Pharmacological prevention in oncology

PHARMACOLOGICAL PREVENTION
IN ONCOLOGY

Prevention in Prostate Cancer

Giancarlo Comeri
Urologist - Multimedica staff

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

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

CHRONIC INFLAMMATION HAS BEEN
LINKED TO CANCER IN THE:

esophagus
stomach
liver
bile duct
bladder
colon
skin
lung

Meta-analysis of 11 case-control studies revealed a statistically significant
summary OR of prostate cancer of 1.57 for ever having had prostatitis.
Urology
2002;60:78-83

A recent medical records review vs age-matched controls confirms this risk:
Any type of prostatitis: OR 1.7 Acute prostatitis: OR 2.5
Chronic 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 cancer
develops. However, casuality is unclear, because recall bias and detection

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

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

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

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)

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)

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

NP
VEGF

PIN PIN

PCa PCa

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

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

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

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

NEJM 349: 366, 2003

GSTP1 expression

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)

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

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

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

CATEGORY IV PROSTATITIS

EPS/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)

PATTERNS OF INFLAMMATION IN BPH

Segregated glandular prostatitis Periglandular prostatitis Diffuse stromal prostatitis

Periglandular and stromal prostatitis Lymphoid nodular prostatitits Acute necrotizing prostatitis

PROSTATIC INFLAMMATION AND PSA:
THE IRANI’S SCALE

Extent 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

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

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

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

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

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)

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)

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)

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)

PROSTATE CANCER CHEMOPREVENTIVE
AGENTS IN PHASE III CLINICAL TRIALS
5alpha–reductase inhibitors: FINASTERIDE

PCPT
(Prostate Cancer Preventive Trial)

Initiated and funded by NCI
Population: 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.

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)

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)

SELENIUM

Selenium is a trace nutrient essential for the activity of Glutathione
Peroxidase, wich may reduce oxidative damage to DNA

A 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 study
200 ng/day selenomethionine + 400 IU racemic alfa-tocopherol
Target accrual of 32.400 individuals and results expected in 2013

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)

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

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

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.

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

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

DIETARY INTAKE OF ANTIOXIDANTS

Intake of different antioxidants that might attenuate
cell and genome damage inflicted by inflammatory
oxidants (eg superoxide, nitric oxide and peroxynitrite)
has been found to protect against prostate cancer
development

Consumption of crociferous vegetables containing
isothiocyanates such as SULFORAPHANE reduce prostate
cancer risk, acting as antioxidants by inducing a plethora
of carcinogen detoxification enzymes
(Cohen et Al, J Natl Cancer Inst, 2000; Dinkova-Kostova et Al, Free Radic Biol med,
2000)

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

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)

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)

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.

THANK YOU

FOR YOUR ATTENTION!

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

Pharmacological prevention in oncology

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