PHARMACOLOGICAL PREVENTION       IN ONCOLOGY Prevention in Prostate Cancer         Giancarlo Comeri         Urologist - Mu...
EPIDEMIOLOGY OF PROSTATE CANCER------------------------------------------------ • Prostate cancer is the most common non–c...
CAUSES OF PROSTATE CANCER• The cause(s) of prostate cancer have not yet  been clarified.• Although heritable factors are i...
CHRONIC INFLAMMATION HAS BEEN   LINKED TO CANCER IN THE:         esophagus         stomach         liver         bile duct...
Meta-analysis of 11 case-control studies revealed a statistically significantsummary OR of prostate cancer of 1.57 for eve...
THE SOURCE OF PROSTATIC             INFLAMMATION• Infectious agents (uropathogens, sexually transmitted  organisms, propio...
CHRONIC INFECTION AND CANCER• Some virus induce cancers by acting directly on target  cells:       • Human papillomaviruse...
CHRONIC INFLAMMATION AND CANCER•    Inflammation may contribute to carcinogenesis by several     potential mechanisms, inc...
1. Cytokines and growth factors• Produced by macrophages, T lymphocytes or even  tumor cells themselves        –Tumor necr...
Tumor Necrosis Factor-a (TNF-a)• Pro-inflammatory cytokine• TNF-a may act as a tumor promoter:          – Suppresses andro...
Vascular endothelial grow factor (VEGF)• Expressed in HGPIN and PCa with a trend for  increasing staining intensity with l...
NPVEGFPIN         PINPCa         PCa
CHRONIC INFLAMMATION AND CANCER•    Inflammation may contribute to carcinogenesis by several     potential mechanisms, inc...
2. Cyclooxygenase-2 (COX-2)•   TNF-a and EGF induce COX-2 overexpression•   Overexpression     of   COX-2    -->      incr...
COX-2
CHRONIC INFLAMMATION AND CANCER•    Inflammation may contribute to carcinogenesis by several     potential mechanisms, inc...
3. Reactive oxygen species (ROS)    and reactive nitrogen species (RNS)•    ROS: such as hydrogen peroxide and free radica...
3. Reactive oxygen species (ROS) and       reactive nitrogen species (RNS)•   ROS and RNS can damage cellular lipids, prot...
3. Reactive oxygen species (ROS) and       reactive nitrogen species (RNS)•    GSTP1 in normal prostate epithelial cells  ...
NEJM 349: 366, 2003GSTP1 expression
Candidate HPC genes• RNASEL (a candidate tumor suppressor gene within the  HPC1 locus located on 1q24-25)• MSR1 (located o...
Candidate HPC genes• RNASEL and MRS1 encode proteins with critical  functions in host response to infections• Mutations in...
PROLIFERATIVE INFLAMMATORY             ATROPHY (PIA)•   The morphological manifestation of all repeated bouts of    injury...
Atrophy merging with HG-PIN
NEJM 349: 366, 2003
HISTOPATHOLOGIC CLASSIFICATION SYSTEM FOR CHRONIC PROSTATIC INFLAMMATION• Anatomic localisation                          g...
CATEGORY IV PROSTATITISEPS/VB3                             32,2 – 42%                                                  (Po...
PATTERNS OF INFLAMMATION IN BPH   Segregated glandular prostatitis       Periglandular prostatitis    Diffuse stromal pros...
PROSTATIC INFLAMMATION AND PSA:              THE IRANI’S SCALEExtent    Infiltration          aggressiveness              ...
MANAGEMENT OF CHRONIC PROSTATITIS•   Antibiotics such as Fluoroquinolones•   Alpha-blockers with or without antibiotics•  ...
FLUORQUINOLONS ARE THE CHOISE DRUGS FOR TREATMENT OF CHRONIC BACTERIAL            PROSTATITIS• Good activity vs Gram + and...
ANTI-INFLAMMATORY TARGETS AND PREVENTION OF PCa• Cytokines         Anti-inflammatory cytokines (Interleukin-12)• NF-kB    ...
ASPIRIN AND RISK FOR PROSTATE CANCER• Among the prospective studies the relative risk of prostate cancer  for aspirin and ...
SELECTIVE COX-2 INHIBITORS IN CP/CPPS--------------------------------------------------------  Rofecoxib, Celecoxib, Valde...
PROSTATE CANCER CHEMOPREVENTION      SELECTIVE COX-2 INHIBITORS• An industry – sponsored large scale trial of ROFECOXIB wa...
COX-2 INHIBITORS: ADVERSE EVENTS• 14 trial reports with 116094 participants• 6394 composite renal events and 286 arrhythmi...
ALLOPURINOL FOR CHRONIC PROSTATITIS    Reflux of urine into prostatic ducts causes prostatic inflammation via high    conc...
PROSTATE CANCER CHEMOPREVENTIVE    AGENTS IN PHASE III CLINICAL TRIALS    5alpha–reductase inhibitors: FINASTERIDE        ...
PROSTATE CANCER CHEMOPREVENTIVE       AGENTS IN PHASE III CLINICAL TRIALS  5-alpha reductase inhibitors: DUTASTERIDE      ...
PROSTATE CANCER CHEMOPREVENTIVE      AGENTS IN PHASE III CLINICAL TRIALS                           VITAMIN E•    ALFA-TOCO...
PROSTATE CANCER CHEMOPREVENTIVE     AGENTS IN PHASE III CLINICAL TRIALS                 SELENIUMSelenium is a trace nutrie...
PROSTATE CANCER CHEMOPREVENTIVE  AGENTS IN PHASE I-II CLINICAL TRIALS:  SELECTIVE OESTROGEN RECEPTOR  MODULATORS (SERMs):T...
PROSTATE CANCER CHEMOPREVENTIVE   AGENTS IN PHASE I-II CLINICAL TRIALS:    DIFLUOROMETHYL ORNITHINE (DFMO)• DFMO is an irr...
PROSTATE CANCER CHEMOPREVENTIVE AGENTS IN PHASE I-II CLINICAL TRIALS:              VITAMIN D• In experimentl models of pro...
PROSTATE CANCER CHEMOPREVENTIVE  AGENTS IN PHASE I-II CLINICAL TRIALS:           SOY ISOFLAVONES• A prospective study of 1...
PROSTATE CANCER CHEMOPREVENTIVE  AGENTS IN PHASE I-II CLINICAL TRIALS:               LYCOPENE• Prospective case-control st...
PROSTATE CANCER CHEMOPREVENTIVE  AGENTS IN PHASE I-II CLINICAL TRIALS:         GREEN TEA CATECHINS• Epidemiological and ca...
DIETARY INTAKE OF ANTIOXIDANTS Intake of different antioxidants that might attenuatecell and genome damage inflicted by in...
CURCUMIN---------------------------------------------• Curcumin, traditionally used as a seasoning spice in Indian cuisine...
QUERCETINE• Poliphenolic bioflavonoid (red wine, green tea, onions and spices)• Antioxidant and anti-inflammatory properti...
ROTATION DIET IN FOOD INTOLERANCE•   Minimal persistent prostate inflammation with increased production    of endogenous f...
CONCLUSIONS• Additional well designed basic, clinical and epidemiological studies  are needed to resolve whether intrapros...
THANK YOUFOR YOUR ATTENTION!
NF-kB• NF-kB is a transcription factor that regulates the expression of  various genes that control apoptosis, viral repli...
Pharmacological prevention in oncology
Pharmacological prevention in oncology
Upcoming SlideShare
Loading in …5
×

Pharmacological prevention in oncology

1,042 views

Published on

Pharmacological prevention in oncology: prevention in Prostate Cancer

Published in: Health & Medicine, Technology
0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
1,042
On SlideShare
0
From Embeds
0
Number of Embeds
17
Actions
Shares
0
Downloads
0
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide

Pharmacological prevention in oncology

  1. 1. PHARMACOLOGICAL PREVENTION IN ONCOLOGY Prevention in Prostate Cancer Giancarlo Comeri Urologist - Multimedica staff
  2. 2. EPIDEMIOLOGY OF PROSTATE CANCER------------------------------------------------ • Prostate cancer is the most common non–cutaneous malignant neoplasm in men in Western countries • The number of afflicted men is increasing rapidly • Finding strategies for the prevention of prostate cancer is a crucial medical challenge
  3. 3. CAUSES OF PROSTATE CANCER• The cause(s) of prostate cancer have not yet been clarified.• Although heritable factors are implicated, immigration studies indicate the environmental exposures are also important• Data from histopathological, molecular and genetic epidemiological studies show that chronic inflammation can be the most important factor in prostate carcinogenesis
  4. 4. CHRONIC INFLAMMATION HAS BEEN LINKED TO CANCER IN THE: esophagus stomach liver bile duct bladder colon skin lung
  5. 5. Meta-analysis of 11 case-control studies revealed a statistically significantsummary OR of prostate cancer of 1.57 for ever having had prostatitis. Urology2002;60:78-83A recent medical records review vs age-matched controls confirms this risk:Any type of prostatitis: OR 1.7 Acute prostatitis: OR 2.5Chronic bacterial prostatitis: OR 1.6 Chronic pelvic pain syndrome: OR 0.9 (Robert et Al. Epidemiology, 2004)Infections may represent one mechanism through which prostate cancerdevelops. However, casuality is unclear, because recall bias and detection
  6. 6. THE SOURCE OF PROSTATIC INFLAMMATION• Infectious agents (uropathogens, sexually transmitted organisms, propionibacterium acnes, nanobacteria)• Urine reflux in prostatic ducts (uric acid)• Corpora amylacea• Dietary factors (red meat and animal fats through formation or heterocyclic amines)• Oestrogens (cause of autoimmune reactions and chronic inflammation)• Break of immune tolerance to prostate antigens
  7. 7. CHRONIC INFECTION AND CANCER• Some virus induce cancers by acting directly on target cells: • Human papillomaviruses • Epstein-Barr virus• For most of the infectious agents, included those of STIs, the disease appears by an indirect mechanism: • Long-standing chronic inflammation leads to prolonged exposure of tissues to cancer-causing agents produced in response to infection or toxins
  8. 8. CHRONIC INFLAMMATION AND CANCER• Inflammation may contribute to carcinogenesis by several potential mechanisms, including: • Elaboration of cytokines and growth factors that favor tumor cell growth (TNF-alfa, VEGF, etc) • Induction of cyclooxygenase-2 (COX-2) in macrophages and epithelial cells • Generation of mutagenic reactive oxygen species (ROS) and reactive nitrogen species (RNS)• The processes are interrelated
  9. 9. 1. Cytokines and growth factors• Produced by macrophages, T lymphocytes or even tumor cells themselves –Tumor necrosis factor-a (TNF-a) –Vascular endothelial growth factor (VEGF) –Migration inhibitory factor (MIF) –Interleukins (IL-1, IL-8, etc) and Chemokines (CXC group)
  10. 10. Tumor Necrosis Factor-a (TNF-a)• Pro-inflammatory cytokine• TNF-a may act as a tumor promoter: – Suppresses androgen receptor expression: -> loss of androgen responsiveness – Induces COX-2 and other angiogenic factors, matrix metalloproteases and chemokines: -> pro- carcinogenic activity – Stimulates tumor cell proliferation (activation of NF-kB)
  11. 11. Vascular endothelial grow factor (VEGF)• Expressed in HGPIN and PCa with a trend for increasing staining intensity with lack of differentiation• Production induced by PGE2 and TNF-a - Mitogen for endothelial cells –Induces angiogenesis –Regulates vascular permeability
  12. 12. NPVEGFPIN PINPCa PCa
  13. 13. CHRONIC INFLAMMATION AND CANCER• Inflammation may contribute to carcinogenesis by several potential mechanisms, including: • Elaboration of cytokines and growth factors that favor tumor cell growth (TNF-alfa, VEGF, etc) • Induction of cyclooxygenase-2 (COX-2) in macrophages and epithelial cells • Generation of mutagenic reactive oxygen species (ROS) and reactive nitrogen species (RNS)• The processes are interrelated
  14. 14. 2. Cyclooxygenase-2 (COX-2)• TNF-a and EGF induce COX-2 overexpression• Overexpression of COX-2 --> increased tumorigenesis in animal models• COX-2 overexpression in PCa and HGPIN compared with NP and BPH• Increases cell growth and reduced apoptosis• COX-2 inhibitors (non-steroidal anti-inflammatory agents) decrease growth and increase apoptosi
  15. 15. COX-2
  16. 16. CHRONIC INFLAMMATION AND CANCER• Inflammation may contribute to carcinogenesis by several potential mechanisms, including: • Elaboration of cytokines and growth factors that favor tumor cell growth (TNF-alfa, VEGF, etc) • Induction of cyclooxygenase-2 (COX-2) in macrophages and epithelial cells • Generation of mutagenic reactive oxygen species (ROS) and reactive nitrogen species (RNS)• The processes are interrelated
  17. 17. 3. Reactive oxygen species (ROS) and reactive nitrogen species (RNS)• ROS: such as hydrogen peroxide and free radicals• Macrophages: byproduct of the oxidative metabolism• Variety of cell types in response to inflammatory cytokines and during the metabolism of carcinogens• Neutralized by intra-cellular antioxidants (vitamin E and b-carotenes) and by cellular enzymes (such as GSTs)• Oxidative stress
  18. 18. 3. Reactive oxygen species (ROS) and reactive nitrogen species (RNS)• ROS and RNS can damage cellular lipids, proteins and DNA which can ultimately lead to carcinogenesis.• ROS/RNS damage to DNA may result in mutagenesis or altered expression of transcriptional factors involved in carcinogenesis.• ROS may also cause methylation• Damage may also occur to critical DNA repair enzymes• Selenium and Vitamin E reduce the generation of ROS or increase the removal of ROS
  19. 19. 3. Reactive oxygen species (ROS) and reactive nitrogen species (RNS)• GSTP1 in normal prostate epithelial cells - Inactivation of oxidant carcinogens via conjugation to reduced gluthatione• Inactivation of GSTP1 in PCa and HGPIN via CpG island hypermethylation• Other antioxidant enzymes also have a low expression in PCa and HGPIN
  20. 20. NEJM 349: 366, 2003GSTP1 expression
  21. 21. Candidate HPC genes• RNASEL (a candidate tumor suppressor gene within the HPC1 locus located on 1q24-25)• MSR1 (located on 8p22, encodes subunits of class A macrophage-scavenger receptor 1)• CYP17 (located on 10q24.3, encodes cytochrome P-450c17a, an enzyme that catalyzes key reactions in sex-steroid biosynthesis)• HPC2/ELAC2 (located on 17p11 and is considered a tumor suppressor gene)• BRCA2 (located on chromosome 13q)• CHEK2 (encodes an upstream regulator of p53 in the DNA damage signaling pathway)
  22. 22. Candidate HPC genes• RNASEL and MRS1 encode proteins with critical functions in host response to infections• Mutations in these genes might reduce the ability to eradicate infectious agents, thus resulting in chronic inflammation• Inflammatory cells elaborate numerous microbiological oxidants that might cause cellular or genomic damage in the prostate
  23. 23. PROLIFERATIVE INFLAMMATORY ATROPHY (PIA)• The morphological manifestation of all repeated bouts of injury (and cell death) to the prostate epithelium was described by Angelo De Marzo in 1999 (Am J Pathol )• Focal atrophic lesions containing activated inflammatory cells and proliferating epithelial cells are often directly adjacent to HGPIN, PCa or to both• Somatic genomic abnormalities are similar to those in cells with HGPIN and PCa
  24. 24. Atrophy merging with HG-PIN
  25. 25. NEJM 349: 366, 2003
  26. 26. HISTOPATHOLOGIC CLASSIFICATION SYSTEM FOR CHRONIC PROSTATIC INFLAMMATION• Anatomic localisation glandular periglandular stromal• Extension focal multifocal diffuse• Grading 1 2 3 Nickel et Al. BJU Int., 2001
  27. 27. CATEGORY IV PROSTATITISEPS/VB3 32,2 – 42% (Potts, 2000; Carver, 2003)BPH 43,1 – 100% (Nickel et Al. BJU Int. 1999)BIOPSIES 40 - 95% (Stancick,2004; Shattermann et Al, 2003)RADICAL PROSTATECTOMIES 95% (Gerstenbluth et Al, J Urol, 2002) In Japan, where PCa prevalence is very low, only 11,2% of screened population for high PSA has hystologic evidence of NIH IV prostatitis ( Shimomura et Al, 2003)
  28. 28. PATTERNS OF INFLAMMATION IN BPH Segregated glandular prostatitis Periglandular prostatitis Diffuse stromal prostatitisPeriglandular and stromal prostatitis Lymphoid nodular prostatitits Acute necrotizing prostatitis
  29. 29. PROSTATIC INFLAMMATION AND PSA: THE IRANI’S SCALEExtent Infiltration aggressiveness PSA elevation 0 no phlogistic cells no contact between +/- phlogistic cells and glandular epithelium 1 diffuse stromal contact between infiltration/no inflammatory infiltrate +/- limphoid nodules and glandular epithelium 2 limphoid nodules diffuse stromal infiltration not aggregated with disruption <25% + of glandular epithelium 3 wide inflammatory disruption > 25% ++ areas of aggregated of glandular epithelium infiltration Irani et Al. J Urol. 1997
  30. 30. MANAGEMENT OF CHRONIC PROSTATITIS• Antibiotics such as Fluoroquinolones• Alpha-blockers with or without antibiotics• NSAIDs• Allopurinol• Finasteride• Pentosan• Mepartricin• Amitryptiline• Analgesics, including centrally effective drugs• Muscle relaxants such as Valium or Baclofen• Phytotherapy• Physiotherapy with biofeedback• Thermotherapy and TUNA• Prostatic massage• Perineal skin application of Capsaicin• Sacral and pudendal neuromodulation
  31. 31. FLUORQUINOLONS ARE THE CHOISE DRUGS FOR TREATMENT OF CHRONIC BACTERIAL PROSTATITIS• Good activity vs Gram + and Gram – usually isolated in CBP• Favourable pharmacocynetic proprieties and elevated diffusion into prostatic tissue• Clinical and microbiological efficacy widely tested• Long time period treatment (not less than 4-6 weeks)• Best results with NSAIDs’ association
  32. 32. ANTI-INFLAMMATORY TARGETS AND PREVENTION OF PCa• Cytokines Anti-inflammatory cytokines (Interleukin-12)• NF-kB Salicylates• COX-2 Non-steroidal anti-inflammatory drugs Selective COX-2 inhibitors• PPARg Prostaglandins Thiazolidinediones (e.g., troglitazone, etc)• Reactive Oxygen Species Anti-oxidants: vitamin E, b Carotene Phytochemicals/free radical scavengers
  33. 33. ASPIRIN AND RISK FOR PROSTATE CANCER• Among the prospective studies the relative risk of prostate cancer for aspirin and non aspirin NSAIDs use ranges from 0.45 for multiple daily use to 1.05 for twice or more per week (Roberts et Al, Mayo Clin Proc, 2002 Leitzmann et al, Cancer Epidemiol Biomarkers Prev,2002; Dasgupta et Al, Cancer J, 2006)• In Baltimore Longitudinal Study of Aging only men < 70 years old who had ever used aspirin or ibuprofen had a statistically significant lower risk of prostate cancer (RR = 0,76 and 0.79 rispecrively). No difference statistically significant in men > 70’ Cancer Epidemiol Biomarkers & Prev, 2005)• In Italian multicentric case control study odds ratio (OR) for regular aspirin use was 1,10 = no protective role of regular aspirin use is observed on prostate cancer risk
  34. 34. SELECTIVE COX-2 INHIBITORS IN CP/CPPS-------------------------------------------------------- Rofecoxib, Celecoxib, Valdecoxib, Parecoxib, Etoricoxib and Lumiracoxib• Only one trial with Rofecoxib 25 and 50 mg for six weeks in the treatment of CP/CPPS (161 patients)• Only 50 mg reached statistical significance (symptoms, pain and quality of life) versus placebo (Nickel et Al, J Urol,2003)
  35. 35. PROSTATE CANCER CHEMOPREVENTION SELECTIVE COX-2 INHIBITORS• An industry – sponsored large scale trial of ROFECOXIB was closed after the drug was withdrawn from the market because of concerns over its cardiovascular safety.• In another study the biological activity of CELECOXIB was assessed in recurrent prostate cancer following PSA doubling times (DT) as outcome variables. Study terminated early due to concerns about possible cardiovascuklar side effects Before discontinuation 78 men were randomly assigned to Celecoxib (400 mg twice daily) or the placebo group Compared with placebo, Celecoxib significantly decrease mean PSA velocity and tended to increase the proportion of men who doubled their PSADT (Smith et Al, 2006)
  36. 36. COX-2 INHIBITORS: ADVERSE EVENTS• 14 trial reports with 116094 participants• 6394 composite renal events and 286 arrhythmia events• Compared with controls Rofecoxib was associated with increased risk of arrhythymia ( RR=2,90) and renal events (RR=1,53): removed from the marketplace (2004)• Celecoxib was associated with lower risk of renal dysfunction (RR=0.61) compared with controls but the risk of cardiovascular events may be increased• Valdecoxib: increased risk of cardiovascular adverse events and increased risk of serious skin reactions: removed from marketplace (2005)• Other agents of same family were not significantly associated with risks of adverse events (Zhang et Al. JAMA, 2006)
  37. 37. ALLOPURINOL FOR CHRONIC PROSTATITIS Reflux of urine into prostatic ducts causes prostatic inflammation via high concetration of purine and pyrimidine base-containing metabolites in prostatic secretions (Persson et al, J Urol. 1996)• Allopurinol is used hoping to lower prostatic levels of uric acid and improving symptoms• Only one trial with 54 men met study inclusion criteria• There was a statistically significant change favoring allopurinol in patient- reported discomfort between the study and control group at follow-up• No side effects in patients receiving allopurinol (McNaughton Collins and Wilt, The Cochrane Librrary, 2006)
  38. 38. PROSTATE CANCER CHEMOPREVENTIVE AGENTS IN PHASE III CLINICAL TRIALS 5alpha–reductase inhibitors: FINASTERIDE PCPT (Prostate Cancer Preventive Trial)Initiated and funded by NCIPopulation: 18882 men (DRE normal and PSA < 3)Prostate cancer was detected in 18.4% of men in finasteride group and 24.4% in the placebo group (-24.8%, p<0,001).However tumors were of Gleason score 7-10 in 6.4% of the finasteride- treated men compared with 5,1% of the placebo group (p=0,005) (Thompson et Al., 2006)The explanation for more aggressive tumors in the men treated with finasteride so far remains elusive.
  39. 39. PROSTATE CANCER CHEMOPREVENTIVE AGENTS IN PHASE III CLINICAL TRIALS 5-alpha reductase inhibitors: DUTASTERIDE REDUCE (Reduction of Prostate Cancer Events Trial)• So far 8000 men have been recruited to receive either 0.5 mg of Dutasteride or placebo for 4 years• Study is ongoing• Results in 2010 (Andriole et Al, 2004)
  40. 40. PROSTATE CANCER CHEMOPREVENTIVE AGENTS IN PHASE III CLINICAL TRIALS VITAMIN E• ALFA-TOCOPHEROL supplementation, in attempt to assess efficacy in preventing lung cancer, showed a 32% decrease in PCa incidence and a 41% decrease in PCa mortality (Clark et Al, The Alpha- Tocoferol Beta Carotene Ca Prevention study Group, 1998)• ALFA and GAMMA TOCOPHEROL correlates with a lower risk of developing prostate cancer (Weinstein et al, 2005)• A dose- response analysis showed statistically relationship between vitamin E dosage and all-cause mortality, with increase risk for dosage of > 150 IU/day (Miller et al, 2005)
  41. 41. PROSTATE CANCER CHEMOPREVENTIVE AGENTS IN PHASE III CLINICAL TRIALS SELENIUMSelenium is a trace nutrient essential for the activity of Glutathione Peroxidase, wich may reduce oxidative damage to DNAA dosage of 200 ng/day of selenomethionine showed 63% of reduction in the incidence of prostate cancer (Meuillet et Al, 2004)SELECT (Selenium and Vit.E Cancer Prevention Trial)Sponsored by NCI: randomized, prospective, double blind study200 ng/day selenomethionine + 400 IU racemic alfa-tocopherolTarget accrual of 32.400 individuals and results expected in 2013
  42. 42. PROSTATE CANCER CHEMOPREVENTIVE AGENTS IN PHASE I-II CLINICAL TRIALS: SELECTIVE OESTROGEN RECEPTOR MODULATORS (SERMs):TOREMIFENE• In phase II exploratory trial in men with HGPIN , after 4 months of treatment with daily oral dose of TOREMIFENE, 18 men had a repeat prostate biopsy with significant less HGPIN than historical controls. (Steiner and Pound, 2003)• A currently open 485 patients placebo controlled , randomized dose finding phase II-III clinical trial is investigating the efficacy of TOREMIFENE in reducing prostate cancer incidence in men with HGPIN (Price et Al,2006)
  43. 43. PROSTATE CANCER CHEMOPREVENTIVE AGENTS IN PHASE I-II CLINICAL TRIALS: DIFLUOROMETHYL ORNITHINE (DFMO)• DFMO is an irreversible inhibithor of ornithine decarboxylase involved in synthesis of polyamines; it possesses cytostatic and cytotoxic effects (Messing et Al, 1999)• The administration of DMSO at 0.5 g/m2 daily for 4 weeks to men scheduled for interventions to treat either BPH or PCa resulted in reduction of polyamine pools, including spermine ( Simoneau et Al., 2001)• These results may warrant further study as a possible chemopreventive agent for prostate cancer
  44. 44. PROSTATE CANCER CHEMOPREVENTIVE AGENTS IN PHASE I-II CLINICAL TRIALS: VITAMIN D• In experimentl models of prostate cancer active form of Vitamin D (1alpha, 25-D3) inhibits proliferation of human prostate cancer cells through mechanisms that include cell cycle arrest, induction of apoptosis and altered activation of grow factor signaling.• Population based studies with Vitamin D have not provided any significant data supporting a protective effect of vitamin D in prostate carcinogenesis ( Packianathan et Al., 2004)• Furthermore the use of vitamine D analogs in humans has been limited by their hypercalcemic effects, but newer analogs with more tolerable toxicity are currently being tested in phase I and II trials
  45. 45. PROSTATE CANCER CHEMOPREVENTIVE AGENTS IN PHASE I-II CLINICAL TRIALS: SOY ISOFLAVONES• A prospective study of 12395 men from Seventh Day Adventists in California demonstrated that frequent consumption of SOY MILK (at least daily) was associated with 70% reduction in the risk of developing prostate cancer ( Jacobsen et Al., 1998)• No large scale clinical trials using soy or soy based products as chemopreventive agents in prostate cancer have been reported.
  46. 46. PROSTATE CANCER CHEMOPREVENTIVE AGENTS IN PHASE I-II CLINICAL TRIALS: LYCOPENE• Prospective case-control studies and meta-analysis of observational studies have shown that TOMATO PRODUCTS may play a role in the prevention of prostate cancer ( Kirsh et Al., 2006)• Supplementation of lycopene enriched products or tomato products for several weeks prior to radical prostatectomy induce apoptotic cells death along with modulations in oxidative stress and tumor biology markers.• A phase II randomized clinical trial of 15 mg of lycopene twice daily for 3 weeks prior prostatectomy exhibited a decrease in the plasma IGF-I levels with no significant changes in Bax e Bcl-2 (Kucuk et Al., 2001) and another study with 30 mg daily of lycopene extract showed prostatic volume reduction in prostate cancer patients (Kucuk et Al., 2002)• Randomized trials to evaluate the efficacy of lycopene are still ongoing
  47. 47. PROSTATE CANCER CHEMOPREVENTIVE AGENTS IN PHASE I-II CLINICAL TRIALS: GREEN TEA CATECHINS• Epidemiological and case control studies have garnered support for the chemopreventive properties of green tea (Jian et Al., 2004)• In a recent study on 60 volunteers with HGPIN green tea compounds in capsule form of 200 mg was administered three times per day. Following 1 year of treatment only 3% of patients of green tea group were diagnosed with cancer compared with 30% in the placebo group. (Bettuzzi et Al., 2006)• Another clinical study used 250 mg dose of green tea polyphenols twice daily: 6 out of 19 patients had disease control for 3 to 5 months and a single patient achieved a PSA response > 50% (Choan et Al., 2005)• These results suggest that green tea possesses cancer preventive properties and minimal anti-neoplastic activity against advance stage prostate cancer
  48. 48. DIETARY INTAKE OF ANTIOXIDANTS Intake of different antioxidants that might attenuatecell and genome damage inflicted by inflammatoryoxidants (eg superoxide, nitric oxide and peroxynitrite)has been found to protect against prostate cancerdevelopment Consumption of crociferous vegetables containingisothiocyanates such as SULFORAPHANE reduce prostatecancer risk, acting as antioxidants by inducing a plethoraof carcinogen detoxification enzymes(Cohen et Al, J Natl Cancer Inst, 2000; Dinkova-Kostova et Al, Free Radic Biol med,2000)
  49. 49. CURCUMIN---------------------------------------------• Curcumin, traditionally used as a seasoning spice in Indian cuisine, has been reportede to decrease the proliferation potential of prostate cancer cells through - down regulation of AR gene expression, activator protein-1 (AP-1), and NF-kB. (Johng Rhim,Int. J. Og Oncology, 2002) - free radical scavenging ability and antioxidant efficiency (Khopde et Al. Biophys Chem. 1999) Clinical trials are not as yet available
  50. 50. QUERCETINE• Poliphenolic bioflavonoid (red wine, green tea, onions and spices)• Antioxidant and anti-inflammatory properties: inhibits IL-8 and MCP-1 (Monocyte chemoattractant protein-1) and inhibits the activation of NF-kB by TNF-alpha implicated in CPPS pathogenesis• 30 patients vs placebo• 500 mg 2 times daily ( 1 month)• 67% vs 20% had improved more than 25% in symptoms;• Significant improvement in 82% if Quercetine is associated with bromelain and papain (open label)• Interaction with Quinolones (competitive inhibitor of DNA gyrase) (Shoskes et Al. Urology,1999)
  51. 51. ROTATION DIET IN FOOD INTOLERANCE• Minimal persistent prostate inflammation with increased production of endogenous free radicals could be due to daily intaking of intolerant foods. (Sampson, J allergy Clin Immunol, 2004)• IgE studies can be used to detect real allergies while DRIA test (Dinamometric Research Into Allergies) can discovery individual food-intolerance ( Speciani et al, Allergy, 1992)• Rotation diet can re-establish the food tolerance, reduces cholesterol and positively increases the LAG-TIME (an in-vitro test which exprimes the resistance to oxidative stress). This prove the strong relationship between oxidative stress and diet (Perrone et Al, 2003)
  52. 52. CONCLUSIONS• Additional well designed basic, clinical and epidemiological studies are needed to resolve whether intraprostatic chronic inflammation is a rational target for prostate cancer prevention• If so, prostatic infections could be cleared with antibiotics or antiviral agents, inflammation could be inhibited by antiinflammatory agents, and reactive byproducts of the inflammatory response could be quenched by dietary and supplemental antioxidants• The PCPT trial emphasizes that cancer chemoprevention trials are not easy to design or interpret .To ensure that all adverse effects of chemopreventive agents are detected, randomizeed controlled trials need to be carefully monitored for sufficient period of time• Recent advances in molecular targeted researches may lead to the development of “smart agents” capables of preventing or delaying the onset of prostate cancer.• At present there is no convincing clinical proof or evidence that phytochemicals, in spite of encouraging experimental results, might be used in an attempt to cure the cancer of the prostate.
  53. 53. THANK YOUFOR YOUR ATTENTION!
  54. 54. NF-kB• NF-kB is a transcription factor that regulates the expression of various genes that control apoptosis, viral replication, tumorigenesis, various immune diseases and inflammation• Various carcinogens and tumor promoters have been shown to activate NF-kb and this activation blocks apoptosis and promotes proliferation• Tumor microenvironment can induce NF-kB activation• Several genes involved in tumor initiation, promotion and metastasis are regulated by NF-kB• Various chemopreventive agents and phytochemicals downregulate the NF-kB activation and can suppress the expression of genes involved in carcinogenesis of prostate cancer

×