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Major advantages of "early" administration of
endocrine combination therapy in advanced prostate
cancer.
Labrie F, Dupont A, Cusan L, Gomez JL, Diamond P
Endocrine Research Clinic, CHUL Research Center, Quebec City,
Quebec, Canada.
Clin Invest Med 1993 Dec;16(6):493-8
Combination therapy with the antiandrogen flutamide and the
luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6,
des-Gly-NH2(10)] LHRH ethylamide or orchiectomy was
administered to 268 patients with previously untreated
metastatic stage D2 prostate cancer for an average of 1,191 d
(3.26 y). Only 17 of the 268 evaluable patients (6.5%) showed
no objective positive response to the combination therapy
assessed according to the National Prostatic Cancer Project
objective criteria of response. The median duration of the
disease-free response was 2.23 y and median overall survival
was 3.58 y. The median survival for patients with only 1-5
bone metastases was not yet reached at 8 y, but for patients
with 6-10 bone lesions, 11-40 bone lesions, and multiple bone
metastases (superscan), median survival was markedly reduced
to 3.56, 2.36, and 1.76 y, respectively. Analysis of patients
according to general symptomatology, pain, and performance
status showed median survivals of 5.47, 2.71, and 2.1 y for
minimal, moderate, and severe symptoms, respectively. The
present data demonstrate that administration of combination
therapy to stage D2 prostate cancer patients having 1-5 bone
metastases adds a minimum of 4.4 y of good quality life
compared with patients whose disease is slightly more
advanced. Our findings clearly demonstrate the major
importance of starting combination therapy as soon as possible
after diagnosis of metastatic prostatic cancer.
Maximal androgen blockade: final analysis of EORTC
phase III trial 30853. EORTC Genito-Urinary Tract Cancer
Cooperative Group and the EORTC Data Center.
Denis LJ, Keuppens F, Smith PH, Whelan P, de Moura JL,
Newling D, Bono A, Sylvester R
Department of Urology, A.Z. Middelheim, Antwerp,
Belgium.
Eur Urol 1998;33(2):144-51
OBJECTIVES: This prospective, randomized phase III study
was initiated to compare the efficacy and side effects of
bilateral orchiectomy versus a combination of a luteinizing
hormone-releasing hormone agonist depot formulation, goserelin
acetate (3.6 mg s.c. once every 4 weeks) and flutamide (250 mg
3 x daily) in patients with metastatic prostate cancer.
METHODS: Relative treatment efficacy was assessed by
comparing the two treatment groups with respect to response,
time to first progression, progression-free survival, duration
of survival and time to death due to malignant disease.
RESULTS: There was a difference in response only with
respect to a more frequent decrease to normal of the serum
prostate acid phosphatase in patients assigned to maximal
androgen blockade treatment. Additionally, maximal androgen
blockade treatment showed significantly better results for
duration of survival (p = 0.04), time to death due to
malignant disease (p = 0.008), time to first progression (p =
0.009) and progression-free survival (p = 0.02). The most
frequent side effects for both treatments included hot flushes
and gynaecomastia.
CONCLUSIONS: Increased time to progression and duration of
survival is achieved by the combination of flutamide and
goserelin when compared to bilateral orchiectomy.
Treatment with finasteride following radical
prostatectomy for prostate cancer.
Andriole G, Lieber M, Smith J, Soloway M, Schroeder F, Kadmon
D, DeKernion J, Rajfer J, Boake R, Crawford D, et al
Merck Research Laboratories, Rahway, New Jersey.
Urology 1995 Mar;45(3):491-7
OBJECTIVES. The objective of this study was to evaluate the
effect of finasteride (10 mg/d) or placebo on serum
prostate-specific antigen (PSA) and recurrence rates in men
with detectable PSA levels after radical prostatectomy.
METHODS. A total of 120 men, 48 to 89 years old, previously
treated with radical prostatectomy for prostate cancer within
the past 10 years, with serum PSA levels between 0.6 and 10.0
ng/mL, with no evidence of skeletal metastasis on bone scan,
and with no previous androgen deprivation therapy, were
treated with 10 mg finasteride or placebo in a double-blind
fashion for 12 months. After the first year, all patients were
treated with finasteride for an additional 12 months. Primary
endpoints were serum PSA levels and recurrence rates defined
as positive bone scan or positive biopsy.
RESULTS. Patients treated with finasteride had a delayed
increase in serum PSA compared with placebo of approximately 9
months in the first year and 14 months by the end of the
second year. Patients with baseline PSA levels less then 1.0
ng/mL had no significant increase in serum PSA during the 2
years of treatment. Fewer recurrences were observed in the
finasteride group, but these differences were not
statistically significant. Finasteride was well tolerated, and
side effects were balanced between treatment groups.
CONCLUSIONS. The results of this study indicate that
treatment with finasteride delays but does not prevent the
rise in serum PSA observed in untreated patients with
detectable PSA levels after radical prostatectomy. The
reduction in local and distant recurrences in the finasteride
group suggests that the effect on PSA reflects a direct effect
on tumor growth without affecting the initial response to
subsequent hormonal therapy. These data require confirmation
by studies that are longer and larger, focused on
demonstrating significant differences in progression rates and
survival before the use of finasteride can be considered as an
option for men with detectable PSA levels after radical
prostatectomy.
Finasteride and flutamide as potency-sparing
androgen-ablative therapy for advanced adenocarcinoma of the
prostate.
Brufsky A, Fontaine-Rothe P, Berlane K, Rieker P, Jiroutek M,
Kaplan I, Kaufman D, Kantoff P
Division of Medical Oncology, Dana-Farber Cancer Institute,
Boston, Massachusetts, USA.
Urology 1997 Jun;49(6):913-20
OBJECTIVES: Androgen ablation with luteinizing
hormone-releasing hormone (LHRH) agonists, orchiectomy, or
oral estrogens has significant untoward sexual side effects.
We evaluated a combination of finasteride and flutamide as
potency-sparing androgen ablative therapy (AAT) for advanced
adenocarcinoma of the prostate. In addition, we evaluated
whether finasteride provided additional intraprostatic
androgen blockade to flutamide.
METHODS: Twenty men with advanced prostate cancer were
given flutamide, 250 mg orally three times daily. Serum
prostate-specific antigen (PSA) values were measured weekly.
At a nadir PSA value, finasteride, 5 mg orally every day, was
added. PSA values were then measured weekly until a second
nadir PSA value was achieved. Sexual function was evaluated at
baseline, at the second nadir PSA value, and every 3 months
thereafter. Testosterone, dihydrotestosterone (DHT), and
dehydroepiandrostenedione (DHEA) levels were measured at
baseline and at the first and second nadir PSA values.
RESULTS: The median follow-up period was 16.9 months.
Therapy failed in 1 patient with Stage D2 disease at 12
months, but an additional response to subsequent LHRH agonist
therapy was observed. One patient developed National Cancer
Institute grade 3 diarrhea and was withdrawn from the study.
Seven of 20 men developed mild gynecomastia, and 3 of 20
developed mild transient liver function test elevations. Mean
PSA levels were 94.6 +/- 38.2 ng/mL at baseline and 7.8 +/-
2.7 and 4.7 +/- 2.2 ng/mL at the first and second PSA nadir
values, respectively (P = 0.034). Mean percent decline in PSA
value from baseline was 87.0 +/- 3.1% with flutamide alone and
94.0 +/- 1.9% with both flutamide and finasteride (P = 0.001).
Eleven of 20 men were potent at baseline. At the second nadir
PSA value, 9 (82%) of 11 were potent, whereas 2 (18%) of 11
were impotent. With longer follow-up (median 16.4 months), 6
(55%) of 11 men were potent, 2 (18%) of 11 were partially
potent, and 3 (27%) of 11 were impotent. With flutamide alone,
testosterone rose a mean of 77 +/- 14.7% of baseline (P =
0.0001), DHEA fell a mean of 32.4 +/- 4.6% (P = 0.0001), and
DHT was unchanged. With the addition of finasteride,
testosterone rose another 14 +/- 6% (P = 0.06, not
significant), DHEA was unchanged, and DHT fell a mean of 34.8
+/- 4.7% (P = 0.0009).
CONCLUSIONS: Finasteride and flutamide were safe and well
tolerated as AAT for advanced prostate cancer. Finasteride
provided additional intraprostatic androgen blockade to
flutamide, as measured by additional PSA suppression. Sexual
potency was preserved initially in most patients, although
there was a reduction in potency and libido in some patients
on longer follow-up. Further evaluation of this therapy is
needed.
A case for synchronous reduction of testicular
androgen, adrenal androgen and prolactin for the treatment of
advanced carcinoma of the prostate.
Rana A, Habib FK, Halliday P, Ross M, Wild R, Elton RA,
Chisholm GD
University Department of Surgery/Urology, Western General
Hospital, Edinburgh, U.K.
Eur J Cancer 1995 Jun;31A(6):871-5
The present study was undertaken mainly to investigate
whether prolactin manipulation combined with maximal androgen
blockage improves the effectiveness of treatment in advanced
prostatic cancer. The efficacy of oral hydrocortisone as an
alternative to commercial anti-androgens in reducing the
adrenal androgens, and of bromocriptine in reducing the
prolactin level were also examined. A consecutive series of 30
patients with untreated and advanced prostatic cancer were
entered into a three-arm prospective randomised trial. 10
patients received subcapsular orchiectomy alone (arm 1),
another 10 had subcapsular orchiectomy plus flutamide (arm 2),
and the remaining 10 had subcapsular orchiectomy plus oral
hydrocortisone and bromocriptine (arm 3). Clinical and
biochemical parameters, including trans-rectal
ultrasound-determined prostatic volumes, hormonal profiles and
radionuclide bone scan were evaluated at regular intervals. At
12 months, serum testosterone was reduced by more than 90% in
all arms, however, maximum suppression of androstenedione,
prolactin, and reduction of prostatic volumes were only
observed in arm 3; this was reflected by the significant
improvement in clinical response in arm 3 compared with other
arms. This study suggests that a combined maximal suppression
of androgens and prolactin offers a significant improvement in
response over conventional treatments without prolactin
suppression in the treatment of advanced prostatic cancer.
Importantly, a better clinical outcome in arm 3 was still
apparent at the end of 36 months.
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.
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.
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.
Protection against tumor promotion in mouse skin by
silymarin .
Agarwal R; Katiyar S K; Mukhtar H
Dep. Dermatol., Case Western Reserve Univ., Cleveland, OH
44106, USA
Eighty-sixth Annual Meeting of the American Association for
Cancer Research
Toronto, Ontario, Canada March 18-22, 1995
Proceedings of the American Association for Cancer Research
Annual Meeting 36 ( 0 ): p 593 1995
No abstract.
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.
Genistein inhibits the growth of human-patient BPH
and prostate cancer in histoculture.
Geller J, Sionit L, Partido C, Li L, Tan X, Youngkin T,
Nachtsheim D, Hoffman RM
AntiCancer, Inc., San Diego, California 92111, USA.
Prostate 1998 Feb 1;34(2):75-9
BACKGROUND: There is strong epidemiological evidence that
prostate disease is significantly less prevalent in the
Orient, where the intake of soy products is very high, than in
the United States. We therefore undertook a study of the
effects of genistein, a major component of soy, on growth of
human-patient benign prostatic hypertrophy (BPH) and prostate
cancer tissue in three-dimensional collagen gel-supported
histoculture.
METHODS: Surgical specimens of human BPH and cancer were
histocultured for 5 days to study the effects of genistein on
growth, as measured by inhibition of 3H-thymidine
incorporation per microgram protein on day 5.
RESULTS: Genistein in doses of 1.25-10 micrograms/ml
decreased the growth of BPH tissue in histoculture in a
dose-dependent manner, with little additional effect at higher
doses. Prostate cancer tissue in histoculture was similarly
inhibited by these doses of genistein.
CONCLUSIONS: Genistein decreases the growth of both BPH and
prostate cancer tissue in histoculture. The data suggest that
genistein has potential as a therapeutic agent for BPH and
prostate cancer.
Treatment of early recurrent prostate cancer with
1,25-dihydroxyvitamin D3.
Gross C, Stamey T, Hancock S, Feldman D
Department of Medicine, Stanford University School of
Medicine, California, USA.
J Urol 1998 Jun;159(6):2035-9; discussion 2039-40
Published erratum appears in J Urol 1998 Sep;160(3 Pt
1):840
PURPOSE: Substantial experimental and epidemiological data
indicate that 1,25-dihydroxyvitamin D3 (calcitriol) has potent
antiproliferative effects on human prostate cancer cells. We
performed an open label, nonrandomized pilot trial to
determine whether calcitriol therapy is safe and efficacious
for early recurrent prostate cancer. Our hypothesis was that
calcitriol therapy slows the rate of rise of prostate specific
antigen (PSA) compared with the pretreatment rate.
MATERIALS AND METHODS: After primary treatment with
radiation or surgery recurrence was indicated by rising serum
PSA levels documented on at least 3 occasions. Seven subjects
completed 6 to 15 months of calcitriol therapy, starting with
0.5 microg. calcitriol daily and slowly increasing to a
maximum dose of 2.5 microg. daily depending on individual
calciuric and calcemic responses. Each subject served as his
own control, comparing the rate of PSA rise before and after
calcitriol treatment.
RESULTS: As determined by multiple regression analysis, the
rate of PSA rise during versus before calcitriol therapy
significantly decreased in 6 of 7 patients, while in the
remaining man a deceleration in the rate of PSA rise did not
reach statistical significance. Overall the decreased rate of
PSA rise was statistically significant (p = 0.02 Wilcoxon
signed rank test). Dose dependent hypercalciuria limited the
maximal calcitriol therapy given (range 1.5 to 2.5 microg.
daily).
CONCLUSIONS: This pilot study provides preliminary evidence
that calcitriol effectively slows the rate of PSA rise in
select cases, although dose dependent calciuric side effects
limit its clinical usefulness. The development of calcitriol
analogues with decreased calcemic side effects is promising,
since such analogues may be even more effective for treating
prostate cancer.
19-nor-hexafluoride analogue of vitamin D3: a novel
class of potent inhibitors of proliferation of human breast
cell lines.
Koike M, Elstner E, Campbell MJ, Asou H, Uskokovic M,
Tsuruoka N, Koeffler HP
Division of Hematology/Oncology, Cedars-Sinai Research
Institute, UCLA School of Medicine, Los Angeles, California
90048, USA.
Cancer Res 1997 Oct 15;57(20):4545-50
Breast cancer cells express vitamin D3 receptors and
1,25-dihydroxyvitamin D3 suppressed growth of these cells. We
have synthesized six novel vitamin D3 analogues to identify
those with expanded capacity to inhibit the proliferative
ability of breast cancer cells. These analogues incorporated
many of the structural motifs shown previously to have
antiproliferative activity in several cell types. Six breast
cancer cell lines were used as targets. Dose-response studies
showed that each of the analogues had antiproliferative
activities, and LH [1,25-(OH)2-16-ene-23-yne-26,27-F6-19-nor
D3] was the most potent analogue, suppressing at 10(-11) M
greater than 50% clonal proliferation (ED50) of the MCF-7 and
SK-BR-3 breast cancer cells, increasing the proportion of
MCF-7 cells in the G0-G1 phase, and decreasing those in the S
phase of the cell cycle. Pulse-exposure studies showed that a
3-day exposure to LH (10(-7) M) in liquid culture was adequate
to achieve a 50% inhibition of MCF-7 clonal growth in soft
agar in the absence of the analogue, suggesting that the
growth inhibition mediated by LH is irreversible. The
cyclin-dependent kinase inhibitor known as p27Kip1 helps
regulate the cell cycle and can mediate growth arrest in
response to extracellular growth inhibitors. The analogue LH
(10(-7) M) induced elevated expression of p27Kip1 in MCF-7 and
SK-BR-3 cells. Taken together, these results indicate that LH
is an extremely potent vitamin D3 analogue markedly inhibiting
clonal growth of MCF-7 and SK-BR-3 cells with concomitant cell
cycle arrest at G0-G1 and increased expression of p27Kip1.
Compound LH is worthy of in vivo analysis for possible future
clinical trials.
The effect of calcium supplementation on the
circadian rhythm of bone resorption.
Blumsohn A, Herrington K, Hannon RA, Shao P, Eyre DR, Eastell
R
Department of Human Metabolism and Clinical Biochemistry,
University of Sheffield, England.
J Clin Endocrinol Metab 1994 Sep;79(3):730-5
Bone resorption shows a circadian rhythm in human subjects,
but the physiological mechanisms underlying this rhythm are
unknown. We compared the circadian rhythm of bone collagen
degradation in 18 premenopausal women before and after oral
calcium supplementation (1000 mg calcium for 14 days).
Subjects were randomized to receive calcium at either 0800 h
or 2300 h. Continuous 48-h urine collections and 1 day of 4-h
urine collections were obtained before and after the 14-day
supplementation period. We measured urinary deoxypyridinoline
(Dpd) and the cross-linked N-telopeptide of type I collagen
(NTx) as biochemical markers of bone resorption. There was a
significant effect of time of day on excretion of Dpd and NTx
(analysis of variance, P < 0.001) with peak excretion
between 0300-0700 h and a nadir between 1500-1900 h. The mean
amplitude (peak to trough) was similar for Dpd and NTx (70.3%
and 63.3%, respectively). Evening calcium supplementation
resulted in marked suppression of the nocturnal increase in
Dpd and NTx and reversed the usual nocturnal increase in the
level of parathyroid hormone. In contrast, morning calcium
supplementation had no significant effect on the circadian
rhythm of Dpd or NTx. Evening calcium supplementation
suppressed overall daily excretion of Dpd by 20.1% (P = 0.03)
and NTx by 18.1% (P = 0.03). Morning calcium supplementation
had no significant effect on overall daily excretion of either
Dpd or NTx. We conclude that evening calcium supplementation
suppresses the circadian rhythm of bone resorption. The daily
rhythm of PTH secretion or calcium intake is likely to be an
important determinant of this rhythm. Experimental protocols
designed to investigate the effect of calcium supplementation
on bone mineral density should take the timing of
supplementation into account.
Why drinking green tea could prevent cancer.
Jankun J, Selman SH, Swiercz R, Skrzypczak-Jankun E
Department of Urology, Medical College of Ohio, Toledo
43699-0008, USA.
jerzy@golemxiv.dh.mco.edu
Nature 1997 Jun 5;387(6633):561
No abstract.
Selective inhibition of steroid 5 alpha-reductase
isozymes by tea epicatechin-3-gallate and
epigallocatechin-3-gallate.
Liao S, Hiipakka RA
Ben May Institute, University of Chicago, IL 60637,
USA.
Biochem Biophys Res Commun 1995 Sep
25;214(3):833-8
Inhibitors of 5 alpha-reductase may be effective in the
treatment of 5 alpha-dihydrotestosterone-dependent
abnormalities, such as benign prostate hyperplasia, prostate
cancer and certain skin diseases. The green tea catechins,
(-)epigallocatechin-3-gallate and (-)epicatechin-3-gallate,
but not (-)epicatechin and (-)epigallocatechin, are potent
inhibitors of type 1 but not type 2 5 alpha-reductase.
(-)Epigallocatechin-3-gallate also inhibits accessory sex
gland growth in the rat. These results suggest that certain
tea gallates can regulate androgen action in target
organs.
Growth inhibition and regression of human prostate
and breast tumors in athymic mice by tea epigallocatechin
gallate.
Liao S, Umekita Y, Guo J, Kokontis JM, Hiipakka RA
Ben May Institute, Department of Biochemistry and Molecular
Biology, University of Chicago, IL 60637, USA.
Cancer Lett 1995 Sep 25;96(2):239-43
The human prostate cancer cell lines, PC-3
(androgen-insensitive) and LNCaP 104-R (androgen-repressed)
were inoculated subcutaneously into nude mice to produce
prostate tumors. Intraperitoneal injection of green tea
(-)epigallocatechin-3-gallate but not structurally related
catechins, such as (-)epicatechin-3-gallate, inhibited the
growth and rapidly reduced the size of human prostate tumors
in nude mice. (-)Epigallocatechin-3-gallate also rapidly
inhibited the growth of tumor growth formed by the human
mammary cancer cell line MCF-7 in nude mice. It is possible
that there is a relationship between the high consumption of
green tea and the low incidence of prostate and breast cancers
in some Asian countries.
Intake of carotenoids and retinol in relation to
risk of prostate cancer.
Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA,
Willett WC
Channing Laboratory, Department of Medicine, Harvard Medical
School, Boston, MA 02115, USA.
Natl Cancer Inst 1995 Dec 6;87(23):1767-76
BACKGROUND: Several human studies have observed a direct
association between retinol (vitamin A) intake and risk of
prostate cancer; other studies have found either an inverse
association or no association of intake of beta-carotene (the
major provitamin A) with risk of prostate cancer. Data
regarding carotenoids other than beta-carotene in relation to
prostate cancer risk are sparse.
PURPOSE: We concluded a prospective cohort study to examine
the relationship between the intake of various carotenoids,
retinol, fruits, and vegetables and the risk of prostate
cancer.
METHODS: Using responses to a validated, semiquantitative
food-frequency questionnaire mailed to participants in the
Health Professionals Follow-up Study in 1986, we assessed
dietary intake for a 1-year period for a cohort of 47,894
eligible subjects initially free of diagnosed cancer.
Follow-up questionnaires were sent to the entire cohort in
1988, 1990, and 1992. We calculated the relative risk (RR) for
each of the upper categories of intake of a specific food or
nutrient by dividing the incidence rate of prostate cancer
among men in each of these categories by the rate among men in
the lowest intake level. All P values resulted from two-sided
tests.
RESULTS: Between 1986 and 1992, 812 new cases of prostate
cancer, including 773 non-stage A1 cases, were documented.
Intakes of the carotenoids beta-carotene, alpha-carotene,
lutein, and beta-cryptoxanthin were not associated with risk
of non-stage A1 prostate cancer; only lycopene intake was
related to lower risk (age- and energy-adjusted RR = 0.79; 95%
confidence interval [CI] = 0.64-0.99 for high versus low
quintile of intake; P for trend = .04). Of 46 vegetables and
fruits or related products, four were significantly associated
with lower prostate cancer risk; of the four--tomato sauce (P
for trend = .001), tomatoes (P for trend = .03), and pizza (P
for trend = .05), but not strawberries--were primary sources
of lycopene. Combined intake of tomatoes, tomato sauce, tomato
juice, and pizza (which accounted for 82% of lycopene intake)
was inversely associated with risk of prostate cancer
(multivariate RR = 0.65; 95% CI = 0.44-0.95, for consumption
frequency greater than 10 versus less than 1.5 servings per
week; P for trend = .01) and advanced (stages C and D)
prostate cancers (multivariate RR = 0.47; 95% CI = 0.22-1.00;
P for trend = .03). No consistent association was observed for
dietary retinol and risk of prostate cancer.
CONCLUSIONS: These findings suggest that intake of lycopene
or other compounds in tomatoes may reduce prostate cancer
risk, but other measured carotenoids are unrelated to
risk.
IMPLICATIONS: Our findings support recommendations to
increase vegetable and fruit consumption to reduce cancer
incidence but suggest that tomato-based foods may be
especially beneficial regarding prostate cancer risk.
Effects of lycopene on spontaneous mammary tumour
development in SHN virgin mice.
Nagasawa H, Mitamura T, Sakamoto S, Yamamoto K
Experimental Animal Research Laboratory, Meiji University,
Kanagawa, Japan.
Anticancer Res 1995 Jul-Aug;15(4):1173-8
Effects of the chronic ingestion of lycopene, a carotenoid
from tomato, on the development of spontaneous mammary tumours
were examined in a high mammary tumour strain of SHN virgin
mice. Beginning at 40 days of age, the control and the
experimental groups were allowed free access to an AIN-76TM
diet and a diet supplemented further with lycopene at the
concentration of 5.0 x 10(-5)%, respectively. The treatment
significantly suppressed the mammary tumour development, which
suppression was associated with the decrease in the mammary
gland activity of thymidylate synthetase, and serum levels of
free fatty acid and prolactin. Body weight was little affected
and no deleterious side-effects of lycopene were detected. All
results show that lycopene could be promising as a
chemopreventive agent for mammary and other types of
tumours.
Identification of tricyclic analogs related to
ellagic acid as potent/selective tyrosine protein kinase
inhibitors.
Dow RL, Chou TT, Bechle BM, Goddard C, Larson ER
Central Research Division, Pfizer Inc., Groton, Connecticut
06340.
J Med Chem 1994 Jul 8;37(14):2224-31
The plant-derived natural product ellagic acid (1) has
recently been identified as a potent, though nonselective,
inhibitor of the tyrosine-specific protein kinase pp60src.
This report details efforts directed toward the identification
of tricyclic structures related to ellagic acid, with enhanced
specificity for inhibition of pp60src over other protein
kinases. Phenanthridinone and carbazole core structures were
selected for investigation, since N-functionalization allows
for the synthesis of numerous analogs which can be utilized to
probe enzyme-inhibitor interactions. These ring systems were
prepared via a general sequence of biaryl bond formation
followed by cyclization to form the desired tricyclic ring
systems. N-Alkylation, -acylation, or -sulfonylation and
deprotection with boron tribromide afford the target
tetraphenolic phenanthridinones 5 and carbazoles 9. Several
analogs from both of these series have potencies comparable to
that of 1 and exhibit substantially enhanced selectivities for
inhibition of pp60src relative to protein kinase A (PKA), a
serine/threonine protein kinase. Carbazole-based analogs
9j,m,p are submicromolar inhibitors of pp60src, with potency
for the target tyrosine kinase comparable to that of ellagic
acid (1), however with 2 orders of magnitude greater
selectivity versus that for PKA. As seen for ellagic acid,
members of the phenanthridinone-based series (e.g., 5a)
exhibited inhibition of pp60src in a manner which is partial
mixed noncompetitive with respect to ATP, while analogs in the
carbazole series (e.g., 9a) inhibit pp60src in an ATP
competitive manner.
Ellagic acid induces transcription of the rat
glutathione S-transferase-Ya gene.
Barch DH, Rundhaugen LM, Pillay NS
Department of Medicine, Lakeside Veterans Affairs Medical
Center, Chicago, IL.
Carcinogenesis 1995 Mar;16(3):665-8
Induction of glutathione S-transferase (GST) enzymes can
increase detoxification of carcinogens and reduce
carcinogen-induced mutagenesis and tumorigenesis. To determine
if the anticarcinogen ellagic acid induces cellular enzymes
which detoxify carcinogens, we examined the effect of ellagic
acid on the expression of glutathione S-transferase-Ya. Rats
fed ellagic acid demonstrated significant increases in total
hepatic GST activity, hepatic GST-Ya activity and hepatic
GST-Ya mRNA. To determine if the observed increase in GST-Ya
mRNA was due to ellagic acid inducing transcription of the
GST-Ya gene, transfection studies were performed with plasmid
constructs containing various portions of the 5' regulatory
region of the rat GST-Ya gene. The transfection studies
demonstrated that ellagic acid increased GST-Ya mRNA by
inducing transcription of the GST-Ya gene and demonstrated
that this induction is mediated through the antioxidant
responsive element of the GST-Ya gene.
Combination of screening and preoperative endocrine
therapy: the potential for an important decrease in prostate
cancer mortality.
Labrie F, Cusan L, Gomez JL, Diamond P, Candas B
Prostate Cancer Research Unit, CHUL Research Center, Le
Centre Hospitalier de l'Universite Laval, Quebec,
Canada.
J Clin Endocrinol Metab 1995 Jul;80(7):2002-13
Prostate cancer is the second cause of cancer death in men
in the Western world; its medical and social impact is
comparable to that of breast cancer in women. Although it is
well recognized that early treatment is the only possibility
for reducing the high rate of death from prostate cancer,
screening and even early treatment are controversial issues
due mainly to arguments based upon old literature and lack of
awareness of the significant advances recently made in this
field. As it is well known that surgical removal of
organ-confined prostate cancer cures the disease, and it has
been demonstrated that annual screening with prostate-specific
antigen coupled with digital rectal examination followed, when
indicated, by transrectal ultrasonography of the prostate more
than doubles the proportion of organ-confined disease,
screening alone offers the possibility of at least doubling
the number of patients curable from prostate cancer or the
potential for a cure to an estimated 45% of prostate cancer
patients compared to a maximum of 20% in the absence of
screening. It is important to mention that screening does not
detect small and insignificant cancers, especially when random
biopsies are not performed routinely. The critical volume of
prostate cancer is estimated at 0.3 cm or a tumor 7.5 mm in
diameter, if spherical. Such a tumor should increase serum
prostate-specific antigen by 0.5 ng/mL. Contrary to the belief
that screening detects cancers that are too small, the fact is
that screening detects prostate cancer too late or nonorgan-
or nonspecimen-confined cancer in 35-50% of cases. There is,
thus, a narrow window when prostate cancer can be detected at
a curable stage, and even the best available screening
techniques cannot succeed in all cases. It should be mentioned
that the recent improvements of the technique of radical
prostatectomy have markedly improved the acceptability of
surgery. Concerning the recent publicity related to watchful
waiting, it is essential to indicate that all such reports
support the notion that prostate cancer grows slowly, but
steadily and irremediably, with increasing malignancy and risk
of distant metastases and death if sufficient time is allowed.
Another serious limitation of watchful waiting is that the
available prognostic factors have a large margin of error and
cannot predict with certainty the rate of progression of the
tumor.
Diagnosis of advanced or noncurable prostate cancer
can be practically eliminated by prostate-specific
antigen.
Labrie F, Candas B, Cusan L, Gomez JL, Diamond P, Suburu R,
Lemay M
Prostate Cancer Clinical Research Unit, CHUL Research Center,
Quebec, Canada.
Urology 1996 Feb;47(2):212-17
OBJECTIVES: To determine the percentage of localized and
potentially curable prostate cancers diagnosed at follow-up
screening visits compared with the first screening visit.
METHODS: Within the context of a prospective screening
study performed in randomly chosen men aged between 45 and 80
years, up to 6-year follow-up screening visits have been
performed with serum prostate-specific antigen (PSA)
measurement and digital rectal examination (DRE) followed by
transrectal ultrasonography of the prostate when PSA or DRE is
abnormal.
RESULTS: Of the 117 prostate cancers diagnosed at 14,554
annual follow-up visits, only 1 cancer (0.9%) was metastatic
compared with 8% (26/322) at 8029 first visits. Moreover, 97%
of the cancers detected at follow-up visits could be
identified by PSA alone compared with 86% at first visit. The
incidence of 0.8% per year during 15 years of screening
between the ages of 55 and 70 years would diagnose localized
prostate cancer in 12% of the population, a value not too
different from the 10% diagnosed with prostate cancer during
life-time in the absence of screening.
CONCLUSIONS: The present data show that annual screening
with PSA diagnoses clinically localized prostate cancer in
more than 95% of cases, thus almost completely eliminating the
diagnosis of metastatic prostate cancer. Moreover, the number
of prostate cancers diagnosed is not significantly increased
by screening.
Evaluation of prostAsure index in the detection of
prostate cancer: a preliminary report.
Babaian RJ, Fritsche HA, Zhang Z, Zhang KH, Madyastha KR,
Barnhill SD
Department of Urology, University of Texas M. D. Anderson
Cancer Center, Houston 77030, USA.
Urology 1998 Jan;51(1):132-6
OBJECTIVES: Although prostate-specific antigen (PSA) has
revolutionized the detection of prostate cancer, it has
definite limitations with respect to its clinical sensitivity
and specificity. Because a substantial number (20% to 40%) of
men undergoing radical prostatectomy have a PSA level of 4.0
ng/mL or less, any new test offering diagnostic improvement
must perform well in patients whose PSA level is less than or
equal to 4.0 ng/mL, as well as in patients whose PSA is
greater than 4.0 ng/mL. The performances of two tests, the
ProstAsure index and the percent free PSA test, were evaluated
in detecting cancer.
METHODS: We retrospectively analyzed serum samples from 225
men who were grouped into three categories: 94 men who had a
normal digital rectal examination and a serum PSA level of 4.0
ng/mL or less, 77 men who were clinically suspected of having
benign prostatic hyperplasia (BPH) with a serum PSA level of
4.0 ng/mL or less, and 54 men with localized prostate cancer.
The PSA assays were performed using the Hybritech and Tosoh
assays and the ProstAsure index was determined by Global
Health Net, Savannah, Ga. Receiver operator characteristic
(ROC) curves were constructed to evaluate the performance of
these two tests, and the areas under the curve were compared
for significance.
RESULTS: The sensitivity and specificity of detecting
prostate cancer using ProstAsure were 93% and 81%,
respectively. Using a cutoff value of 15%, the sensitivity and
specificity of detecting cancer for percent free PSA were 80%
and 74%, respectively (sensitivity increased to 93% and
specificity to 59% for free PSA at 19%). In men with a total
serum PSA level of 4.0 ng/mL or less, ProstAsure had a lower
false-positive rate compared to free PSA level at 19% for men
with or without clinical BPH as well as for men without
clinical BPH using a 15% free PSA threshold. ProstAsure left
fewer cancers undetected (7%) compared to free PSA at the 15%
cutoff (20%).
CONCLUSIONS: In this study of selected men, ROC curve
analysis shows a statistically significant advantage in
performance (P = 0.0023) for the ProstAsure index compared to
free PSA in detecting prostate cancer.
Prostate cancer detection in men with serum PSA
concentrations of 2.6 to 4.0 ng/mL and benign prostate
examination. Enhancement of specificity with free PSA
measurements.
Catalona WJ, Smith DS, Ornstein DK
Division of Urologic Surgery, Department of Surgery,
Washington University School of Medicine, St. Louis, Mo 63110,
USA.
JAMA 1997 May 14;277(18):1452-5
OBJECTIVE: To determine the detection rate of prostate
cancer in a screening population of men with prostate-specific
antigen (PSA) concentrations of 2.6 to 4.0 ng/mL and a benign
prostate examination, to assess the clinicopathological
features of the cancers detected, and to assess the usefulness
of measuring the ratio of free to total PSA to reduce the
number of prostatic biopsies.
DESIGN: A community-based study of serial screening for
prostate cancer with serum PSA measurements and prostate
examinations.
SETTING: University medical center.
SUBJECTS: A total of 914 consecutive screening volunteers
aged 50 years or older with serum PSA levels of 2.6 to 4.0
ng/mL who had a benign prostate examination and no prior
screening tests suspicious for prostate cancer, 332 (36%) of
whom underwent biopsy of the prostate.
MAIN OUTCOME MEASURES: Cancer detection rate, clinical and
pathological features of cancers detected, and specificity for
cancer detection using measurements of percentage of free
PSA.
RESULTS: Cancer was detected in 22% (73/332) of men who
underwent biopsy. All cancers detected were clinically
localized, and 81% (42/52) that were surgically staged were
pathologically organ confined. Ten percent of the cancers were
clinically low-volume and low-grade tumors, and 17% of those
surgically staged were low-volume and low-grade or moderately
low-grade tumors (possibly harmless). Using a percentage of
free PSA cutoff of 27% or less as a criterion for performing
prostatic biopsy would have detected 90% of cancers, avoided
18% of benign biopsies, and yielded a positive predictive
value of 24% in men who underwent biopsy.
CONCLUSIONS: There is an appreciable rate of detectable
prostate cancer in men with serum PSA levels of 2.6 to 4.0
ng/mL. The great majority of cancers detected have the
features of medically important tumors. Free serum PSA
measurements may reduce the number of additional biopsies
required by the lower PSA cutoff.
Prospective longitudinal evaluation of men with
initial prostate specific antigen levels of 4.0 ng./ml. or
less.
Harris CH, Dalkin BL, Martin E, Marx PC, Ahmann FR
Section of Urology, University of Arizona College of Medicine
and Tucson Veterans Affairs Medical Center, USA.
J Urol 1997 May;157(5):1740-3
PURPOSE: We evaluated the 3-year longitudinal changes in
serial serum prostate specific antigen (PSA) levels in men
with an initial PSA of 4.0 ng./ml. or less and no suspicion of
prostate cancer.
MATERIALS AND METHODS: A total of 760 men with an initial
PSA of 4.0 ng./ml. or less plus a normal or suspicious digital
rectal examination and a benign prostate biopsy was enrolled
into an every 4-month PSA monitoring study.
RESULTS: Of the 559 men with an initial PSA of 2.0 ng./ml.
or less only 3 (0.5%) had a persistently abnormal PSA for 3
years and 1 cancer (0.2%) was detected, and 48 men had a PSA
velocity of 0.8 ng./ml. per year or more at year 1 but only 1
(2%) had a persistent rate of increase (2.4 ng./ml. Per year)
at 3 years. Of the 201 men with a PSA of 2.1 to 4.0 ng./ml. 85
had an abnormal PSA but only 37 (43%) met the criteria for
biopsy. Only 8 of 23 biopsies (35%) revealed cancer. Of the
201 men 24 had a PSA velocity of 0.8 ng./ml. Per year or more
at year 1 but only 4 had persistence for 3 years. All 4 men
had cancer but they were identified as at high risk by PSA
criteria.
CONCLUSIONS: Men with a PSA of 2.0 ng./ml. or less are at
low risk for an abnormal PSA or cancer within 3 years and
annual monitoring may not be necessary. However, annual
monitoring is clinically useful in men with an initial PSA of
2.1 to 4.0 ng./ml. Also, serial monitoring with interval
testing in men whose PSA becomes greater than 4.0 ng./ml. Is
beneficial in identifying a high risk group requiring biopsy.
Finally, PSA velocity did not add further to cancer detection
in this population.
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