CANCER ADJUVANT THERAPY

1. CANCERADJUVANT THERAPY Presented by: Dr. Melvyn A Sydney-Smith.KGSJ Australian College of Holistic Medicine On behalf of: Professor Ian Brighthope © 2001 ACNEM & Ian Brighthope

2. Cancer ~ therapeutic concepts • Are we winning the war against cancer? ~OR~ • Are we ‘fighting’ in the wrong field? • Is the whole concept of “fighting cancer” advantageous ? • Is cancer therapy locked into a limited and ineffective paradigm ? © 2001 ACNEM & Ian Brighthope

3. Cancer ~ the statistics Cancer Incidence Rates* per 100,000, All Sites Combined, All Races, 1975-2003 Men Women *Age-adjusted to the 2000 US standard population and adjusted for delay in reporting. Source: Surveillance, Epidemiology, and End Results Program, 1973-2003, Division of Cancer Control and Population Sciences, National Cancer Institute, 2006. © 2001 ACNEM & Ian Brighthope

4. 2007 Estimated US Cancer Cases* Women678,060 Prostate 29% Lung & bronchus 15% Colon & rectum 10% Urinary bladder 7% Non-Hodgkin 4% lymphoma Melanoma of skin 4% Kidney 4% Leukemia 3% Oral cavity 3% Pancreas 2% All Other Sites 19% • 26% Breast • 15% Lung & bronchus • 11% Colon & rectum • 6% Uterine corpus • 4% Non-Hodgkin lymphoma • 4% Melanoma of skin • 4% Thyroid • 3% Ovary • 3% Kidney • 3% Leukemia • 21% All Other Sites *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2007. © 2001 ACNEM & Ian Brighthope

5. Cancer Death Rates*, All Sites Combined ~ All Races ~ US, 1975-2003 Rate Per 100,000 Men Both Sexes Women The death rate from all cancers combined has decreased by 1.6% per year since 1993 among men and by 0.8% per year since 1992 among women. Compared to the peak rates in 1990 for men and 1991 for women, the cancer death rate for all sites combined in 2003 was 16.3% lower in men and 8.5% lower in women. © 2001 ACNEM & Ian Brighthope

6. Change in the US Death Rates* by Cause, 1950 & 2004 Rate Per 100,000 1950 2004 HeartDiseases CerebrovascularDiseases Pneumonia/Influenza Cancer Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised. 2004 Mortality Data: US Mortality Public Use Data Tape, 2004, NCHS, Centers for Disease Control and Prevention, 2006 © 2001 ACNEM & Ian Brighthope

7. Cancer cell properties • Cells that become cancerous have basically undergone genetic mutation(s) • Genetic polymorphism  Altered DNA metabolism • E.g. MTHFR gene • DNA breaks secondary to: • Environmental and endogenous molecular toxins • that has altered: • Intracellular regulatory pathways • Silenced p53 gene activity (tumour suppressor gene) • Reduced activity of apoptosis pathways • Enhanced NF-Kappa-B activity • Increased protein kinase C (PKC) activity © 2001 ACNEM & Ian Brighthope

8. Cancer cell properties • Other molecular alterations include: • Cell response to tissue regulatory signalling molecules • Cytokines, eicosanoids & growth factors • Enhanced Ras protein activation (farnesylation) due to Ras gene mutations • Reduced cell antigen expression • Impaired immune recognition and NK T-cell activity • Reduced aerobic enzyme activity and concomitant increased anaerobic enzyme activity • Increased production of angiogenesis stimulatory molecules such as bFGF and VEGF • Increased production of connective tissue lyase enzymes © 2001 ACNEM & Ian Brighthope

9. Cancer therapy • PREVENTION ~ the best form of therapy • AVOID ~ • Toxic environments ~ chemicals, heavy metals & radiation and high stress living • Toxic foods ~ trans fats, saturated fats, barbecued meats and baked goods, high GI/GL foods • EMPHASISE ~ • Beneficial foods ~ protein, fibre, fruits and vegetables • Omega-3-EFAs • Regulate carbohydrate intake • Clean environments • Relaxation and meditation practice © 2001 ACNEM & Ian Brighthope

10. Cancer therapy ~ Critical Factors • Evaluate molecular biology of tumour cell population • Analyse tumour cell sensitivity to chemotherapy agents • Protect against anaemia • Inhibit COX-2 enzyme activity • Suppress Ras oncogene expression • Correct coagulation abnormalities • Maintain bone integrity • Inhibit angiogenesis • Block collagen lysis • Maintain nutritional status • Accessory cytotoxic therapy © 2001 ACNEM & Ian Brighthope

11. Cancer therapy ~ Critical Factors • Evaluate molecular biology of tumour cell population • Tumour promoting genes • Tumour suppressor genes • Cell receptor sites ~ signalling “docking” sites • Cellular differentiation IMPATH INC ~ www.impath.com • Analyse tumour cell sensitivity to chemotherapy agents • Chemo-sensitivity testing allows for assay-directed therapy • Improve prognosis www.rationaltherapeutics.com © 2001 ACNEM & Ian Brighthope

12. Cancer therapy ~ Critical Factors • Protect against anaemia • Anaemia increases mortality risk by 65% Caro et al, 2001 • May occur due to: • Chemotherapy inhibition of bone marrow activity • Nutrient deficiency • Cancer-related increased cytokine release ~ TNF-a and IL-1 Cazzola, 2000 • Anaemia may stimulate VEGF release via intratumoural hypoxia  promotes angiogenesis and tumour cell growth Dunst et al. 1999 • Cancer-related anaemia responds to erythropoietin therapyoptimal Hb level: 15.5 – 17 (males) and 13.5 – 15 (females) • Don’t forget to check for iron & folate deficiency © 2001 ACNEM & Ian Brighthope

13. Cancer therapy ~ Critical Factors • Inhibit COX-2 enzyme activity • COX-2 mediated Arachidonic Acid metabolism produces Prostaglandin E2 (PGE2) ~ a pro-inflammatory eicosanoid • Unduly elevated COX-2 activity stimulates cancer cell growth • via angiogenesis and NF-Kappa-B activation • Hypoxic zones in solid tumours upregulate COX-2 activity ~ • E.g. pancreatic Ca shows 60-fold increase Tucker et al, Cancer Research, 1999 • NSAID therapy reduces COX-2 activity and improves response to cancer therapy Reddy et al, 2000; Nakasugi et al, 1997; Knorr, 2000 • COX-2 inhibitors & NSAIDS have a high adverse effect profile MIMS Manual, 2007 © 2001 ACNEM & Ian Brighthope

14. Cancer therapy ~ Critical Factors • COX-2 Inhibition:many natural products inhibit COX-2 activity without the adverse effects of medications • Green tea EGCG ~ epigallocatechin gallate ~Noreen et al, 1998 • Curcumin ~ reduces TXA2 & PGE2 ~ Newmark et al, 2000 • Ginger ~ inhibits COX-2 & regulates COX-1 ~ Reiter et al, 2001 • Feverfew ~ inhibits both COX and LOX ~ reduces HETE which promotes angiogenesis ~ Sheehan et al, 2002 • Berberine ~ Goldenseal, Oregon Grape Seedmultiple reports of anti-CA activity ~ Chen, 1999; Newmark, 2000 • Omega-3-EFAs © 2001 ACNEM & Ian Brighthope

15. Cancer therapy ~ Critical Factors Ras oncogene expression • Ras proteins integrate the regulatory signals that govern the cell cycle and proliferation • Bound to inner cell membranes and behave as a relay switch ~ • Respond to external cell stimuli to activate internal pathways that direct cell division, differentiation and even apoptosis • de-activate when the signal ceases • Mutations in the H, N or K-Ras genes causes cancer-genesis and upregulated cell proliferation • Ras gene mutations occur in 30-40% of all human cancers:pancreas 80%, colon 50%, lung 40% and liver 30% ~ melanoma & myeloid leukaemia also 30% • Mutated Ras protein is always in active form ~ switch is on ~ • Persistent signal to cell division and proliferation © 2001 ACNEM & Ian Brighthope

16. Suppress Ras oncogene expression • Statin therapy: • Inhibit HMG-CoA reductase  reduce farnesyl pyrophosphate production, which is essential to Ras protein maturation • In primary liver Ca patients, Statin + 5-FU doubled median survival time, from 9/12 to 18/12 • Omega-3-EFAs: • Reduces Ras protein localisation to cell membrane • Markedly improved survival times to >12/12 in terminal Ca patients compared to 3/12 in non-treated patients • Citrus oil extract: contains limonene • Inhibits farnesyl transferase and reduces Ras protein maturation • Animal studies report reduced cell replication © 2001 ACNEM & Ian Brighthope

17. Ras oncogene suppression • Garlic ~ Allium sativa • Diallyl disulphide inhibits H-Ras oncogenes and significantly restrains tumour growth and induced lung Ca cell apoptosis • S-allyl cysteine inhibited human melanoma cell growth and also counters Doxirubin cardiotoxicity • Garlic also boosts: • Immune system function • Antioxidant capacity • Aged garlic extract seems to be most effective • Green Tea polyphenols • Inhibit Ras oncogenes and also reduce NF-Kappa-B activity • Multiple studies report a beneficial impact on chemotherapy response, enhanced cancer cell apoptosis and long-term survival © 2001 ACNEM & Ian Brighthope

18. Correct coagulation abnormalities • Hyper-coagulation problems commonly occur in cancer patients • Overt thrombosis & pulmonary embolus • Fibrin deposition on Ca cell surfaces promotes angiogenesis and retards immune recognition Cosgrove et al, 2002 • Low-molecular weight Heparin reportedly: • Reduces mortality rate after surgery • improves long-term survival • Reduce metastatic disease • Look for low-normal PT & PTT with high-normal D-dimer, Fibrin-split products (FSP), fibrinogen and platelet count • Also, elevated alpha-1-antitrypsin & Factor VIII © 2001 ACNEM & Ian Brighthope

19. Correct coagulation abnormalities • Several natural products may be helpful: • Quercetin and Bromelain may increase fibrinolysis • Pancreatic enzymes ~ high dose ~ are reportedly effective in removing fibrin deposits • Omega-3-EFAs and mixed tocopherols are reported to reduce platelet activation • Garlic and Ginkgo biloba also reduce platelet activation © 2001 ACNEM & Ian Brighthope

20. Maintain bone integrity • Many types of cancer show a proclivity to metastasise to bone: • Particularly carcinoma of breast & prostate, • Osteopenia and osteoporosis commonly occur following chemotherapy and anti-hormone therapy • Prostate Ca cells produce IL-6, which promotes bone loss • bone loss increases production of bone-derived growth factors ~ TGF-beta1 • These growth factors further stimulate prostate Ca cell growth • Bisphosphonate therapy improves bone integrity and markedly reduces metastatic bone disease © 2001 ACNEM & Ian Brighthope

21. Maintain bone integrity • Always check bone density and urinary telopeptide levels • Nutrients for bone health include: • Calcium, magnesium, zinc & boron • Protein ~ and EAAs such as Lysine • Vit C • Vit D and Vit K ~ stimulate osteocalcin activity • Vit D & K reportedly improve bone protein matrix synthesis • Also, are exhibit substantial anti-proliferative activity • Possible role also for fluoride !!! and strontium !!! © 2001 ACNEM & Ian Brighthope

22. Inhibit angiogenesis • Solid tumours cannot grow beyond 2cm3 without a blood supply • Tumour growth occurs concurrently with rapid vascularisation • Triggered by angiogenic growth factors, produced by the cancer cells • Many agents promote angiogenesis ~ • Oestrogen, IL-8, TNF-alpha, PGE2, • Growth factors: bFGF, VEGF, GCSF • Intratumoural hypoxia • Interruption of angiogenesis reduces tumour growth • Angiostatin & endostatin ~ 100% success in mouse model • Thalidomide © 2001 ACNEM & Ian Brighthope

23. Inhibiting angiogenesis • Many natural agents also inhibit angiogenesis activity: • Curcumin & Green Tea • Lactoferrin • N-acetylcysteine • Resveratrol • Retinoic acid & Vit D • Chondroitin and various cartilage extracts © 2001 ACNEM & Ian Brighthope

24. Block collagen lysis • Cancer cells spread throughout tissues because they secret a variety of enzymes that dissolve collagen and hyaluronic acid • Collagen is a hydroyxlated polymer of lysine & proline • Collagen synthesis may be stimulated by high-dose ascorbate, lysine & proline ~ • High dose ascorbate, lysine & proline has been reported to: • retards cancer cell growth ~and~ • induce cancer regression • Side benefit is improved energy possibly related to improved carnitine synthesis © 2001 ACNEM & Ian Brighthope

25. Maintain nutritional status • Multiple nutrient imbalances are commonly present in patients presenting with cancer: • Protein / carbohydrate imbalance • Insulin Resistance with XS protein catabolism and lipogenesis • Antioxidant depletion • Ascorbate, tocopherols and flavonoids • Coenzyme Q10, Glutathione, Lipoic acid • High omega-6/omega-3 EFA balance • Mineral deficiency • Zinc, selenium, magnesium, chromium and possibly iron © 2001 ACNEM & Ian Brighthope

26. Maintain nutritional status • Nutrient depletion • Vit B6, folic acid and Niacin • Gastrointestinal disturbance • Maldigestion ~ • Related to stress, dietary imbalance and food reactivity • Impaired protein synthesis • Bowel dysbiosis ~ • Related to both maldigestion and prior antibiotic or steroid use • Hepatic detoxification disorder • Both Cyp450 activity and impaired conjugation reactions • Hormone imbalance ~ low DHEA and possibly melatonin © 2001 ACNEM & Ian Brighthope

27. TREATMENT PLAN: systematic & integrated • Digestion • Diet • Antioxidant capacity • Essential Fatty Acid balance • Bowel dysbiosis • Specific therapy • Neurotransmitter balance • Hepatic detoxification • Hormonal balance © 2001 ACNEM & Ian Brighthope

28. Accessory cytotoxic therapy • high-dose IV ascorbate therapy • Should be given by IV drip ~ once or twice a week • Particularly post-surgery • Also useful during radiation and chemotherapy • NB: remote risk of renal oxalosis ~ always check renal function before and after treatment • Added Vit B6, zinc, magnesium & GTH enhance effect • Consider high-dose oral lysine with ascorbate therapy © 2001 ACNEM & Ian Brighthope

29. Adjunctive nutrients • Alpha-Lipoic acid • Carotenoids • Coenzyme Q10 • Conjugated Linoleic Acid • Berberine ~ Goldenseal, Oregon Grape Seed • Feverfew, Ginger, Garlic • Green Tea & Curcumin • Omega-3-EFAs • Inositol-hexaphosphate © 2001 ACNEM & Ian Brighthope

30. Adjunctive nutrients • Lactoferrin • Oriental mushroom extracts • Modified Citrus Pectin • N-acetylcysteine • Resveratrol • Selenium • Milk thistle • Soy protein and isoflavones • Thymus extract • Vitamin A ~ also Vit D & Vit K & • mixed tocopherols & tocotrienols © 2001 ACNEM & Ian Brighthope

31. Medications: • Cimetidine • Statins therapy + Co-Q10 • Bisphosphonates • Hormonal therapy • DHEA • Melatonin • DMSO A wide variety of therapies the main thing is to integrate it. © 2001 ACNEM & Ian Brighthope