Cancer
•Ovarian Cancer •Lung Cancer
•Testicular Cancer •Colon Cancer
Google search on “Salvestrol Case Studies"

42. * experience since 2004 with practitioners & patients.
max 120,000 points

43. Observer Magazine
Best & Brightest
Innovation Award 2005

44. Acknowledgements
Cancer Drug Discovery Group
Danny Burke
Paul Butler
Nicola Wilsher
Elugba Wanogoe
Ketan Ruparelia
Hoon Tan
Asma Patel
Dyan Ankrett
Somchaiya Surichan
Vasilios Androutsopoulos
Saba Lodhi
Ken Beresford
Ellen Gao
Randolf Arroo
Meng Wang
Toks Taiwo