I nutraceutici in oncologia

Adventurous TRPs: deorphanizing TRPs with small molecules natural products
I nutra c eutic i in onc olog ia :
S oluzione s em plic e a problem i
c om ples s i o na tura m orta di c onc etti
nebulos i, idee c onfus e e teorie
s pec ula tive?
G iovanni Appendino
Università del P iemonte O rientale
D ipartimento di S cienze del Farmaco
Perchè parlare di supprotive
care erbale
I prodotti erba li ha nno il potenzia le di
D im inuire g li effetti c o lla tera li di dia g nos tic a e tera pia
onc o log ic a (c hirurg ia , c hem o- e ra diotera pia )
q
NUC
LE re
A um
enta
l’effic a c ia
US
(c hem os ens ibilizza zione)
q
della
tera pia
G ene
Promoter
M ig lio ra re la qua lità di vita del pa ziente o nc olog ic o
q
L ’evidenza è tutta via prec linic a o a l m a s s im o
riferim ento a deg li s tudi c linic i m olto lim ita ti
fa
Le persone non sono dei roditori giganti
L’evidenza è aneddotica
C ome: Utilizzo di prodotti erbali
durante terapia oncologica
Pazienti oncologici che combinano prodotti
erbali con trattamenti oncologici: 80%.*
NUC LE
Caratteristiche
dell’utilizzo:
US
G ene
Ø Promoter
Non dichiarato
Ø
Ø
ai medici curanti
Utilizzo di prodotti di dubbia qualità tecnica
Utilizzo di dosaggi e modelli di
somministrazione non validati
*
Xu, W. E ur. J. C ancer C are 2006, 15, 397-403.
Quando sono utilizzati I
prodotti erbali
P reventiva (P rim a del tra tta m ento ):
P revenzione tos s ic ità C T s c a ns
Ø
A diuva nte (D ura nte il tra tta m ento ):
G enera le: a um ento della qua lità di vita
q
C a c hes s ia
q
Fa tic a
q
N a us ea
NUC
LE
S pec ific
a: m
itig a zionedi
q
USindotta da ra diotera pia a lla pelvi
C is tite
q
M uc
os ite indo tta da ra dio - e c hem io tera pia
G
ene
q
R a dioderm a tite
Promoter
q
E dem a indo tto da ra dio tera pia
q
G eno to s s ic ità indo tta da io dio ra dioa ttivo
q
T os s ic ità epa tic a
q
C a rdio to s s ic ità da a ntra c ic line
Ø
P os t tra tta m ento :
q
L infedem a
q
A um ento di pes o
q
V a m pa te di c a lo re e fra g ilità o s s ea
q
A um ento di D is ea s e Free S urviva l (S FS ) e prevenzione di ric a dute
Ø
S upportive care preventivo
C A NC ER DIA G NOS IS C A N INDUC E C A NC ER
R a dia tio n ex po s ure fro m a full bo dy s c a n is the
s a m e a s s ta nding 2.4 k m a w a y fro m the a to m ic
bo m b bla s ts in J a pa n during W o rld W a r I I
I n term s o f ra dia tio n ex po s ure, a C T s c a n
is equiva lent to 30-440 c hes t X -ra ys
N um ber o f C T s c a ns perfo rm ed every da y in U S : c a 200,000
NUC
LE % o f c a nc ers c a us ed by C T s c a ns : c a . 0.4 % o f a ll
E s tim
a ted
dia gUS
no s ed c a nc ers (1.5-2% ba s ed o n c urrent us e o f C T )
G ene
Promoter
N. E ng. J. Med. 2007, 357, 2277-
G inkgo and radiation
G inko is extraordinarily res is tant to
radiation:
Ginkgo trees are the only form of higher
life that survived the atomic bombing at
Hiroshima in 1945 within 2 km from the
blast. Six of these trees are still preserved
NUC LE
US
G ene
Promoter
http://kwanten.home.xs4all.nl/hiroshim
G inkgo and the nuclear meltdown at
C hernobyl
When taken orally three times a day, 40
mg. of Ginkgo biloba provided recovery
workers at C hernobyl protection from
radiation-induced clastogenicity
NUC LE
US
G ene
Promoter
Free R ad. B iol. Med. 1995, 18, 985-991
Mechanism of the anti-clastogenic effects of
ginkgo
The blood of people irradiated accidentally or for therapeutic reasons
contains chromosome-damaging factors known as clastogenic factors (CF)
Clastogenic activity can persist in blood several years after radiation
exposure, and are a risk factor for the late effects of ionizing radiation.1
CF are formed via the intermediacy of superoxide and generate superoxide.
Their formation is inhibited by the enzyme superoxide dismutase (SOD),
that quenches the superoxide ion radical.
Ginkgo extracts have superoxide scavenging properties, and could be
considered
as bio lo g ic a l a na lo g ues o f S O D , an enzyme that is not orally
NUC LE
active,US
and would have to be injected for in vivo clinical activity.
G ene
Promoter
Dardano, A. et al. J. C lin. E ndocrinol. Metab. 2007, 92, 4286-
G inkgo and radioiodine-induced
genotoxicity- G raves’ disease study
N a ture o f the s tudy: Placebo-controlled
L o c a tio n: Dipartimento di Medicina Interna, Pisa University (Italy)
P o pula tio n: 25 patients (19 women, mean age 47.9 ± 15.3 yr), all
nonsmokers, affected by relapsing Graves’ disease and undergoing
131I treatment.
NUC LE
D o s aUS
g e a nd dura tio n o f the interventio n: 120 mg/die Tanakan
from day -3 to day +30 respect to treatment
G ene
Promoter
E nd-po int: a) clastogenic score
b) efficacy of the therapy (reduction of tyroid volume)
R es ults : s ig nific a nt reduc tio n o f the c la s tog enic s c o re
no effec t o n the effic a c y o f the thera py*
Dardano, A. et al. J. C lin. E ndocrinol. Metab. 2007, 92, 42864289
*Efficacy: 100% in the treatment branch, 93% in the placebo; Later developemtn of
hypothirodidism: 63% of patients in the treatment branch, 73% in the placebo group
G inkgo and radioiodine-induced
genotoxicity- Tyroid cancer study
N a ture o f the s tudy: Placebo-controlled
L oc a tio n: Dipartimento di Medicina Interna, Pisa University (Italy)
P o pula tion: 23 patients (age 18-73 yr), all nonsmokers, affected by tyroid
cancer that had undergone near-total thyroidectomry and 131I treatment.
D o s a g e a nd dura tion o f the interventio n: 120 mg/die Tanakan from day -3
to dayNUC
+30LE
respect to treatment
US
E nd-po int: a) clastogenic score and lynphocytes MN
G ene
level in culture assay of plasma and blood
Promoter
b) thyroid hormone profile
R es ults : S ig nific a nt reduc tio n o f the c la s to g enic s c o re a nd
lym pho c ytes
N o differenc e in the thyro id ho rm o ne profile
betw een the tw o g ro ups .
*Efficacy: 100% in the treatment branch, 93% in the placebo; Later developemtn of hypothirodidism:
63% of patients in the treatment branch, 73% in the placebo group
Dardano, A. et al. Thyroid. 2012, 22, 318-324
S upportive c a re a diuva nte
Farmaci a base di
cannabinoidi
NABILONE
(Cesamet®)
capsule da 1 mg
Prodotto dalla Cambridge
Laboratories Ltd (UK).
NUC LEUS
G ene Promoter
DRONABINOL
(Marinol®)
capsule da 2.5 - 5 - 10
mg di THC
semisintetico. (Unimed
Pharmaceuticals, USA)
NABIXOMOLS
(Sativex®)
Spray oro-mucosale
2.7 mg THC , 2.5mg
CB /spruzzo (0.1mL)
GWPharma (UK).
L’olio di S imson: il caso di S tephanie Larue
NUC LEUS
G ene Promoter
L’olio di S imson: il caso di
S tephanie Larue
NUC LEUS
G ene Promoter
Purtroppo la marijuana NON
cura il cancro
NUC LEUS
G ene Promoter
C urcumin is very popular
within the cancer population
C hallenging the use of turmeric during
cancer therapy borders on criminal
J ames Duke (J. Am. Herbalist G uild
2010, 9, 60-61)
NUC LE
US
G ene
Promoter
http://margaret.healthblogs.org/life-with-myeloma/discovery-of-curcumin/my-curcumin-protocol/my-curcumin-cocoa-mass-recipe-in-eng
The curcumin-gemcitabine combination
N a ture o f the s tudy:Open-label, phase I
L o c a tio n: Dept. of Oncology, Rambam Health Care Campus (Haifa, Istrael)
P o pula tio n: 17 patients with advanced pancreatic cancer.
D o s a g e a nd dura tio n o f the interventio n: Gemcitabine (1000 mg/m2)
IV.weekly for 3-4 weeks + oral curcumin (8 g/day).for all the duration of
N U C LE
the treatment
US
E nd-po
G eneint: Determination of MTD
Promoter
R es ults : L o w c o m plia nc e to c urc um in a t 8 g /da y, a nd need to reduc e it a t 4 g /da y.
W ithin the 11 eva lua ted pa tients , 4 ha d s ta ble dis ea s e, 6 tum or prog res s io n a nd 1
pa rtia l res po ns e. 5 pa tients enrolled s uffered intra c ta ble a bdo m ina l fullnes s or
pa in, a nd ha d to dis c ontinue c urc um in.
Form ula tion o f c urc um in different fro m unfo rm ua lted c urc um in s ho uld be
inves tig a ted in future s tudies
Epelbaum, R. et al, Nutr. C ancer.. 2010, 62, 1137-1141
The curcumin-docetaxel combination
N a ture o f the s tudy:Open-label, phase I
L o c a tio n: Centre d’Investigation Clinique (Clermont-Ferrand, France)
P o pula tio n: 14 patients with advanced or metastatic breast cancer.
D o s a g e a nd dura tio n o f the interventio n: Docetaxel (100 mg/m2)
IV every
Curcumin orally up to 6 g/day for seven days (from
N U C3Lweeks.
E
d-4 to d+2).
US
G ene
EPromoter
nd-po int: Primary: determination of maximal tolerated dose (MTD)
Secondary: toxicity, safety, tumor markers measurements
(VEGF…) and objective clinical response of the combination
R es ults : M T D = 8 g /die c urc um in, but po o r c o m plia nc e bec a us e of the
num ber of pills to ta k e
S o m e im pro vem ents in bio lo g ic a l a nd c linic a l res pons es in
m os t
pa tients
Bayet-Robert, M. et al, C ancer B iol. Ther.. 2010, 9, 8-14
Effect of Meriva ® on the quality of life of cancer
patients
N a ture of the s tudy: Placebo-controlled study
L o c a tio n: Università di Chieti-Pescara (Italy) and University of Milano
P o pula tio n: 160 cancer patients chemo- and radiotherapy naif
treated, after surgery, with chemotherapy (80) or radiotherapy (80),
and divided between control and treatment groups. All patients in
N U C LE
reasonaly good condition (Karnofsky scale score >70)
US
GDene
o s a g e a nd dura tio n o f the interventio n: 3 x 500 mg Meriva® daily
Promoter
for 8 weeks after the end of the first treatment, started at least one
month after surgery
E nd-po int: Semi-quantitative evaluation of treatment side-effects
Plasma oxidative status
R es ults :
S ig nific a nt differenc e betw een the tw o g roups in term s o f
T rea tm ent s ide-effec ts
P la s m a o x ida tive s ta tus
Quality of life according to the Karnofky
Performance S cale index
N U C LE
US
G ene
Promoter
M eriva ®e s uppo rtive
c a re
Nausea indotta da chemioterapia
N U C LE
US
G ene
Promoter
Incidenza della naus ea indotta da chemioterapia: >70%
(Ryan J . L. ,et al. S upp. C are C ancer. 2011, in press.)
G inger for the reduction of chemotherapy-induced
nausea
N a ture o f the s tudy: Randomized, double-blind, placebo-controlled,
multicenter
L oc a tio n: Dept. of Dermatology, University of Rochester Medical Center
(Rochester, US) (Coordination)
P o pula tion: 744 adult cancer patients divided into four arms: one placebo
and three dosages of ginger (0.5 g, 1 g, 1.5 g)
D o s a g e a nd dura tion o f the interventio n: 3 caps/day ginger or placebo
N U Cfor
L E6 days (from -3 to +3 of the beginning of chemotherapy). 5twice/day
HT(3) U
antagonist
administered as antiemetic on day 1. Each cap contains 8.5
S
mg
gingeroids
G ene
Promoter
E nd-po int: Determination of optimal dosage and efficacy for the reduction of
nausea on day 1 of chemotherapy
R es ults : S ig nific a nt reduc tio n o f na us e a t da y 1 o f c hem othera py
c om pa red to pla c ebo fo r the 0.5 g a nd 1 g dos a g es (17-34 m g
g ing ero ids /die)
Ryan, J . L..et al, S upport C are C ancer.. 2010
Tossicità epatica
N U C LE
US
G ene
Promoter
Incidenza di tos s icità epatica: 33-66% , ( 50% di g rado III or IV)
(Floyd J . et al. S emin O ncol. 2006; 33, 50-67.).
S iliphos® for the prevention of
chemotherapy- induced liver toxicity
Nature of the study
Placebo-controlled
Number of patients
24 (T) , 26 (P); age 2-19
Dosage of Siliphos (as silybin)
5.1 mg/Kg/die
Duration of the study
56 days (28 treatment; 28
discontinuation, then blood analysis)
N U C LE
End Point
US
G ene
Promoter
Location of the trial
Major investigator
Liver health as measured by
biochemical assays (AST, ALT, TB)
Children Hospital New Presbyterian
(Columbia and Cornell University
associated)
Prof. K. Kelly
Ladas E. J . . et al. C ancer 2010, 320-334
THE STUDY MADE HEADLINE NEWS
WHAT THE STUDY AUTHORS SAID
“Milk this tle needs to be s tudied further, to see how effective
it is for a longer course of treatment, and whether it works well in
reducing liver inflammation in other types of cancers and with
other types of chemotherapy. However, our results are promis ing
as there are no s ubs titute medications for treating liver toxicity.”
K. Kelly, from a press releas e
of the American C ancer
S ociety
Edema indotto da
radioterapia
NUC LE
US
G ene
Promoter
B oswellia as a steroid-sparing agent for cerebral
edema
N a ture o f the s tudy: randomized, placebo-controlled, double blind
L oc a tio n: Dept. Radiation Oncology, Univeristy Hospital, Freiburg (Germany)
P o pula tion: 44 patients with primary or secondary malignant cerebral
tumors, receiving radiotherapy.
D o s a g e a nd dura tion o f the interventio n: 4.2 g of Boswellia Extract
(BSE)/day
NUC LE
US
E nd-po int: Primary: Volume of cerebral edema measured by MRI
G ene
Secundary: toxicity, cognitive function, quality of life, need for
Promoter
dexamethasone
medication
R es ults : S ig nific a tive reduc tio n (>75% ) in 60% of pa tients rec eiving B S E
26% w ith pla c ebo
N o s ig nific a nt a dvers e rea c tions
N o s ig nific a tn effec t on qua lity o f life, c o g nitive func tio n, a nd
us e of dex a m etha s one
Kirste, S.. et al, C ancer. 2011, 117, 3788-3795
vs
C istite indotta da radioterapia
NUC LE
US
G ene
Promoter
C ranberry for prostate cancer related UTI
Nature of the study
Controlled
Number of patients
370 (184 treatment + 186 control)
Dosage
200 mg of a standardized cranberry extract
(30% PAC according to EU Pharmacopoeia)
Duration of the study
6-7 weeks, starting the day of bladder
catheterization
End Point
NUC LE
Objective: Number of UTI as established by
uroculture
Subjective:urinary symptoms (nycturia,
mictional urgency and frequency, dysuria
US
G ene
Promoter
Location
Results
Italy (Cremona hospital, radiology center)
Statistically significant reduction of UTI (9% in
the treatment branch vs 24% in the control)
and of the urinary symptoms
Bonetta, A.; Di Pierro, F. submitted for publication
S upporting care pos t-trattamento
C oumarins, phenolics and the
treatment of cancer lymphedema
Nature of the s tudy: controlled study
Location: Istituto Nazionale per la Ricerca sul Cancro (Genova, Italy)
Population: 21 breast cancer survivors with chronic upper arm lymphedema
secondary to removal of axilary lymphnodes.
NUC LE
Dos ag e and duration of the intervention: 400 mg of a standardized
US officinale extract standardized in coumarin (8 mg) in a single daily
Melilotus
G ene
administration
for 6 months.
Promoter
End-point: reduction of lymphedema, as measured by upper arm
circumpherence.
R es ults : Modes t, but s tatis tically s ig nificant reduction of edema (5% of
the initial value) and dis comfort.
Pastura, G. et al.. C lin. Ter. 1999, 150, 403408
The potential of combining phenolics and
using new formulations
NUC LE
US
G ene
Promoter
Pastura, G. et al.. C lin. Ter. 1999, 150, 403408
A umento di peso
NUC LE
US
G ene
Promoter
Green tea and post-treatment overweight
status
Nature of the s tudy: placebo-controlled
Location: Dept. Nutritional Sciences, University of Ariziona
Population: 54 overweight breast cancer survivors (BMI: 30.1 Kg/m-2).
Dos ag e and duration of the intervention: 960 mL/day of decaffeinated green
tea vs placebo tea (Lipton tea bags, ca 60 mg catechins/bag, 4 bags/day)/ 6
months
NUC LE
US
End-point: a) weight
G ene b) body composition and resting metabolic rate
Promoter
c) energy intake, glucose, HOMA-IR, lipid profile
R es ults : Modes t reduction of weig ht (-1.2 K g vs + 0.2 in control)
S ig nificant reduction in energ y intake
Increas e of choles terol HDL
Nons ig nificant improvement of HDL/LDL ratio and HOMA-IR
Stendell-Hollis, N.R. J.Hum. Nutr. D iet 2010, 23, 590-
C onclusioni
E ’ più importante conoscere che persona ha
una malattia piuttosto che quale malattia ha
una persona
Ippocrate
NUC LE
US
G ene
Promoter
Martirio di
Sant’Agata
Giovanni
Lanfranco, inizio
XVII secolo