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Prevention of radioinduced cystitis by orgotein: a
randomized study.
Sanchiz F, Milla A, Artola N, Julia JC, Moya LM, Pedro A,
Vila A
Center of Radiotherapy and Oncology of Catalonia, Clinica
Platon, Barcelona, Spain.
Anticancer Res 1996 Jul-Aug;16(4A):2025-8
On the basis of previous experiences indicating that the
anti-oxidant agent Cu/Zn superoxide dismutase (SOD) is an
effective drug in reducing acute and late radiation-induced
tissue injury, in the Center of Radiotherapy and Oncology of
Catalonia, Barcelona, Spain in 1990 we implemented a
randomized prospective study to analyze the incidence and
grade of side effects in a group of bladder cancer patients.
After surgery patients were randomly allocated to receive
either: Option A: Radiotherapy or Option B: Radiotherapy + SOD
8 mgr/IM/day, after each radiotherapeutic application. Between
January 1990 and January 1995 a total of 448 patients were
included (226 A/ 222 B). Apart from cutaneous side effects, a
highly significant incidence of radioinduced acute cystitis
and rectitis was detected in patients not treated by SOD.
Which was similar to the delayed side effects. From our data
we can conclude that SOD is effective in decreasing acute
radioinduced damage, and also in preventing the appearance of
more delayed disorders.
Pathological features of hereditary prostate
cancer.
Bastacky SI, Wojno KJ, Walsh PC, Carmichael MJ, Epstein
JI
Department of Pathology, Johns Hopkins University School of
Medicine, Baltimore, Maryland 21287-2101.
J Urol 1995 Mar;153(3 Pt 2):987-92
The aim of this study was to characterize the pathological
features of hereditary prostate cancer, a recently recognized
variant of prostate cancer with an autosomal dominant
inheritance of a rare highly penetrant gene associated with
early onset of disease. We compared the histology at radical
prostatectomy of clinical stage T2 prostate cancer, including
its relationship to prostatic intraepithelial neoplasia, in
men with a family history of prostate cancer to those without
a family history of prostate cancer. Three cohorts
(hereditary, familial and sporadic) were identified based on
pedigree analysis. A hereditary subgroup (28 patients) met 1
of the following 3 criteria: 1) cluster of greater than 3
affected relatives within the nuclear family, 2) occurrence of
prostate cancer in each of 3 generations in either the proband
paternal or maternal lineage, or 3) a cluster of 2 relatives
affected at an early age of less than 55 years. This subgroup
was compared to an age-matched subgroup with family history of
prostate cancer (26 patients) yet the aforementioned
conditions for inclusion within the hereditary subgroup were
not met and to a sporadic subgroup without a family history of
prostate cancer (27 patients). All parameters were
statistically similar among the groups except that hereditary
and familial group multifocal tumors were of lower grade (p =
0.0001), sporadic cases had a greater proportion of small
multifocal cancers associated with prostatic intraepithelial
neoplasia (p = 0.02) and the familial group had a weaker
correlation between total tumor volume and grade. In
conclusion, our analysis failed to demonstrate substantial
pathological differences among hereditary, familial and
sporadic forms of prostate cancer. Rather, our data are
remarkable for the wide range of all parameters studied in
each group. Even the sporadic cases had features, such as
increased numbers of precursor lesions and tumor
multifocality, which in other organs are commonly associated
with either hereditary cancer or cancer arising in a field
effect due to diffuse exposure to a carcinogen.
Familial risk factors for prostate cancer.
Carter BS, Steinberg GD, Beaty TH, Childs B, Walsh PC
Department of Epidemiology, School of Hygiene and Public
Health, Johns Hopkins Medical Institutions, Baltimore,
Maryland 21205.
Cancer Surv 1991;11:5-13
This chapter describes the application of the genetic
epidemiological approach to the study of human prostate
cancer. We review the evidence for the familial clustering of
prostate cancer and the Mendelian nature of this aggregation.
The nature of this clustering is such that the closer
genetically a man is to an affected relative and the greater
number of relatives affected in a man's family, the greater
his risk of prostate cancer. A complex segregation analysis of
the 691 prostate cancer families showed that prostate cancer
clustering can be explained by Mendelian inheritance of a rare
autosomal gene producing prostate cancer at an early age. A
model of inherited prostate cancer in the setting of multistep
carcinogenesis is presented. The implications of these data
for clinicians who diagnose and treat prostate cancer are also
discussed.
Mendelian inheritance of familial prostate
cancer.
Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC
Department of Epidemiology, Johns Hopkins School of Hygiene
and Public Health, Baltimore, MD.
Proc Natl Acad Sci U S A 1992 Apr
15;89(8):3367-71
Previous studies have demonstrated familial clustering of
prostate cancer. To define the nature of this familial
aggregation and to assess whether Mendelian inheritance can
explain prostate cancer clustering, proportional hazards and
segregation analyses were performed on 691 families
ascertained through a single prostate cancer proband. The
proportional hazards analyses revealed that two factors, early
age at onset of disease in the proband and multiple affected
family members, were important determinants of risk of
prostate cancer in these families. Furthermore, segregation
analyses revealed that this clustering can be best explained
by autosomal dominant inheritance of a rare (q = 0.0030)
high-risk allele leading to an early onset of prostate cancer.
The estimated cumulative risk of prostate cancer for carriers
revealed that the allele was highly penetrant: by age 85, 88%
of carriers compared to only 5% of noncarriers are projected
to be affected with prostate cancer. The best fitting
autosomal dominant model further suggested that this inherited
form of prostate cancer accounts for a significant proportion
of early onset disease but overall is responsible for a small
proportion of prostate cancer occurrence (9% by age 85). These
data provide evidence that prostate cancer is inherited in
Mendelian fashion in a subset of families and provide a
foundation for gene mapping studies of heritable prostate
cancer. Characterization of genes involved in inherited
prostate cancer could provide important insight into the
development of this disease in general.
Family history and the risk of prostate
cancer.
Steinberg GD, Carter BS, Beaty TH, Childs B, Walsh PC
Brady Urological Institute, Johns Hopkins Hospital,
Baltimore, MD 21205.
Prostate 1990;17(4):337-47
A case-control study was performed to estimate the relative
risk of developing prostate cancer for men with a positive
family history. Extensive cancer pedigrees were obtained on
691 men with prostate cancer and 640 spouse controls. Fifteen
percent of the cases but only 8% of the controls had a father
or brother affected with prostate cancer (P less than .001).
Men with a father or brother affected were twice as likely to
develop prostate cancer as men with no relatives affected. In
addition, there was a trend of increasing risk with increasing
number of affected family members such that men with two or
three first degree relatives affected had a five and 11-fold
increased risk of developing prostate cancer. Recognizing that
9-10% of U.S. men will develop prostate cancer in their
lifetime, men with a family history of prostate cancer should
be advised of their significantly increased prostate cancer
risk and should undergo appropriate screening measures for
this disease.
Familial patterns of prostate cancer: a
case-control analysis.
Spitz MR, Currier RD, Fueger JJ, Babaian RJ, Newell GR
Department of Cancer Prevention and Control, University of
Texas M.D. Anderson Cancer Center, Houston.
J Urol 1991 Nov;146(5):1305-7
Epidemiological data have not yet enabled physicians to
look beyond age and race to identify men at increased risk for
prostate cancer. We conducted a hospital-based case-control
study of familial patterns of prostate cancer with
self-reported data from a risk-factor questionnaire. There
were 385 patients with histologically confirmed prostate
cancer, and 385 race and age-matched (+/- 5 years) controls
with other cancers. Family history, available for 378 patients
and 383 controls, was positive for prostate cancer in 13.0%
versus 5.7%, respectively. The difference was significant at p
= 0.01. The over-all age-adjusted risk estimate for men with a
first-degree relative with prostate cancer was significantly
elevated (odds ratio of 2.41), as were the individual risk
estimates for having a father or brother with prostate cancer
(odds ratio of 2.24 and 2.66). Having a second-degree relative
(grandfather or uncle) with prostate cancer also conferred
elevated but not statistically significant risk. These data
accord well with the few previously published case-control
studies of familiarity of prostate cancer. On the basis of
these findings, one should consider recommending participation
in early detection programs for prostate cancer in a man whose
father or brother has had the disease.
Inhibition of arachidonate 5-lipoxygenase triggers
massive apoptosis in human prostate cancer cells.
Ghosh J, Myers CE
University of Virginia Cancer Center, Charlottesville, VA
22908, USA.
Proc Natl Acad Sci U S A 1998 Oct
27;95(22):13182-7
Diets high in fat are associated with an increased risk of
prostate cancer, although the molecular mechanism is still
unknown. We have previously reported that arachidonic acid, an
omega-6 fatty acid common in the Western diet, stimulates
proliferation of prostate cancer cells through production of
the 5-lipoxygenase metabolite, 5-HETE
(5-hydroxyeicosatetraenoic acid). We now show that 5-HETE is
also a potent survival factor for human prostate cancer cells.
These cells constitutively produce 5-HETE in serum-free medium
with no added stimulus. Exogenous arachidonate markedly
increases the production of 5-HETE. Inhibition of
5-lipoxygenase by MK886 completely blocks 5-HETE production
and induces massive apoptosis in both hormone-responsive
(LNCaP) and -nonresponsive (PC3) human prostate cancer cells.
This cell death is very rapid: cells treated with MK886 showed
mitochondrial permeability transition between 30 and 60 min,
externalization of phosphatidylserine within 2 hr, and
degradation of DNA to nucleosomal subunits beginning within
2-4 hr posttreatment. Cell death was effectively blocked by
the thiol antioxidant, N-acetyl-L-cysteine, but not by
androgen, a powerful survival factor for prostate cancer
cells. Apoptosis was specific for 5-lipoxygenase-programmed
cell death was not observed with inhibitors of
12-lipoxygenase, cyclooxygenase, or cytochrome P450 pathways
of arachidonic acid metabolism. Exogenous 5-HETE protects
these cells from apoptosis induced by 5-lipoxygenase
inhibitors, confirming a critical role of 5-lipoxygenase
activity in the survival of these cells. These findings
provide a possible molecular mechanism by which dietary fat
may influence the progression of prostate cancer.
Induction of cyclo-oxygenase-2 mRNA by
prostaglandin E2 in human prostatic carcinoma cells.
Tjandrawinata RR, Dahiya R, Hughes-Fulford M
Department of Medicine, University of California, San
Francisco, USA.
Br J Cancer 1997;75(8):1111-8
Prostaglandins are synthesized from arachidonic acid by the
enzyme cyclo-oxygenase. There are two isoforms of
cyclooxygenases: COX-1 (a constitutive form) and COX-2 (an
inducible form). COX-2 has recently been categorized as an
immediate-early gene and is associated with cellular growth
and differentiation. The purpose of this study was to
investigate the effects of exogenous dimethylprostaglandin E2
(dmPGE2) on prostate cancer cell growth. Results of these
experiments demonstrate that administration of dmPGE2 to
growing PC-3 cells significantly increased cellular
proliferation (as measured by the cell number), total DNA
content and endogenous PGE2 concentration. DmPGE2 also
increased the steady-state mRNA levels of its own inducible
synthesizing enzyme, COX-2, as well as cellular growth to
levels similar to those seen with fetal calf serum and phorbol
ester. The same results were observed in other human cancer
cell types, such as the androgen-dependent LNCaP cells, breast
cancer MDA-MB-134 cells and human colorectal carcinoma DiFi
cells. In PC-3 cells, the dmPGE2 regulation of the COX-2 mRNA
levels was both time dependent, with maximum stimulation seen
2 h after addition, and dose dependent on dmPGE2
concentration, with maximum stimulation seen at 5 microg
ml(-1). The non-steroidal anti-inflammatory drug flurbiprofen
(5 microM), in the presence of exogenous dmPGE2, inhibited the
up-regulation of COX-2 mRNA and PC-3 cell growth. Taken
together, these data suggest that PGE2 has a specific role in
the maintenance of human cancer cell growth and that the
activation of COX-2 expression depends primarily upon newly
synthesized PGE2, perhaps resulting from changes in local
cellular PGE2 concentrations.
Prostate cancer and supplementation with
alpha-tocopherol and beta-carotene: incidence and mortality in
a controlled trial.
Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK,
Hartman AM, Haapakoski J, Malila N,
Rautalahti M, Ripatti S, Maenpaa H, Teerenhovi L, Koss L,
Virolainen M, Edwards BK
Department of Public Health, University of Helsinki,
Finland.
J Natl Cancer Inst 1998 Mar 18;90(6):440-6
BACKGROUND: Epidemiologic studies have suggested that
vitamin E and beta-carotene may each influence the development
of prostate cancer. In the Alpha-Tocopherol, Beta-Carotene
Cancer Prevention Study, a controlled trial, we studied the
effect of alpha-tocopherol (a form of vitamin E) and
beta-carotene supplementation, separately or together, on
prostate cancer in male smokers.
METHODS: A total of 29133 male smokers aged 50-69 years
from southwestern Finland were randomly assigned to receive
alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents,
or placebo daily for 5-8 years (median, 6.1 years). The
supplementation effects were estimated by a proportional
hazards model, and two-sided P values were calculated.
RESULTS: We found 246 new cases of and 62 deaths from
prostate cancer during the follow-up period. A 32% decrease
(95% confidence interval [CI] = -47% to -12%) in the incidence
of prostate cancer was observed among the subjects receiving
alpha-tocopherol (n = 14564) compared with those not receiving
it (n = 14569). The reduction was evident in clinical prostate
cancer but not in latent cancer. Mortality from prostate
cancer was 41% lower (95% CI = -65% to -1%) among men
receiving alpha-tocopherol. Among subjects receiving
beta-carotene (n = 14560), prostate cancer incidence was 23%
higher (95% CI = -4%-59%) and mortality was 15% higher (95% CI
= -30%-89%) compared with those not receiving it (n = 14573).
Neither agent had any effect on the time interval between
diagnosis and death.
CONCLUSIONS: Long-term supplementation with
alpha-tocopherol substantially reduced prostate cancer
incidence and mortality in male smokers. Other controlled
trials are required to confirm the findings.
Vitamin E inhibits the high-fat diet promoted
growth of established human prostate LNCaP tumors in nude
mice.
Fleshner N, Fair WR, Huryk R, Heston WD
Urologic Oncology Research Laboratory, Sloan Kettering
Institute For Cancer Research, New York, New York, USA.
J Urol 1999 May;161(5):1651-4
PURPOSE: Prostate cancer has become an important public
health problem in the Western world. It is currently the most
common diagnosed cancer and the second leading cause of cancer
deaths among North American men. Prostate cancer possesses a
unique descriptive epidemiology which suggests that
environmental factors (such as dietary fat consumption) play a
pivotal role in tumor progression. Data from our institution
have demonstrated that diets high in fat content can
accelerate the growth of human LNCaP prostate cancer cells.
One of the hypothesized mechanisms of dietary fat induced
growth is oxidative stress. Our purpose was to determine the
effect of supplemental Vitamin E, a potent intracellular
antioxidant, on the high-fat promoted growth of transplanted
LNCaP cells in the athymic mouse.
MATERIALS AND METHODS: Tumors were induced by subcutaneous
injection of 10(6) LNCaP cells. Mice were fed a control diet
consisting of 40.5% of total calories from dietary fat. Once
tumors were formed, PSA values were obtained and animals were
randomized into 4 groups of 12. The animals were then assigned
to one of 4 dietary plans. Group 1 received the control diet
of 40.5%-kcal fat. Group 2 received the 40.5%-kcal fat diet
plus supplemental Vitamin E. Group 3 received a diet of
21.2%-kcal fat. Group 4 received the 21.2%-kcal fat diet plus
supplemental Vitamin E. Food intake, animal weights, and tumor
volumes were recorded weekly. Survival analyses with time to a
target volume of 0.523 cm.3 (defined as failure) were used to
compare tumor growth among the 4 groups. Two-sided tests (log
rank test) with alpha set at 0.05 were used to determine
significance.
RESULTS: Tumor growth rates were highest in the animals fed
a 40.5%-kcal fat diet (p <0.05 group 1). Tumors in animals
fed 40.5%-kcal fat plus Vitamin E, 21.2%-kcal fat, and
21.2%-kcal fat plus Vitamin E, experienced statistically
indistinguishable growth rates. No significant differences
were noted in total ingested calories, animal weight gain or
initial PSA levels.
CONCLUSIONS: These data suggest that the mechanism of
dietary fat induced growth of human prostate cancer cells is
mediated by oxidative stress. It also raises the possibility
of a therapeutic benefit of vitamin E in preventing prostate
cancer.
Effects of selenium supplementation for cancer
prevention in patients with carcinoma of the skin. A
randomized controlled trial. Nutritional Prevention of Cancer
Study Group.
Clark LC, Combs GF Jr, Turnbull BW, Slate EH, Chalker DK,
Chow J, Davis LS, Glover RA, Graham GF, Gross EG, Krongrad A,
Lesher JL Jr, Park HK, Sanders BB Jr, Smith CL, Taylor
JR
Arizona Cancer Center, College of Medicine, University of
Arizona, Tucson, USA.
JAMA 1996 Dec 25;276(24):1957-63
Published erratum appears in JAMA 1997 May
21;277(19):1520
OBJECTIVE: To determine whether a nutritional supplement of
selenium will decrease the incidence of cancer.
DESIGN: A multicenter, double-blind, randomized,
placebo-controlled cancer prevention trial.
SETTING: Seven dermatology clinics in the eastern United
States.
PATIENTS: A total of 1312 patients (mean age, 63 years;
range, 18-80 years) with a history of basal cell or squamous
cell carcinomas of the skin were randomized from 1983 through
1991. Patients were treated for a mean (SD) of 4.5 (2.8) years
and had a total follow-up of 6.4 (2.0) years.
INTERVENTIONS: Oral administration of 200 microg of
selenium per day or placebo.
MAIN OUTCOME MEASURES: The primary end points for the trial
were the incidences of basal and squamous cell carcinomas of
the skin. The secondary end points, established in 1990, were
all-cause mortality and total cancer mortality, total cancer
incidence, and the incidences of lung, prostate, and
colorectal cancers.
RESULTS: After a total follow-up of 8271 person-years,
selenium treatment did not significantly affect the incidence
of basal cell or squamous cell skin cancer. There were 377 new
cases of basal cell skin cancer among patients in the selenium
group and 350 cases among the control group (relative risk
[RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218
new squamous cell skin cancers in the selenium group and 190
cases among the controls (RR, 1.14; 95% CI, 0.93-1.39).
Analysis of secondary end points revealed that, compared with
controls, patients treated with selenium had a nonsignificant
reduction in all-cause mortality (108 deaths in the selenium
group and 129 deaths in the control group [RR; 0.83; 95% CI,
0.63-1.08]) and significant reductions in total cancer
mortality (29 deaths in the selenium treatment group and 57
deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total
cancer incidence (77 cancers in the selenium group and 119 in
controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of
lung, colorectal, and prostate cancers. Primarily because of
the apparent reductions in total cancer mortality and total
cancer incidence in the selenium group, the blinded phase of
the trial was stopped early. No cases of selenium toxicity
occurred.
CONCLUSIONS: Selenium treatment did not protect against
development of basal or squamous cell carcinomas of the skin.
However, results from secondary end-point analyses support the
hypothesis that supplemental selenium may reduce the incidence
of, and mortality from, carcinomas of several sites. These
effects of selenium require confirmation in an independent
trial of appropriate design before new public health
recommendations regarding selenium supplementation can be
made
Inhibitory effects of selenium on the growth of
DU-145 human prostate carcinoma cells in vitro.
Webber MM, Perez-Ripoll EA, James GT
Biochem Biophys Res Commun 1985 Jul
31;130(2):603-9
The growth of DU-145 human prostate carcinoma cells is
reduced to 50% of control by 1 X 10(-6) M to 2 X 10(-6) M
selenium and to 2% of control at 10(-4)M selenium. These cells
show greater sensitivity to inhibition of growth or DNA
synthesis by selenium than human W1-38 and HeLa cells and
mouse mammary tumor cells. It has been shown that selenium
inhibits carcinogenesis and reduces the incidence of chemical
carcinogen and virus-induced tumors of a variety of organs in
animals. Selenium may also inhibit the growth of certain tumor
cells of non-human origin. To our knowledge, this is the first
study on the effects of selenium on the growth of human tumor
cells. From extrapolation, it is deduced that selenium serum
levels in humans living in high selenium areas may be as high
as 10(-6) M and could be effective in inhibiting the growth of
tumor cells in vivo. These findings have implications in the
prevention and intervention of prostate cancer in man.
Genistein inhibits proliferation and in vitro
invasive potential of human prostatic cancer cell lines.
Santibanez JF, Navarro A, Martinez J
Unidad de Biologia Celular, INTA, Universidad de Chile,
Santiago, Chile.
Anticancer Res 1997 Mar-Apr;17(2A):1199-204
Genistein -a natural flavone compound with antitumor
activity- has been proposed as an effective agent to prevent
the expression of metastasic capacity in hormone-dependent
cancers. The present study represents an effort to assess the
efficacy of Genistein in inhibiting the proliferation and
expression of the in vitro invasive capacity of tumoral
prostatic cells with different invasive potential. In a cell
culture system, genistein appeared to be cytotoxic and
inhibitory of miaration through a Material barrier to PC-3
cells, the more aggressive invasive cell-line studied. DU-145
and LNCaP cells, which are less invasive than PC-3, are less
affected by Genistein both with respect to proliferation rate
and inhibition of u-PA and 72 kDa Gelatinase secretion.
Measurement of the level of tyrosine-phosphoproteins in the
three cell lines studied also showed that PC-3 cells are the
most sensitive cells, with a possible molecular target in a
membrane-bound protein of 130 kDa.
Genistein and biochanin A inhibit the growth of
human prostate cancer cells but not epidermal growth factor
receptor tyrosine autophosphorylation.
Peterson G, Barnes S
Department of Biochemistry, University of Alabama, Birmingham
35294-0019.
Prostate 1993;22(4):335-45
The effect of the isoflavones, genistein, daidzein, and
biochanin A on the growth of the LNCaP and DU-145 human
prostate cancer cell lines has been examined. Genistein and
biochanin A, but not daidzein, inhibit both serum and
EGF-stimulated growth of LNCaP and DU-145 cells (IC50 values
from 8.0 to 27 micrograms/ml for serum and 4.3 to 15
micrograms/ml for EGF), but have no significant effect of the
EGF receptor tyrosine autophosphorylation. In contrast,
tyrphostin 25, a specific EGF receptor tyrosine kinase
inhibitor, inhibits EGF-stimulated growth and EGF receptor
tyrosine autophosphorylation in these whole cells, but does
not inhibit serum-stimulated growth. These data suggest that
the mechanism of action of genistein and biochanin A does not
depend on inhibition of EGF receptor tyrosine
autophosphorylation, but on a more distal event in the EGF
receptor-mediated signal transduction cascade.
Antiproliferative effect of Pygeum africanum
extract on rat prostatic fibroblasts.
Yablonsky F, Nicolas V, Riffaud JP, Bellamy F
Laboratoires Debat, groupe Fournier, Garches, France.
J Urol 1997 Jun;157(6):2381-7
Published erratum appears in J Urol 1997 Sep;158(3 Pt
1):889
The effect of a Pygeum africanum extract (Tadenan) (Pa),
used in the treatment of micturition disorders associated with
BPH, has been examined on the proliferation of rat prostatic
stromal cells stimulated by different growth factors. EGF,
bFGF, and IGF-I but not KGF are mitogenic for prostatic
fibroblasts in culture. Pygeum africanum inhibits both basal
and stimulated growth with IC50 values of 4.5, 7.7 and 12.6
micrograms./ml. for EGF, IGF-I and bFGF, respectively,
compared to 14.4 micrograms./ml. for untreated cells, the
inhibition being stronger towards EGF. Pygeum africanum
inhibited the proliferation induced by TPA or PDBu in a
concentration-dependent manner with IC50 values of 12.4 and
8.1 micrograms./ml. respectively. The antiproliferative
effects of Pa were not ascribed to cytotoxicity. These results
show that Pygeum africanum is a potent inhibitor of rat
prostatic fibroblast proliferation in response to direct
activators of protein kinase C, the defined growth factors
bFGF, EGF and IGF-I, and the complex mixture of mitogens in
serum depending on the concentration used. PKC activation
appears to be an important growth factor-mediated signal
transduction for this agent. These data suggest that
therapeutic effect of Pygeum africanum may be due at least in
part to the inhibition of growth factors responsible for the
prostatic overgrowth in man.
A flavonoid antioxidant, silymarin, inhibits
activation of erbB1 signaling and induces cyclin-dependent
kinase inhibitors, G1 arrest, and anticarcinogenic effects in
human prostate carcinoma DU145 cells.
Zi X, Grasso AW, Kung HJ, Agarwal R
Department of Dermatology, Case Western Reserve University,
Cleveland, Ohio 44106, USA.
Cancer Res 1998 May 1;58(9):1920-9
Prostate cancer (PCA) is the most common nonskin malignancy
and the second leading cause of cancer deaths in United States
males. One practical and translational approach to control PCA
is to define a mechanism-based anticarcinogenic agent(s).
Recently, we showed that silymarin, a flavonoid antioxidant
isolated from milk thistle, possesses exceptionally high to
complete protective effects against experimentally induced
tumorigenesis. Because the epidermal growth factor receptor
(erbB1) and other members of the erbB family have been shown
to play important roles in human PCA, efforts should be
directed to identify inhibitors of this pathway for PCA
intervention. In this study, we assessed whether silymarin
inhibits erbB1 activation and associated downstream events and
modulates cell cycle regulatory proteins and progression,
leading to growth inhibition of human prostate carcinoma DU145
cells. Treatment of serum-starved cells with silymarin
resulted in a significant inhibition of transforming growth
factor alpha-mediated activation of erbB1 but no change in its
protein levels. Silymarin treatment of cells also resulted in
a significant decrease in tyrosine phosphorylation of an
immediate downstream target of erbB1, the adapter protein SHC,
together with a decrease in its binding to erbB1. In the
studies analyzing cell cycle regulatory molecules, silymarin
treatment of cells also resulted in a significant induction of
cyclin-dependent kinase inhibitors (CDKIs) Cip1/p21 and
Kip1/p27, concomitant with a significant decrease in CDK4
expression, but no change in the levels of CDK2 and CDK6 and
their associated cyclins E and D1, respectively. Cells treated
with silymarin also showed an increased binding of CDKIs with
CDKs, together with a marked decrease in the kinase activity
of CDKs and associated cyclins. In additional studies,
treatment of cells grown in 10% serum with anti-epidermal
growth factor receptor monoclonal antibody clone 225 or
different doses of silymarin also resulted in significant
inhibition of constitutive tyrosine phosphorylation of both
erbB1 and SHC but no change in their protein levels.
Furthermore, whereas silymarin treatment resulted in a
significant increase in the protein levels of both Cip1/p21
and Kip1/p27, monoclonal antibody 225 showed an increase only
in Kip1/p27. These findings suggest that silymarin also
inhibits constitutive activation of erbB1 and that the
observed effect of silymarin on an increase in CDKI protein
levels is mediated via inhibition of erbB1 activation only in
the case of Kip1/p27; however, additional pathways independent
of inhibition of erbB1 activation are possibly responsible for
the silymarin-caused increase in Cip1/p21 in DU145 cells. In
other studies, silymarin treatment also induced a G1 arrest in
the cell cycle progression of DU145 cells and resulted in a
highly significant to complete inhibition of both
anchorage-dependent and anchorage-independent growth of DU145
cells in a dose- and time-dependent manner. Taken together,
these results suggest that silymarin may exert a strong
anticarcinogenic effect against PCA and that this effect is
likely to involve impairment of erbB1-SHC-mediated signaling
pathway, induction of CDKIs, and a resultant G1 arrest.
Protective and therapeutic effect of silymarin on
the development of latent liver damage.
Kropacova K, Misurova E, Hakova H
Department of Cellular and Molecular Biology Faculty of
Sciences, University of P. J. Safarik, Kosice, Slovakia.
kbmb@kosice.upjs.sk
Radiats Biol Radioecol 1998 May-Jun;38(3):411-5
Radioprotective and therapeutical effect of silymarin
(Flavobion) on development and repair of latent injury in rat
liver was examined by its application during the continual
gamma irradiation (dose rates 0.2 and 0.6 Gy/day) or after
acute gamma irradiation (dose 6 Gy). Silymarin influence was
evaluated on the basis of mitotic index and chromosomal
aberration frequency in the liver regenerating after partial
hepatectomy. We have found that silymarin application
stimulates the process of liver regeneration in non-irradiated
rats as well as in irradiated ones. Positive effect of
silymarin (100 mg per kg p.o. ones per day) was manifested at
both dose rates of continual irradiation with increase in
mitotic activity and mitigation of chromosomal erration
frequency in the regenerating liver in comparison with
non-protected irradiated animals. Curative effect of silymarin
(70 mg/kg p.o., twice per day) was shown especially after 14
days of its postradiation application.
Protective effects of silymarin against
photocarcinogenesis in a mouse skin model.
Katiyar SK, Korman NJ, Mukhtar H, Agarwal R
Department of Dermatology, Case Western Reserve University,
Cleveland, OH 44106, USA.
J Natl Cancer Inst 1997 Apr 16;89(8):556-66
BACKGROUND: Nonmelanoma skin cancer is the most common
cancer among humans; solar UV is its major cause. Therefore,
it is important to identify agents that can offer protection
against this cancer.
PURPOSE: We evaluated the protective effects of silymarin,
a flavonoid compound isolated from the milk thistle plant,
against UVB radiation-induced nonmelanoma skin cancer in mice
and delineated the mechanism(s) of its action.
METHODS: For long-term studies, three different protocols
of treatment were employed, each evaluating protection by
silymarin at a different stage of carcinogenesis. Female SKH-1
hairless mice were subjected to 1) UVB-induced tumor
initiation followed by phorbol ester-mediated tumor promotion,
2) 7,12-dimethylbenz[a]anthracene-induced tumor initiation
followed by UVB-mediated tumor promotion, and 3) UVB-induced
complete carcinogenesis. Forty mice were used in each protocol
and were divided into control and treatment groups. Silymarin
was applied topically at a dose of 9 mg per application before
UVB exposure, and its effects on tumor incidence (% of mice
with tumors), tumor multiplicity (number of tumors per mouse),
and average tumor volume per mouse were evaluated. In
short-term studies, the following parameters were measured:
formation of sunburn and apoptotic cells, skin edema,
epidermal catalase and cyclooxygenase (COX) activities, and
enzymatic activity and messenger RNA (mRNA) expression for
ornithine decarboxylase (ODC), a frequently observed marker at
tumor promotion stage. Fisher's exact test was used to
evaluate differences in tumor incidence, two-sample Wilcoxon
rank sum test was used for tumor multiplicity and tumor
volume, and Student's t test was used for all other
measurements. All statistical tests were two-sided.
RESULTS: In the protocol with UVB-induced tumor initiation,
silymarin treatment reduced tumor incidence from 40% to 20% (P
= .30), tumor multiplicity by 67% (P = .10), and tumor volume
per mouse by 66% (P = .14). In the protocol with UVB-induced
tumor promotion, silymarin treatment reduced tumor incidence
from 100% to 60% (P<.003), tumor multiplicity by 78%
(P<.0001), and tumor volume per mouse by 90% (P<.003).
The effect of silymarin was much more profound in the protocol
with UVB-induced complete carcinogenesis, where tumor
incidence was reduced from 100% to 25% (P<.0001), tumor
multiplicity by 92% (P<.0001), and tumor volume per mouse
by 97% (P<.0001). In short-term experiments, silymarin
application resulted in statistically significant inhibition
in UVB-caused sunburn and apoptotic cell formation, skin
edema, depletion of catalase activity, and induction of COX
and ODC activities and ODC mRNA expression.
CONCLUSIONS AND IMPLICATION: Silymarin can provide
substantial protection against different stages of UVB-induced
carcinogenesis, possibly via its strong antioxidant
properties. Clinical testing of its usefulness is
warranted.
Protective effects of silymarin against
photocarcinogenesis in a mouse skin model.
Katiyar SK, Korman NJ, Mukhtar H, Agarwal R
Department of Dermatology, Case Western Reserve University,
Cleveland, OH 44106, USA.
J Natl Cancer Inst 1997 Apr 16;89(8):556-66
BACKGROUND: Nonmelanoma skin cancer is the most common
cancer among humans; solar UV is its major cause. Therefore,
it is important to identify agents that can offer protection
against this cancer.
PURPOSE: We evaluated the protective effects of silymarin,
a flavonoid compound isolated from the milk thistle plant,
against UVB radiation-induced nonmelanoma skin cancer in mice
and delineated the mechanism(s) of its action.
METHODS: For long-term studies, three different protocols
of treatment were employed, each evaluating protection by
silymarin at a different stage of carcinogenesis. Female SKH-1
hairless mice were subjected to 1) UVB-induced tumor
initiation followed by phorbol ester-mediated tumor promotion,
2) 7,12-dimethylbenz[a]anthracene-induced tumor initiation
followed by UVB-mediated tumor promotion, and 3) UVB-induced
complete carcinogenesis. Forty mice were used in each protocol
and were divided into control and treatment groups. Silymarin
was applied topically at a dose of 9 mg per application before
UVB exposure, and its effects on tumor incidence (% of mice
with tumors), tumor multiplicity (number of tumors per mouse),
and average tumor volume per mouse were evaluated. In
short-term studies, the following parameters were measured:
formation of sunburn and apoptotic cells, skin edema,
epidermal catalase and cyclooxygenase (COX) activities, and
enzymatic activity and messenger RNA (mRNA) expression for
ornithine decarboxylase (ODC), a frequently observed marker at
tumor promotion stage. Fisher's exact test was used to
evaluate differences in tumor incidence, two-sample Wilcoxon
rank sum test was used for tumor multiplicity and tumor
volume, and Student's t test was used for all other
measurements. All statistical tests were two-sided.
RESULTS: In the protocol with UVB-induced tumor initiation,
silymarin treatment reduced tumor incidence from 40% to 20% (P
= .30), tumor multiplicity by 67% (P = .10), and tumor volume
per mouse by 66% (P = .14). In the protocol with UVB-induced
tumor promotion, silymarin treatment reduced tumor incidence
from 100% to 60% (P<.003), tumor multiplicity by 78%
(P<.0001), and tumor volume per mouse by 90% (P<.003).
The effect of silymarin was much more profound in the protocol
with UVB-induced complete carcinogenesis, where tumor
incidence was reduced from 100% to 25% (P<.0001), tumor
multiplicity by 92% (P<.0001), and tumor volume per mouse
by 97% (P<.0001). In short-term experiments, silymarin
application resulted in statistically significant inhibition
in UVB-caused sunburn and apoptotic cell formation, skin
edema, depletion of catalase activity, and induction of COX
and ODC activities and ODC mRNA expression.
CONCLUSIONS AND IMPLICATION: Silymarin can provide
substantial protection against different stages of UVB-induced
carcinogenesis, possibly via its strong antioxidant
properties. Clinical testing of its usefulness is
warranted.
Proceedings of the American Association for Cancer
Research Annual Meeting
Eighty-sixth Annual Meeting of the American Association for
Cancer Research
Toronto, Ontario, Canada March 18-22, 1995
36 (0): p 593 1995
No abstract.
Hereditary prostate cancer: epidemiologic and
clinical features.
Carter BS, Bova GS, Beaty TH, Steinberg GD, Childs B, Isaacs
WB, Walsh PC
Department of Urology, Johns Hopkins Medical Institutions,
Baltimore, Maryland 21287-2101.
J Urol 1993 Sep;150(3):797-802
No abstract.
Genetic epidemiology of prostate cancer in the Utah
Mormon Genealogy.
Cancer Surv 1:47-69, 1982.
No abstract.
Dietary phytoestrogens and prostate cancer.
Proc Annu Meet Am Assoc Cancer Res 36:687, 1995.
No abstract.
Inhibition of epidermal growth factor receptor
(EGFr) tyrosine kinase activity by silymarin, a polyphenolic
antioxidant and potent cancer chemopreventive agent.
Proc Annu Meet Am Assoc Cancer Res 38:A1766,
1997.
No abstract.
Familial clustering of cancers of the breast and
prostate in a population-based sample of postmenopausal
women.
Proc Annu Meet Am Assoc Cancer Res 35:A1724,
1994.
No abstract.
The anti-oxidant revolution.
Thomas Nelson Publisher. 1994.
No abstract.
Enter the zone.
Regan Books, 1995.
No abstract.
The Anti-aging zone.
Regan Books, 1999.
No abstract.
Natural vitamin E (gamma-tocopherol) demonstrates
greater inhibition of growth on a human prostate cancer cell
line than synthetic vitamin E. (in press)
Anticancer Res 1997 Mar-Apr;17(2A):1199-204
No abstract.
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