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Effects of protein kinase and phosphatase
inhibitors on the growth of human prostatic cancer cells
Konno S.; Cherry J.; Tazaki H.; Mallouh C.; Chiao J.W.
Dr. S. Konno, New York Medical College, Department of
Urology, Valhalla, NY 10595 USA
Medical Science Research (United Kingdom), 1997, 25/5
(353-354)
The effects of protein kinase and phosphatase inhibitors on
cell growth were investigated in human prostatic cancer,
JCA-1, PC-3, and LNCaP cells. All four inhibitors showed a
significant growth inhibitory effect, as determined by the
(3H)thymidine incorporation method. The IC50 (50% inhibitory
concentration) of each inhibitor was then calculated from the
respective growth curves. Among the three cell lines, JCA-1
cells were relatively more susceptible to the inhibitors,
while PC-3 cells were least sensitive. The IC50 data revealed
that calphostin C and okadaic acid were more potent growth
inhibitors than genistein and sodium orthovanadate. These
results suggest that cell growth appears to be more
effectively inhibited by the inhibitors of
Ser/Thr-kinases/phosphatases (i.e. calphostin C and okadaic
acid). Thus the family of Ser/Thr-kinases/phosphatases may be
critically involved in regulating the growth of prostatic
cancer cells.
Phyto-oestrogens and Western diseases
Adlercreutz H.; Mazur W.
Prof. H. Adlercreutz, Department of Clinical Chemistry,
University of Helsinki, Meilahti Hospital, Haartmaninkatu 4,
FIN-00290 Helsinki Finland
Annals of Medicine (United Kingdom), 1997, 29/2
(95-120)
Incidences of breast, colorectal and prostate cancer are
high in the Western world compared to countries in Asia. We
have postulated that the Western diet compared to the
semivegetarian diet in some Asian countries may alter hormone
production, metabolism or action at the cellular level by some
biochemical mechanisms. Our interest has been focused on two
groups of hormone-like diphenolic phyto-oestrogens of dietary
origin, the lignans and isoflavonoids abundant in plasma of
subjects living in areas with low cancer incidence. The
precursors of the biologically active compounds detected in
man are found in soybean products, whole-grain cereal food,
seeds, and berries. The plant lignan and isoflavonoid
glycosides are converted by intestinal bacteria to
hormone-like compounds. The weakly oestrogenic diphenols
formed influence sex-hormone production, metabolism and
biological activity, intracellular enzymes, protein synthesis,
growth factor action, malignant cell proliferation,
differentiation, cell adhesion and angiogenesis in such a way
as to make them strong candidates for a role as natural
cancer-protective compounds. Their effect on some of the most
important steroid biosynthetic enzymes may result in benes and
action in the ce lls preventing development of cancer. Owing
to their oestrogenic activity they reduce hot flushes and
vaginal dryness in postmenopausal women and may to some degree
inhibit osteoporosis, but alone they may be insufficient for
complete protection. Soy intake prevents oxidation of the
low-density lipoproteins in vitro when isolated from
soy-treated individuals and affect favourably plasma lipid
concentrations. Animal experiments provide evidence suggesting
that both lignans and isoflavonoids may prevent the
development of cancer as well as atherosclerosis. However, in
some of these experiments it has not been possible to separate
the phyto-oestrogen effect from the effect of other components
in the food. The isoflavonoids and lignans may play a
significant inhibitory role in cancer development particularly
in the promotional phase of the disease, but recent evidence
points also to a role in the initiation stage of
carcinogenesis. At present, however, no definite
recommendations can be made as to the dietary amounts needed
for prevention of disease. This review deals with all the
above-mentioned aspects of phyto-oestrogens.
Genistein inhibits proliferation and in vitro
invasive potential of human prostatic cancer cell lines
Santibanez J.F.; Navarro A.; Martinez J.
Dr. J. Martinez, Unidad de Biologia Celular, INTA,
Universidad de Chile, Casilla 138-11, Santiago Chile
Anticancer Research (Greece), 1997, 17/2 A
(1199-1204)
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 represethe prolife ration 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 Matriael barrier to PC-3
cells. the more aggressive invasive cell-line studied. DU-145
and LNCalphaP 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.
Soy and rye diets inhibit the development of
Dunning R3327 prostatic adenocarcinoma in rats
Zhang J.-X.; Hallmans G.; Landstrom M.; Bergh A.; Damber
J.-E.; Aman P.; Adlercreutz H.
Sweden
Cancer Letters (Ireland), 1997, 114/1-2
(313-314)
Two experiments were conducted to investigate the effect of
soy and rye on the development of Dunning R3327 prostatic
adenocarcinoma in rats.
Measurement and metabolism of isoflavonoids and
lignans in the human male
Morton M.S.; Matos-Ferreira A.; Abranches-Monteiro L.;
Correia R.; Blacklock N.; Chan P.S.F.; Cheng C.; Lloyd S.;
Chieh-Ping W.; Griffiths K.
United Kingdom
Cancer Letters (Ireland), 1997, 114/1-2
(145-151):
Asian men, who consume a low fat/high fibre soya-based
diet, have very much lower incidence of prostate cancer than
men from North America and Europe. The soya bean is a rich
source of the isoflavonic phyto-oestrogens, daidzein,
genistein and equol, compounds which may be cancer-protective
in Asian populations. The lignans, enterolactone and
enterodiol, plant oestrogens derived from cereals and
vegetables, may act in a similar manner in vegetarian men. We
report here on the measurement of isoflavonoids and lignans,
by gas chromatography-mass spectrometry, in prostatic fluid of
men from Asia and Europe and also on the metabolism of these
compounds in Western men following dietary
supplementation.
Inhibition of N-methyl-N-nitrosourea-induced
mammary tumors in rats by the soybean isoflavones
Constantinou A.I.; Mehta R.G.; Vaughan A.
Dr. A.I. Constantinou, University of Illinois, Department of
Surgical Oncology, College of Medicine, 840 South Wood Street,
Chicago, IL 60612 USA
Anticancer Research (Greece), 1996, 16/6 A
(3293-3298)
Soy-based diets, rich in the isoflavones genistein and
daidzein, are thought to protect against breast and prostate
cancer. Soy-based diets, rich in the isoflavones genistein and
daidzein, are thought to protect against breast and prostate
cancer. We used the N-methyl-N-nitrosourea (MNU)-induced
mammary carcinogenesis animal model to test the effectiveness
of these two isoflavones as chemopreventive agents. Each
isoflavone was injected daily into 35-day-old rats for six
months while we monitored the animals' body weight and mammary
tumor appearance. Genistein was effective in reducing tumor
multiplicity, but it reduced tumor incidence only marginally.
Daidzein was less effective in reducing both tumor incidence
and multiplicity. To investigate genistein's mechanism of
action we determined the topoisomerase II (topo II) activity
and detected the phosphotyrosine-containing peptides in the
extracts of mammary tissues isolated from control and
isoflavone-treated animals. tumors contained over 60-fold
higher topo II enzymatic activity than the mammary glands.
Similarly, more tyrosine phosphopeptides were detectable in
mammary tumors than in mammary glands. Tissue samples from
genistein treated animals contained similar topo II and
protein tyrosine kinase (PTK) activities as the control group.
These data suggest that mammary tumorigenesis is accompanied
by an extensive increase in topo II and PTK activities. The
mechanism of chemoprevention by genistein, however, is
independent of topo II or PTK inhibition.
Genistein-induced apoptosis of prostate cancer
cells is preceded by a specific decrease in focal adhesion
kinase activity
Kyle E.; Neckers L.; Takimoto C.; Curt G.; Bergan R.
USA
Molecular Pharmacology (USA), 1997, 51/2
(193-200)
Genistein (5,7,4'-trihydroxyisoflavone), an isoflavinoid
found in soy beans, has been identified as potentially causal
for the low incidence of metastatic prostate cancer (PCa) in
certain countries. Although genistein- induced PCa cell
adhesion has been identified as a possible causative
mechanism, direct growth inhibition by genistein has been
reported and also could be causal. If in vivo growth
inhibition was significant, then growth inhibition should
occur at concentrations attained with dietary consumption, the
mechanism of growth inhibition should be relevant to PCa, and
genistein (a broad-spectrum in vitro protein-tyrosine kinase
inhibitor) should have relatively specific kinase inhibitory
effects in vivo. These considerations were investigated by
measuring growth inhibitory activity in a variety of PCa cell
lines. Growth inhibitory effects were shown not to occur with
concentrations below the low micromolar range (i.e., 3 logs
above that attained in serum). In-depth mechanistic studies
with the PC3-M metastatic variant cell line demonstrated that
growth inhibition was in was shown to decrease the viability
of nonadherent cells, suggesting a lack of dependence on cell
adhesion for growth inhibition. However, important molecular
and kinetic differences between genistein's effects on growth
in adherent versus nonadherent cells were identified. Specific
suppression of focal adhesion kinase activity (without global
decreases in phosphotyrosine) was shown to precede induction
of apoptosis, which was responsible for growth inhibition in
adherent cells. These findings do not support an in vivo
growth inhibitory role by genistein consumed in quantities
associated with a soy-based diet. They do, however, identify
genistein as a potential therapeutic agent for PCa and as a
tool with which to study the control of apoptosis in PCa.
Genistein-stimulated adherence of prostate cancer
cells is associated with the binding of focal adhesion kinase
to beta-1-integrin
Bergan R.; Kyle E.; Nguyen P.; Trepel J.; Ingui C.; Neckers
L.
Clinical Pharmacology, Building 10, National Cancer
Institute, NIH, Bethesda, MD 20892 USA
Clinical and Experimental Metastasis (United Kingdom), 1996,
14/4 (389-398)
The isoflavinoid genistein is a protein-tyrosine kinase
inhibitor which has been identified as a putative cancer
prevention agent. Its consumption is associated with a low
incidence of clinical metastatic prostate cancer in the face
of a sustained high incidence of organ-confined prostate
cancer. We therefore undertook studies to examine genistein's
effect upon cell adhesion as one possible mechanism by which
it could be acting as an antimetastatic agent. A morphogenic
analysis revealed that genistein caused cell flattening in a
variety of cell lines: PC3-M, PC3, and DU-145 prostate
carcinoma cells, as well as MCF-7 breast carcinoma cells.
Mechanistic studies focused on the highly metastatic PC3-M
cell line, and revealed that cell flattening was accompanied
by an increase in cell adhesion. Further investigations
demonstrated that focal adhesion kinase (FAK) accumulated in
areas of focal cell attachment, and that this accumulation
occurred only when cells were actively undergoing
genistein-mediated morphologic change. Concurrent formation of
a complex between the cell attachment molecule,
beta-1-integrin, and FAK was shown to occur, and to correlate
with transient activation of FAK activity. Genistein is
presented as a novel investigative tool for use in the study
of molecular events involved in the process of cell
adhesion.
Quantification of genistein and genistin in
soybeans and soybean products
Fukutake M.; Takahashi M.; Ishida K.; Kawamura H.; Sugimura
T.; Wakabayashi K.
Biochemistry Division, Natl Cancer Ctr Research Institute,
1-1 Tsukiji, 5-chome, Chuo-ku, Tokyo 104 Japan
Food and Chemical Toxicology (United Kingdom), 1996, 34/5
(457-461)
It has been suggested that the isoflavone, may have some
role as a chemopreventive agent against cancer in humans.
Levels of genistein and its beta-glucoside conjugate,
genistin, ingested in soybeans and related bean products by
the Japanese were quantified by HPLC, to estimate daily intake
of these compounds. Amounts of genistein and genistin in
soybeans, soy nuts and soy powder were in the range of 4.6 to
18.2 and 200.6 to 968.1 microg/g food, respectively. The
values for soy milk and tofu (bean curd) were 1.9 to 13.9 and
94.8 to 137.7 microg/g food, respectively. Levels of
isoflavones in fermented soybean products, miso (bean paste)
and natto (fermented soybeans), were 38.5 to 229.1 microg/food
for genistein and 71.7 to 492.8 microg/g food for genistin.
Thus, the level of genistein in the fermented soybean products
was higher than in soy beans and soybean products such as soy
milk and tofu. From these observations, it is suggested that
the beta-glycosyl bond of genistin is cleaved to produce
genistein by microbes during fermentation to yield mise and
natto. Soy sauce was also found to contain both isoflavones,
but at levels lower than in miso and natto. On the basiual
consumption of soybeans and related products, daily intake of
genistein and genistin by the Japanese is calculated to be
1.5-4.1 and 6.3-8.3 mg/person, respectively. These levels are
much higher than those for Americans or Western Europeans,
whose mortality rates for breast, colon and prostate cancers
are greater than the Japanese.
Molecular effects of genistein on estrogen receptor
mediated pathways
Wang T.T.Y.; Sathyamoorthy N.; Phang J.M.
Lab Nutritional Molecular Regulation, NCI-Frederick Cancer
Res Dev Ctr, NIH, Frederick, MD 21702-1201 USA
Carcinogenesis (United Kingdom), 1996, 17/2
(271-275)
Genistein, a component of soy products, may play a role in
the prevention of breast and prostate cancer. However, little
is known about the molecular mechanisms involved. In the
present study, we examined the effects of genistein on the
estrogen receptor positive human breast cancer cell line
MCF-7. We observed that genistein stimulated
estrogen-responsive pS2 mRNA expression at concentrations as
low as 10-8 M and these effects can be inhibited by tamoxifen.
We also showed that genistein competed with (3H)estradiol
binding to the estrogen receptor with 50% inhibition at 5 X
10-7 M. Thus, the estrogenic effect of genistein would appear
to be a result of an interaction with the estrogen receptor.
The effect of genistein on growth of MCF-7 cells was also
examined. Genistein produced a concentration-dependent effect
on the growth of MCF-7 cells. At lower concentrations
(10-8-10-6 M) genistein stimulated growth, but at higher
concentrations (>10-5 M) genistein inhibited growth. The
effects of genistein on growth at lower concentrations
appeared to be via the estrogen receptor pathway, while the
effects at higher concentrations were independent of the
estrogen receptor. We also found that genistein, though
estrogenic, can interfere with the effects of estradiol. In
addition, prolonged exposure to genistein resulted in a
decrease in estrogen receptor mRNA level as well as a
decreased response to stimulation by estradiol.
Effects of soya consumption for one month on
steroid hormones in premenopausal women: Implications for
breast cancer risk reduction
Lu L.-J.W.; Anderson K.E.; Grady J.J.; Nagamani M.
Preventive Med./Commun. Health Dept., 2.102 Ewing Hall,
University of Texas Medical Branch, Galveston, TX 77555-1110
USA
Cancer Epidemiology Biomarkers and Prevention (USA), 1996,
5/1 (63-70)
Soybean consumption is associated with reduced rates of
breast, prostate, and colon cancer, which is possibly related
to the presence of isoflavones that are weakly estrogenic and
anticarcinogenic. We examined the effects of soya consumption
on circulating steroid hormones in six healthy females 22- 29
years of age. Starting within 6 days after the onset of
menses, the subjects ingested a 12-oz portion of soymilk with
each of three meals daily for 1 month on a metabolic unit.
Daily isoflavone intakes were similar100 mg of daidzein
(mostly as daidzin) and similar100 mg of genistein (mostly as
genistin). Serum 17beta-estradiol levels on cycle days 5-7,
12-14, and 20-22 decreased by 31% (P = 0.09), 81% (P = 0.03),
and 49% (P = 0.02), respectively, during soya feeding.
Decreases persisted for two to three menstrual cycles after
withdrawal from soya feeding. The luteal phase progesterone
levels decreased by 35% during soya feeding (P = 0.002).
Dehydroepiandrosterone sulfate levels decreased progressively
during soya feeding by 14-30% (P = 0.03). Menstrual cycle
length was 28.3 plus or minus 1.9 days before soymilk feeding,
increased to 31.8 plus or minus 5.1 days during the month of
soymilk feeding (P = 0.06), remained increased at 32.7 plus or
minus 8.4 days (P = 0. 11) at one cycle after termination of
soymilk feeding, and returned to pre-soya diet levels five to
six cycles later. These results suggest that consumption of
soya diets containing phytoestrogens may reduce circulating
ovarian steroids and adrenal androgens and increase menstrual
cycle length. Such effects may account at least in part for
the decreased risk of breast cancer that has been associated
with legume consumption.
Early di. An update
D'Amico A.; Motta L.; Ficarra V.; Pianon R.; Malossini G.;
Tallarigo C.; Comunale L.; Mobilio G.
Italy
Medecine Biologie Environnement (Italy), 1996, 24/2
(139-152)
The main disagreements concerning the early diagnosis and
the screening of prostate carcinoma are due to the lack of
clinical evidence that the discovery of an early stage tumor,
followed by a radical surgical treatment, does induce a
prolonged survival of the patients and/or an improvement of
the quality of life. However, many clinical studies on the
epidemiology and the natural history of the disease suggested
the efficacy of the early diagnosis. Moreover, the volume of
neoplasia diagnosed by screening programs and surgically
treated is generally higher than 0.5 ml and this is certainly
an important clinical value. The dosage of serum PSA was
particularly be reliable to detect an early diagnosis,
according to its higher diagnostic accuracy if compared with
digital rectal examination and transrectal ultrasonography.
The combination of these diagnostic methods increased the
accuracy of the whole clinical picture. In order to increase
total PSA specificity by reducing its false positive values,
especially when marker's values are only slightly augmented
(ranged between 4.1 and 10 ng/ml), many approaches may be
adopted, such as the evaluation of PSA velocity (PSAV), the
assessment of PSA density (PSAD), the appropriate use of
specific PSA values according to the different age of the
patients and, especially, the comparison between free and
complexed PSA dosages to total PSA values. In particular, it
has been, recently observed that free PSA and total PSA ratio
shows a more marked specificity than total PSA at the same
degree of sensitivity. However, it is necessary to assess for
international standard parameters concerning both total PSA
and its molecular forms, since clinical observations were
generally carried out through many different laboratory tools
and according to different reference values. Finally, the
research on prognostic factors which might foresee the
developing power of the single tumor detected into the
prostate, may provide useful information in order to select
the patients who may benefit from a radical surgical
treatment.
Prostate-specific antigen as a screening test for
prostate cancer: The United States experience
Arcangeli C.G.; Ornstein D.K.; Keetch D.W.; Andriole
G.L.
USA
Urologic Clinics of North America (USA), 1997, 24/2
(299-306)
Serum PSA-based early detection for prostate cancer has
been studied fairly extensively for the past several years. It
appears that we can state fairly categorically what the
relative performances of total serum PSA, DRE, and TRUS are in
detecting early-stage prostate cancer; that initial screening
is effective in detecting histologically significant and
pathologically organ-confined prostate cancer; that annual,
serial, repetitive screening, at least over a 4- to 5-year
horizon, does not overdetect prostate cancer, and that the
results of early detection will improve as our ability to use
certain PSA transformations such as PSA density, PSA slope,
age-specific PSA adjustment, and knowledge of free versus
total serum PSA is better characterized. These advances in our
ability to diagnose early-stage prostate cancer likely will be
coupled with an increased ability to predict the behavior,
curability, and significance of individual tumors. It is hoped
that information soon will be available to allow physicians to
categorize an individual tumor as insignificant, significant
and surgically curable, or significant and incurable by
standard approaches. This ability, coupled with the demon
strated ability to detect prostate cancer, will make an even
more compelling argument for widespread PSA-based screening.
At present, annual DRE and total serum PSA measurements are
recommended for men older than 50 and among younger men at
high risk for prostate cancer. All suspicious DRE findings
should be evaluated with prostatic biopsy. Among younger men,
PSA levels over 2.5 ng/mL should be considered worrisome and
further evaluated. For men older than 65, serum PSA levels
above 4 ng/mL should be considered abnormal and warrant
biopsy. Men with persistent serum PSA elevation and a negative
biopsy should undergo repeat biopsy at least once, and perhaps
more often if PSA slope exceeds 0.75 per year, if density is
greater than 0.10, or if PSA is less than 20%.
Prostate cancer screening: The controversy
Assaf G.J.
Lebanon
Revue Medicale Libanaise (Lebanon), 1996, 8/3
(152-154)
As of 1993, prostate cancer is the most common cancer among
men in the USA and Canada, and the second leading cause of
cancer deaths in males. In 1980, of patients in whom the
diagnosis of prostate cancer was made clinically, 40% had
disease beyond the prostate gland, for the most part an
incurable condition. One should always bear in mind that
localized prostate cancer is asymptomatic. The obstructive
voiding symptoms rarely occur with localized organ confined
prostate cancer. Few years ago, the PSA (prostate specific
antigen) serologic test was developed, as a methodology for
screening patients for prostate cancer, seeking the detection
of this disease at an early stage. We will discuss the natural
history of prostate cancer, early detection of this disease
and the limitations of the PSA determination.
Clinical utility of measurements of free and total
prostate-specific antigen (PSA): A review
Catalona W.J.
Division of Urologic Surgery, Washington Univ. Sch. of
Medicine, 4960 Childrens' Place, St. Louis, MO 63110 USA
Prostate (USA), 1996, 29/Suppl. 7 (64-69)
BACKGROUND. Prostate-specific antigen (PSA) is a
widely-used tumor marker to aid in the early detection of
prostate cancer. PSA testing has appreciable false-positive
and false-negative results, particularly in the 2.5-10.0 ng/ml
range. Measurements of the percentage of nonprotein-bound
(free) PSA in serum, which is lower in patients with prostate
cancer, has been evaluated as a method for increasing the
accuracy of PSA testing.
METHODS. The literature on forms of PSA in serum, as it
relates to issues of clinical utility for prostate cancer
screening, was reviewed and summarized through May 1996.
RESULTS. Measurements of the percentage of free PSA in
serum increases the accuracy of PSA testing for prostate
cancer in men whose total PSA levels are 2.5-10.0 ng/ml.
Cutoffs for screening are affected by prostate volume and
total PSA levels. One study also demonstrated a correlation
between percentage of free PSA and pathologic features of
cancer aggressiveness.
CONCLUSIONS. Measurement of free PSA in serum has potential
clinical utility for increasing the sensitivity and
specificity of PSA screening. Insufficient data are available
to establish cutoffs to be used in clinical practice. Cutoffs
are affected by total PSA level and prostate volume. The
prevalence rate of cancer in the screened population (age,
race, previous biopsy history, etc.) will also influence
screening cutoffs. Percentage of free PSA may also correlate
with the potential aggressiveness of early-stage prostate
cancer.
Detection of human papillomavirus DNA and p53 gene
mutations in human prostate cancer
Suzuki H.; Komiya A.; Aida S.; Ito H.; Yatani R.; Shimazaki
J.
Department of Urology, School of Medicine, Chiba University,
Inohana 1-8-1, Chuo-ku, Chiba-shi, Chiba 260 Japan
Prostate (USA), 1996, 28/5 (318-324)
The relationship between integration with human
papillomavirus (HPV) and p53 gene mutations in tissues of
prostate cancer was examined. Tissue samples analyzed were
obtained by tofrom autopsy (22 endocrine therapy-resist ant
metastatic disease cases). HPV DNA was detected in 8 of 51
(16%, 5 in stage B and 3 in autopsy cases) by polymerase chain
reaction (PCR) using consensus primers on L1 region. Genotypes
of HPV were entirely type 16. Structural abnormalities of p53
gene were detected in 7 of the 22 autopsy cases (32%) by
PCR-single-strand conformation polymorphism analysis and
direct sequencing. No p53 gene mutation was found in stage B
cancer cases. Analysis of mutation spectra revealed clear
differences between Japanese and Westerners. There was a
significant difference in the mutation frequency between stage
B and autopsy cases (P < 0.01, Fisher's exact test). One
case showed both integration of HPV and p53 gene mutation in
different cancer foci. However, the other cases revealed an
inverse correlation between the presence of HPV DNA and p53
gene mutations. These data show that p53 genetic alteration is
correlated with the progression of prostate cancer, in
contrast to the integration of HPV that may occur in a
relatively early stage. In conclusion, this study may indicate
that either p53 gene mutation or the presence of HPV's
oncogenic protein E6 is involved in the development of
prostate cancer.
Effects of potent vitamin D3 analogs on clonal
proliferation of human prostate cancer cell lines
De Vos S.; Holden S.; Heber D.; Elstner E.; Binderup L.;
Uskokovic M.; Rude B.; Chen D.L.; Le J.; Cho S.K.; Koeffler
H.P.
Dr. S. De Vos, Cedars-Sinai Medical Center, Davis Bldg. 5034,
UCLA School of Medicine, 8700 Beverly Blvd., Los Angeles, CA
90048 USA
Prostate (USA), 1997, 31/2 (77-83)
BACKGROUND. Management of prostate cancer that has spread
outside of the prostate capsule is a difficult problem.
Innovative, non-toxic approaches to the disease are required.
New, relatively non-toxic vitamin D3 analogs have recently
been synthesized. We report that several of these compounds
have marked antiproliferative effects on prostate cells.
METHODS. The clonal antiproliferative activity of five
novel analogs of 1,25 dihydroxyvitamin D3 (1,25(OH)2D3, (cmpd
C)) as well as 1,25(OH)2D3 itself was tested on three human
prostate cancer cell lines (PC-3, LNCaP, and DU-145). The
analogs were 20-epi-22oxa-24a,26a,27a-tri-homo-
1alpha,25(OH)2D3 (code name: KH 1060);
24a26a27a-tri-homo-22,24-diene- 1alpha,25(OH)2D3 (code name:
EB 1089); 1,25(OH)2-16ene-D3 (code name: HM);
1,25(OH)2-16ene-23yne-D3 (code name: V); 1,25(OH)2-20-epi-D3
(code name: MC 1288)).
RESULTS. With the parent compound (1,25(OH)2D3), the
effective dose that inhibited 50% clonogenic growth of PC-3
and LNCaP was 10-8M and 7 x 10-9 M, respectively. For these
prostate cancer cell lines, KH 1060 was the most potent analog
by an order of 25- to 35-fold as compared to cmpd C. The
second and third most potent analogs were HM and MC 1288.
DU-145 was resistant to all the vitamin D3 analogs. The major
side-effect of 1,25(OH)2D3 is the production of hypercalcemia.
The relative inhibitory index (RII) was determined by
comparing the antiproliferative activity of the analog to its
ability to produce hypercalcemia in mice injected
intraperitoneally every other day. The KH 1060 had the best
RTI: 50- to 70- fold greater than 1,25(OH)2D3 for PC-3 and
LNCaP, respectively.
CONCLUSIONS. A trial of one or more of theatment of minimal
residual disease of prostate cancer.
1,25-Dihydroxyvitamin D3 and 9-cis-retinoic acid
act synergistically to inhibit the growthcause accumulation of
cells in G1
Blutt S.E.; Allegretto E.A.; Pike J.W.; Weigel N.L.
USA
Endocrinology (USA), 1997, 138/4 (1491-1497)
Recent studies have suggested that the active metabolite of
vitamin D3, 1,25-dihydroxyvitamin D3, can inhibit the growth
and/or induce the differentiation of a variety of cell types
and that these characteristics might be useful in the
treatment of some cancers. Retinoids also promote the
differentiation and inhibit the growth of some cells. That the
vitamin D receptor acts as a heterodimer with the retinoid X
receptor (RXR) suggests that there may be functional
interactions between 1,25-dihydroxyvitamin D3 and retinoids.
In this study, we show that the combination of 1,25-
dihydroxyvitamin D3 and 9-cis retinoic acid synergistically
inhibits the growth of LNCaP prostate cancer cells. That this
effect is mediated by RXR rather than retinoic acid receptors
was shown using RXR- and retinoic acid receptor-specific
ligands. The vitamin D3 analog, EB1089, inhibited growth more
effectively than 1,25-dihydroxyvitamin D3 and also acted
synergistically with 9-cis-retinoic acid. These treatments
caused cells to accumulate in the G1 phase of the cell cycle,
suggesting that 1,25- dihydroxyvitamin D3 can regulate one or
more factors critical for the G1/S transition.
Vitamin D receptor content and transcriptional
activity do not fully predict antiproliferative effects of
vitamin D in human prostate cancer cell lines
Zhuang S.-H.; Schwartz G.G.; Cameron D.; Burnstein K.L.
USA
Molecular and Cellular Endocrinology (Ireland), 1997, 126/1
(83-90)
Prostate cancer cell lines exhibit variable growth
suppression by the hormonal form molecular basis for this
differential sensitivity to 1,25 D3, we compared growth
response to 1,25 D3, vitamin D receptor (VDR) content and VDR
transcriptional activity in four well-characterized human
prostate cancer cell lines: LNCaP, DU145, PC-3 and ALVA-31. In
PC-3 and DU145 cells, relative lack of growth inhibition by
1,25 D3 (< 10% inhibition) correlates with very low levels
of VDR (9-15 fmol/mg protein) compared to classical vitamin D3
target tissues (similar 75-200 fmol/mg protein). Transfection
of DU145 and PC-3 cells with a VDR cDNA expression vector is
sufficient to establish growth sensitivity to 1,25 D3,
suggesting that low VDR levels are responsible for the failure
of these cell lines to respond to 1,25 D3. LNCaP cells are
highly sensitive to growth inhibition by 1,25 D3 (similar 55%
inhibition) and contain similar 2-3-fold more VDR (25 fmol/mg)
than the relatively 1,25 D3-insensitive PC-3 and DU145 cell
lines. However, ALVA-31 cells display less than 20% growth
inhibition to 1,25 D3 although they contain the highest levels
of VDR (45 fmol/mg) of the four cell lines. Thus, sensitivity
to growth inhibition by 1,25 D3 does not correlate with VDR
content in ALVA-31 and LNCaP cells. This lack of correlation
between VDR density and growth responses to 1,25 D3 led us to
investigate VDR-mediated gene transcription in these cell
lines. We employed two different naturally-occurring vitamin D
response elements (VDREs) linked to a reporter gene. Reporter
gene activation by 1,25 D3 correlated well with VDR content in
all four cell lines. Therefore, compared to LNCaP cells,
decreased sensitivity of ALVA-31 to growth inhibition by 1,25
D3 is not due to a decrease in the general transcriptional
activity of VDR. We conclude that growth inhibition by 1,25 D3
in prostate cancer cells requires VDR but that this response
is modulated by non-receptor factors that are cell
line-specific.
A preliminary report on the use of transfer factor
for treating stage D3 hormone-unr metastatic prostate
cancer
Pizza G.; De Vinci C.; Cuzzocrea D.; Menniti D.; Aiello E.;
Maver P.; Corrado G.; Romagnoli P.; Dragoni E.; LoConte G.;
Riolo U.; Palareti A.; Zucchelli P.; Fornarola V.; Viza
D.
Dr. G. Pizza, Immunodiagnosis/Immunotherapy Unit, 1st
Division of Urology, Sant'Orsola-Malpighi Hospital, Via P.
Palagi 9, 40138 Bologna Italy
Biotherapy (Netherlands), 1996, 9/1-3 (123-132)
As conventional treatments are unsuccessful, the survival
rate of stage D3 prostate cancer patients is poor. Reports
have suggested the existence of humoral and cell-mediated
immunity (CMI) against prostate cancer tumour-associated
antigens (TAA). These observations prompted us to treat stage
D3 prostate cancer patients with an in vitro produced transfer
factor (TF) able to transfer, in vitro and in vivo, CMI
against bladder and prostate TAA. Fifty patients entered this
study and received one intramuscular injection of 2-5 units of
specific TF monthly. Follow-up, ranging from 1 to 9 years,
showed that complete remission was achieved in 2 patients,
partial remission in 6, and no progression of metastatic
disease in 14. The median survival was 126 weeks, higher than
the survival rates reported in the literature for patients of
the same stage.
The role of vitamin D in normal prostate growth and
differentiation
Konety B.R.; Schwartz G.G.; Acierno J.S. Jr.; Becich M.J.;
Getzenberg R.H.
University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA
15213 USA
Cell Growth and Differentiation (USA), 1996, 7/11
(1563-1570)
Although increasing data indicate a role for vitamin D in
prostate cancer, littlis hormone in the noncancerous prostate.
We examined the effect of 1,25-dihydroxyvitamin D3 (1,25 D) on
the growth of noncancerous rat prostates in vivo. Rats were
castrated and treated with vehicle (controls), 1,25 D,
testosterone, or a combination of both hormones for 2 weeks.
Histological examination of the harvested prostates revealed
that 1,25 D had a selective regressive effect on epithelial
cells in treated rats compared to untreated castrated rats and
to normal uncastrated rats. However, 1,25 D stimulated stromal
growth in the prostate. The mean prostatic weight of the
vitamin D-treated rats was twice that of the untreated rats
(0.13 plus or minus SEM 0.005 g versus 0.06 plus or minus SEM
0.006 g). The histological differences were less marked in the
testosterone-supplemented animals. A greater degree of
cellular differentiation was observed in the rats treated with
testosterone and vitamin D compared to rats that received
testosterone supplementation alone. Studies of the nuclear
matrix composition revealed differences between the
testosterone-supplemented and the testosterone and 1,25
D-treated rat prostates. We conclude that in the absence of
testosterone, 1,25 D may exert a growth-promoting effect on
the prostatic stroma in vivo. In concert with testosterone, it
may play an important role in the growth and differentiation
of the normal rat prostate.
Effects of 1,25 dihydroxyvitamin D3 and its
analogues on induction of apoptosis in breast cancer
cells
James S.Y.; Mackay A.G.; Colston K.W.
Department of Clinical Biochemistry, St George's Hospital,
Medical School, London SW17 ORE United Kingdom
Journal of Steroid Biochemistry and Molecular Biology (United
Kingdom), 1996, 58/4 (395-401)
Vitamin D derivatives have been shown both to inhibit the
proliferation of cultured breast cancer cells and totumours in
vivo. We have investig ated the ability of several vitamin D
analogues to promote the regression of experimental rat
mammary tumours. Our results revealed that one vitamin D
compound in particular, EB1089
(1(S),3(R)-dihydroxy-20(R)-5'-ethyl-5'-hydroxy-hepta-
1',3'(E)-dien- 1'-yl)-9,10-secopregna-5(Z),7(E),
10(19)-triene), was highly effective at inhibiting tumour
progression, without causing a significant rise in serum
calcium concentration. Tumour regression occurs when the rate
of cell. death is greater than the rate of cell proliferation.
Apoptosis (programmed or active cell death) is an active,
energy-dependent process in which a distinct series of
biochemical and molecular events leads to the death of cells
by specific signals. We have examined effects of
1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and the synthetic
vitamin D analogue EB1089 on indices of apoptosis in cultured
human breast cancer cells. The effects of the vitamin D
compounds on the expression of two oncoproteins which may
regulate apoptosis, bcl-2 and p53 were examined by Western
analysis. In MCF-7 cell cultures treated for six days with
1,25(OH)2D3 or EB1089 (1 x 10-8 M), bcl-2 protein was reduced
in comparison to control levels, whereas p53 protein was
increased. In addition, the p21 protein, whose gene WAF-1 is
induced by wild type p53, was also increased by both vitamin D
compounds. Using Northern analysis, it was observed that 24-h
treatment of MCF-7 cells with 1 x 10-8 M 1,25(OH)2D3 or EB1089
resulted in an induction of TRPM-2 (clusterin) mRNA, a gene
associated with onset of apoptosis in the involuting prostate.
Fragmentation of genomic DNA is a characteristic feature of
apoptosis. With the terminal deoxynucleotidyl transferase
(TdT) assay, 3'-OH DNA breaks indicative of DNA fragmentation
were detected histochemically in MCF-7 cells treated with 1 x
10-8 M 1,25(OH)2D3 or EB1089 for four days prior to fixation
and TdT reaction. Further evidence of apoptosis was obtained
following six days treatment of MCF-7 cell cultures with 5 x
10-8 M 1,25(OH)2D3 or EB1089, utilizing a cell death ELISA
assay, which measures the presence of histone-associated
oligonucleosome complexes generated from DNA fragmentation.
Taken together our findings indicate that vitamin D
derivatives may play a role in regulating the expression of
genes and protein products implicated in apoptosis.
Vitamin D receptor expression is required for
growth modulation by 1alpha,25-dihydroxyvitamin D3 in the
human prostatic carcinoma cell line ALVA-31
Hedlund T.E.; Moffatt K.A.; Miller G.J.
Department of Pathology, Box B-216, Univ. of Colorado Hlth
Sciences Ctr, 4200 East Ninth Ave., Denver, CO 80262 USA
Journal of Steroid Biochemistry and Molecular Biology (United
Kingdom), 1996, 58/3 (277-288)
Epidemiological data suggest that vitamin D3, obtained from
dietary sources and sunlight exposure, protects against
mortality from prostate cancer (PC). In agreement with this,
the most active vitamin D metabolite
1alpha,25-dihydroxyvitamin D3 (1,25(OH)2 D3) regulates the
growth and differentiation of several human PC cell lines.
Both genomic and non-genomic signalling pathways for 1,25(OH)2
D3 have been reported, although the mechanism of action in PC
cells has not been defined. We now provide data supporting an
active role for the nuclear vitamin D receptor (VDe
growth-inhibitory effects of 1,25(OH)2 D3 on these cells. In
the VDR-rich cell line ALVA-31, the observed changes in growth
by 1,25(OH)2 D3 are preceded by significant changes in VDR
mRNA expression, In contrast, the cell line JCA-1, containing
few VDRs, fails to show both early changes in VDR gene
expression and later changes in growth with 1,25(OH)2 D3. To
assess the role of the VDR more directly, transfection studies
were pursued. ALVA-31 cells were stably transfected with an
antisense VDR cDNA construct in an attempt to reduce VDR
expression. Antisense mRNA expression among clones was
associated with: (a) reduced or abolished sensitivity to the
effects of 1,25(OH)2 D3 on growth; (b) decreased numbers of
VDRs per cell, as measured by radiolabelled-ligand binding;
and (c) a lack of induction of the VDR-regulated enzyme
24-hydroxylase in response to 1,25(OH)2 D3. From these studies
we conclude that the antiproliferative effects of 1,25(OH)2 D3
require expression of the nuclear VDR in this system.
Induction of transforming growth factor-beta
autocrine activity by all-trans-retinoic acid and
1alpha,25-dihydroxyvitamin D3 in NRP-152 rat prostatic
epithelial cells
Danielpour D.
Laboratory of Chemoprevention, National Cancer Institute,
Building 41, Bethesda, MD 20892 USA
Journal of Cellular Physiology (USA), 1996, 166/1
(231-239)
Retinoids and vitamin D analogues are known to inhibit the
proliferation of a variety of cells in culture and prevent the
formation of certain tumors in mammals. Although it is well
established that these hormones control the transcription of
many genes upon binding to and activating specific nuclear
receptors, the mechanisms by which they prevent cancer are as
yet poorly understood. In this study the role of the
transforming growth factor-p (TGF-beta) growth inhibitors, in
promoting the biological activities of all-trans-retinoic acid
(RA) and 1alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3) was
studied in NRP-152 cells, a nontumorigenic epithelial line
derived from rat dorsal-lateral prostate. Inhibition of growth
by nanomolar concentrations of RA was associated with an
increase in both mRNA and protein for all three TGF-beta
isoforms, with greater and much earlier increases for
TGF-betas 2 and 3 (5.5 h) than for TGF-beta1 (24 h). A
monoclonal antibody against TGF-beta and TGF-beta1 latency
associated peptide (LAP), both of which neutralize all three
TGF-beta isoforms, each block the ability of RA to inhibit
growth of NRP-152 cells by >95%. Neutralization of growth
inhibition by isoform-specific antibodies suggested that all
three TGF-betas are involved in this effect. The ability of RA
to upregulate fibronectin and thrombospondin expression in
NRP-152 cells was also blocked by the monoclonal antibody.
1,25-(OH)2D3, which also induced TCF-betas 2 and 3 but not
TGF-beta1, and their respective mRNAs, also induced
fibronectin and thrombospondin through induction of TGF-beta.
Thus, autocrine production of TGF-betas may be a significant
part of the mechanisms by which RA and 1,25-(OH)2D3 promote
cellular differentiation.
Biologically active acylglycerides from the berries
of saw-palmetto (Serenoa repens)
Shimada H.; Tyler V.E.; McLaughlin J.L.
J.L. McLaughlin, DMCMP, Sch. of Pharmacy/Pharmacal Sciences,
Purdue University, West Lafayette, IN 47907 USA
Journal of Natural Products (USA), 1997, 60/4
(417-418)
Brine shrimp lethality-directed fractionation of the 95%
EtOH extract of the powdered, dried berries of Serenoa repens
(Bart.) Small (saw-palmetto) (Palmae) led to the isolation of
two monoacylglycerides, 1-monolaurin (1) and 1-monomyristin
(2). Compounds 1 and 2 showed moderate biological activities
in the brine shrimp lethality test and against renal (A-498)
and pancreatic (PACA-2) human tumor cells; borderline
cytotoxicity was exhibited against human prostatic (PC-3)
cells. The fruits and extracts of saw-palmetto are taken
orally as an herbal medicine to prevent prostatic
hyperplasias.
Effects of the lipidosterolic extract of Serenoa
repens (Permixon (R)) on human prostatic cell lines
Ravenna L.; Di Silverio F.; Russo M.A.; Salvatori L.;
Morgante E.; Morrone S.; Cardillo M.R.; Russo A.; Frati L.;
Gulino A.; Petrangeli E.
Istituto Tecnologie Biomediche, via G. B. Morgagni 30/E,
00161 Roma Italy
Prostate (USA), 1996, 29/4 (219-230)
BACKGROUND. Permixon (R) is a drug used in the treatment of
benign prostatic hyperplasia. We studied its androgenic and
antiandrogenic effects in the prostatic cell line LNCaP and
PC3, respectively responsive and unresponsive to androgen
stimulation.
METHODS. We performed FACScan analysis to investigate
toxicity, 3H thymidine and 35S methionine incorporation to
determine antiproliferative and metabolic effects, electron
microscopy to study ultrastructural changes and cotransfection
experiments to elucidate the role of wild type androgeor.
RESULTS. In LNCaP cell line, Permixon (R) induced a double
proliferative/differentiative effect, not observed in PC3
cells. In PC3 cells cotransfected with wild-type androgen
receptors and CAT reporter genes under the control of a
androgen responsive element, the drug inhibited
androgen-induced CAT transcription.
CONCLUSIONS. Our data indicate a role of the androgen
receptor in mediating the effects of Permixon (R) in LNCaP
cells. Cotransfection experiments in PC3 cells support a clear
antiandrogenic action of the drug.
Comparison of in vitro effects of the pure
antiandrogens OH-flutamide, casodex, and nilutamide on
androgen-sensitive parameters
Simard J.; Singh S.M.; Labrie F.; Schellhammer P.F.; Candas
B.
Canada
Urology (USA), 1997, 49/4 (580-589)
Objectives. A combination of flutamide (Eulexin) or
nilutamide (Anandron) with a luteinizing hormone-releasing
hormone (LHRH) agonist or orchiectomy is the only therapy
demonstrated to prolong life in prostate cancer. Recently, the
low 50-mg daily dose of Casodex, an analogue of the pure
antiandrogen flutamide, was chosen for clinical studies on the
basis that the compound was 5 to 10 times more potent than
flutamide, as suggested by data obtained in the inappropriate
intact rat model. The present study was designed to compare
the in vitro antiandrogenic activity of OH-flutamide (OH-
FLU), the active metabolite of flutamide, Casodex, and
nilutamide.
Methods. The effect of the antiandrogens was tested on two
androgen-sensitive parameters, namely proliferation of the
SEM-107 clone of Shionogi mouse mammary tumor ceils and
secretion of the GCDFP-15 (gross cystic disease fluid protein
15 kDa) in T-47D and ZR-75-1 human breast cancer cells.
Results. The twofold stimulation of Shionogi cell
proliferation caused by a 10-day exposure to 1 nM testosterone
was competitively reversed by incubation with OH-FLU, Casodex,
or nilutamide, at the respective IC50 values of 72, 243, and
412 nM. Moreover, the marked increase in GCDFP-15 release
induced by 1 nM testosterone was blocked by OH-FLU, Casodex,
or nilutamide at respective IC50 values of 29, 180, and 87 nM
in T-47D cells and at 35, 142, and 75 nM in ZR-75-1 cells.
Similar data were detected in 4-androstenedione-induced
Shionogi cell proliferation and in dihydrotestosterone-induced
GCDFP-15 secretion in T-47D cells.
Conclusions. OH-FLU is 3.1 - to 7.8-fold more potent than
Casodex, as measured on two in vitro androgen-sensitive
parameters, in agreement with our recent in vivo data obtained
in the model of castrated rats supplemented with
4-androstenedione implants, in which threefold greater potency
of flutamide was observed. The present data, as well as other
data from the literature, strongly indicate the need to choose
a more appropriate dose of Casodex for the treatment of
prostate cancerlexin/USA scheri ng plough; anadron/FRA roussel
uclaf; ru 23908/FRA roussel uclaf; casodex
Casodex (R) (Bicalutamide): Overview of
a new antiandrogen developed for the treatment of prostate
cancer
Blackledge G.R.P.; Cockshott I.D.; Furr B.J.A.
Dr. G.R.P. Blackledge, Medical Affairs Department, Zeneca
Pharmaceuticals, Mereside, Alderley Park, Macclesfield SK10
4TG United Kingdom
European Urology (Switzerland), 1997, 31/SUPPL. 2
(30-39)
Casodex (R) (bicalutamide, Zeneca Ltd), has been
developed for prostate cancer therapy. Its preclinical,
pharmacokinetic, pharmacodynamic, clinical efficacy and
tolerability data are described, Casodex is a potent and
specific nonsteroidal antiandrogen. Clinical studies indicated
that Casodex is orally bioavailable and well absorbed, with a
plasma hallife of around 1 week. A Casodex dose of 50 mg daily
decreased prostatic acid phosphatase comparable with
castration. This dose was, therefore, evaluated initially as
monotherapy and later as a component of maximal androgen
blockade. Using prostate specific antigen as an end point,
Casodex 150 mg daily was well-tolerated with demonstrable
evidence of activity. Casodex 150 mg monotherapy was less
effective than castration in terms of efficacy in patients
with metastatic disease at entry. However, in patients
non-metastatic at entry, Casodex 150 mg monotherapy appeared
to be equivalent to castration in terms of time to death (data
immature). Casodex was well-tolerated. In combination
treatment, Casodex at 50 mg daily was at least as effective as
750 mg flutamide (Eulexin (R), Schering-Plough International)
with respect to time to treatment failure, equivalent in terms
of survival, and better tolerated with respect to diarrhoea.
In conclusion, Casodex is a good option for the antiandrogen
component of maximal androgen blockade.
Recommended dose of flutamide with LH-RH agonist
therapy in patients with advanced prostate cancer
Akaza H.; Isaka S.; Usami M.; Kanetake H.; Kotake T.; Koiso
K.; Aso Y.
H. Akaza, Department of Urology, Institute of Clinical
Medicine, University of Tsukuba, 1-1 Tennodai, Tsukuba City,
Ibaraki 305 Japan
International Journal of Urology (Japan), 1996, 3/6
(468-471)
Background: in a recent study by the Casodex Combination
Study Group, USA, patients in a flutamide (750 mg/day) plus
LH-RH agonist group showed a high treatment failure rate,
mainly due to flutamide-induced diarrhea and hepatotoxicity.
Our current study was conducted to determine the optimal dose
of flutamide for use in this type of combination therapy.
Methods: In a randomized, multicenter study, 30 patients
(hormone untreated; stage C or D) were divided into 2 groups:
flutamide 250 mg (125 mg x 2; 14 patients) and flutamide 375
mg (125 mg x 3; 16 patients), and each dose combined with
either goserelin acetate (3.6 mg every 4 weeks) or leuprolide
acetate (3.75 mg every 4 weeks). Goserelin and leuprolide were
administered to patients in a 1:1 ratio. Flutamide
monotherapjapan in our previous phase II study. The endpoints
of this pilot study were the objective response and adverse
events during the 12-week treatment.
Results: The objective response rate was 83.3% in the
flutamide 250 mg group and 85.7% in the flutamide 375 mg group
according to the Japanese response criteria for prostate
cancer. Elevated PSA levels fell to within the normal range in
83.3% of the patients in the former group and in 93.3% of the
patients in the latter group. One patient administered 250 mg
of flutamide experienced diarrhea, while the serum COT and/or
GPT were elevated in 3 patients administered 250 mg of
flutamide acid 4 patients administered 375 mg of
flutamide.
Conclusions: Based on the findings of this pilot study of
maximal androgen-depletion therapy for advanced prostate
cancer, 375 mg/day of flutamide is recommended in combination
with an CH-RH agonist. Assessment of the effects of our
recommended regimen on longer term survival, quality of life
and antiandrogen withdrawal syndrome of patients treated
requires additional patients and time for follow-up.
Bicalutamide (Casodex(TM))
Schellhammer P.
USA
Expert Opinion on Investigational Drugs (United Kingdom),
1996, 5/12 (1707-1722)
Bicalutamide (Casodex(TM)) is a relatively new
non-steroidal anti-androgen indicated for use in combination
therapy with castration for the treatment of advanced prostate
cancer. Developed from a series of non-steroidal compounds
related to flutamide, bicalutamide is a potent, orally active,
well tolerated anti-androgen with a hallife compatible with
once-daily administration. In the clinical programme in
prostatic cancer, patients were exposed to bicalutamide in
doses ranging from 10 - 600 mg. Doses of 10 - 200 mg have been
shown to have intrinsic activity in terms of producing
subjective improvement and objective responses, and daily
doses of up to 600 mg are currently being evaluated. Results
of monotherapy studies reveal that 50 mg of bicalutamide is
less effective than castration in patients with advanced
disease; Phase III monotherapy studies are ongoing to compare
150 mg of bicalutamide with castration. In monotherapy
studies, both 50 mg and 150 mg of bicalutamide have an
advantage over castration in allowing patients to maintain
libido and sexual potency. As combination therapy, 50 mg
bicalutamide and a luteinising hormone-releasing hormone
(LHRH) analogue is at least as effective as 750 mg of
flutamide and an LHRH analogue and is better tolerated. The
overall safety and tolerability profile of bicalutamide is
indicative of a well tolerated therapy that has a relatively
low incidence of treatment-related withdrawals. Because of its
efficacy in combination with medical castration, its excellent
safety profile, and its convenient once-daily oral
formulation, bicalutamide represents a valid choice for
anti-androgen therapy when used in combination with castration
for patients with advanced prostate cancer.
U.S. Drug and biologic approvals in 1994-1995
Beary III J.F.; Duchaine C.M.; Rhein R.W. Jr.
Div. Regulatory/Scientific Affairs, Pharmaceutical Research,
Manufacturers of America, 1100 Fifteenth Street NW,
Washington, DC 20005 USA
Drug Development Research (USA), 1996, 37/4
(197-207)
Since the introduction of the Prescription Drug User Fee in
1992, the mean approval time for new drugs has decreased from
29.9 months (1992) to 19.2 months (1995). In 1994, 22 new
drugs and 1 biological were approved. In 1995, 28 drugs and 2
biologicals were approved.
Cryosurgery of prostate cancer. Use of adjuvant
hormonal therapy and temperature monitoring - A one year
follow-up
Lee F.; Bahn D.K.; McHugh T.A.; Kumar A.A.; Badalament
R.A.
Dr. F. Lee, Prostate Center, Crittenton Hospital, 1101 W
University Drive, Rochester, MI 48307 USA
Anticancer Research (Greece), 1997, 17/3 A
(1511-1515)
Objective: To determine the clinical outcomes at one year
of Stages T2-T3 prostate cancer by cryosurgery utilizing
pretreatment with total androgen ablation therapy and
temperature monitoring to control the freez347 pat ients have
had 356 cryosurgical procedures. 280 have reached one year
post treatment. Of these, 131 had re-evalation with prostatic
biopsy and serum PSA.
Methods: Transrectal ultrasound (TRUS) measurement of tumor
size and biopsy of extraprostatic space was used to stage
patients into two main groups: confined (66.6%) versus
non-confined (19.3%). Radiation failures (14.1%) formed a
separate group. Failure rates for the 131 men include all
cancer diagnosed during the one year period following
cryosurgery.
Results: The one year failure rate for the study group was
19.8% (26/131). For stages T2a, T2b C, T3 and radiation
failures, the rates of positive biopsies were 13.9%, 12.9%,
33.3% and 35%, respectively. For those with local control of
cancer (negative biopsy), 80% had prostate specific antigen
(PSA) levels of < 0.5 ng/ml. The statistical variables for
persistent cancer with prostate specific antigen > 0.5
ng/ml were: sensitivity of 66.7%, PPV of 16.7%, NPV of 98% and
specificity of 83.7%. A statistically significant difference
exists between stages T2 vs T3 and radiation failures (p =
< 0.5). Major complications of rectal fistula and total
incontinence for previously non-treated cancer versus
radiation failures were 0.33% and 8.7% respectively, a 26
times greater risk.
Conclusion: Results of cryosurgery for all stages of
prostate cancer at one year are encouraging, being 80% free of
disease (biopsy and prostate specific antigen). The morbidity
of the previously non-treated cancers from this procedure for
us was minimal with high patient acceptance. For radiation
failures a local control rate of 65% was achieved. However,
early in our experience significant morbidity did occur and
our enthusiasm for attempted salvage was initially
tempered.
The potential role of lycopene for human
health
Gerster H.
H. Gerster, Vitamin Research Department, F. Hoffmann-LaRoche
Ltd, Bldg 73/30A, CH-4070 Basel Switzerland
Journal of the American College of Nutrition (USA), 1997,
16/2 (109-126)
Lycopene is one of the major carotenoids in Western diets
and is found almost exclusively in tomatoes and tomato
products. It accounts for about 50% of carotenoids in human
serum. Among the common dietary carotenoids lycopene has the
highest singlet oxygen quenching capacity in vitro. Other
outstanding features are its high concentration in testes,
adrenal gland and prostate. In contrast to other carotenoids
its serum values are not regularly reduced by smoking or
alcohol consumption but by increasing age. Remarkable inverse
relation ships between lycopene intake or serum values and
risk have been observed in particular for cancers of the
prostate, pancreas and to a certain extent of the stomach. In
some of the studies lycopene was the only carotenoid
associated with risk reduction. Its role in cancer risk
reduction still needs to be clarified. Patients with HIV
infection, inflammatory diseases and hyperlipidemia with and
without lipid lowering treatment may have depleted lycopene
serum concentrations. Before embarking on large-scale human
trials the distribution of lycopene and its biological
functions need to be further evaluated.
Lycopene: A biologically important carotenoid for
humans?
Stahl W.; Sies H.
Germany
Archives of Biochemistry and Biophysics (USA), 1996, 336/1
(1-9)
Lycopene is a carotenoid present in human blood (similar0.5
micromol/liter plasma), and the tissue levels vary from 1
nmol/g wet wt in adipose tissue to up to 20 nmol/g wet wt in
adrenals and testes. Its biological activities include
antioxidant activity (singlet oxygen quenching and peroxyl
radical scavenging), induction of cell-cell communication, and
growth control, but no provitamin A activity. Epidemiological
studies suggest protective effects of lycopene on some types
of cancer, e.g., prostate cancer. In vitro and in vivo studies
on growth of tumor cells support this conclusion. The major
sources of lycopene for the human are tomatoes and tomato
products, and bioavailability from different food items varies
considerably. Lycopene oxidation products have recently been
identified in human serum. Suggested health effects of
lycopene require further investigation.
cis-trans lycopene isomers, carotenoids, and
retinol in the human prostate
Clinton S.K.; Emenhiser C.; Schwartz S.J.; Bostwick D.G.;
Williams A.W.; Moore B.J.; Erdman J.W. Jr.
Dana-Farber Cancer Institute, Dana Building, 44 Binney
Street, Boston, MA 02115-6084 USA
Cancer Epidemiology Biomarkers and Prevention (USA), 1996,
5/10 (823-833)
An evaluation of the Health Professionals Follow-Up Study
has detected a lower prostate cancer risk associated with the
greater consumption of tomatoes and related food products.
Tomatoes are the primary dietary source of lycopene, a
non-provitamin A carotenoid with potent antioxidant activity.
Our goal was to define the concentrations of lycopene, other
carotenoids, and retinol in paired benign and malignant
prostate tissue from 25 men, ages 53 to 74, undergoing
prostatectomy for localized prostate cancer. The
concentrations of specific carotenoids in the benign and
malignant prostate tissue from the same subject are highly
correlated. Lycopene and all-trans beta-carotene are the
predominant carotenoids observed, with means plus or minus SE
of 0.80 plus or minus 0.08 nmol/g and 0.54 plus or minus 0.09,
respectively. Lycopene concentrations range from 0 to 2.58
nmol/g, and all-trans beta-carotene concentrations range from
0.09 to 1.70 nmol/g. The 9-cis beta-carotene isomer,
alpha-carotene, lutein, alpha-cryptoxanthin, zeaxanthin, and
beta-cryptoxanthin are consistently detectable in prostate
tissue. No significant correlations between the concentration
of lycopene and the concentrations of any other carotenoid are
observed. In contrast, strong correlations between prostate
beta-carotene and alpha-carotene are noted (correlation
coefficient, 0.88; P < 0.0001), as are correlations between
several other carotenoid pairs, which reflects their similar
dietary origins. Mean vitamin A concentration in the prostate
is 1.52 nmol/g, with a range of 0.71 to 3.30 nmol/g. We
further evaluated tomato- based food products, serum, and
prostate tissue for the presence of geometric lycopene isomers
using high-performance liquid chromatography with a polymeric
C30 reversed phase column. All-trans lycopene accounts for 79
to 91% and cis lycopene isomers for 9 to 21% of total lycopene
in tomatoes, tomato paste, and tomato soup. Lycopene
concentrations in the serum of men range between 0.60 and 1.9
nmol/ml, with 27 to 42% all-trans lycopene and 58 to 73%
cis-isomers distributed among 12 to 13 peaks, depending upon
their chromatographic resolution. In striking contrast with
foods, all-trans lycopene accounts for only 12 to 21% and cis
isomers for 79 to 88% of total lycopene in benign or malignant
prostate tissues. cis Isomers of lycopene within the prostate
are distributed among 14 to 18 peaks. We conclude that a
diverse array of carotenoids are found in the human prostate
with significant intra-individual variation. The presence of
lycopene in the prostate at concentrations that are
biologically active in laboratory studies supports the
hypothesis that lycopene may have direct effects within the
prostate and contribute to the reduced prostate cancer risk
associated with the consumption of tomato-based foods. The
future identification and characterization of geometric
lycopene isomers may lead to the development of novel agents
for chemoprevention studies.
How is individual risk for prostate cancer
assessed?
Giovannucci E.
Channing Laboratory, 180 Longwood Avenue, Boston, MA 02115
USA
Hematology/Oncology Clinics of North America (USA), 1996,
10/3 (537-548)
A man's risk of developing prostate cancer is influenced by
both genetic and nongenetic factors. Genetic factors are
particularly important at younger ages, and the attributable
risk of strong genetic factors could be as high as 43% among
men less than 55 years of age; however, only about 9%, of all
cases may be directly attributable to a family history of
prostate cancer. Race appears to be an important determinant
of risk; African-American men are at high risk, whereas men of
oriental ancestry are at lower risk. The bases of these racial
differences remain obscure but may be related to hormonal
differences. Modifiable risk factors are most important from a
public health perspective. Diet or closely related factors
appear to hold the most promise for prevention, although the
precise factors are unknown. The strongest evidence
indicates that some component of animal fat intake appears to
act as a promoter of prostate cancer. Other dietary factors,
including vitamin D, vitamin E, and beta-carotene and
lycopene, may confer protection, but these require more
study. Many but not all studies that have examined long-term
effects of vasectomy suggest that this procedure may increase
risk of prostate cancer, but whether this association is
causal is not established. Occupational factors, smoking, and
physical activity level do not appear to be major determinants
of prostate cancer risk.
A tomato a day for preventing prostate cancer? Diet
may be key
No author listed
Geriatrics (USA), 1996, 51/2 (21)
No abstract.
Intake of carotenoids and retinol in relation to
risk of prostate cancer
Giovannucci E.; Ascherio A.; Rimm E.B.; Stampfer M.J.;
Colditz G.A.; Willett W.C.
Channing Laboratory, 180 Longwood Ave., Boston, MA 02115
USA
Journal of the National Cancer Institute (USA), 1995, 87/23
(1767-1776)
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 conducted 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.
Whatever happened to beta carotene?
Holzman D.
Journal of the National Cancer Institute (USA), 1995, 87/23
(1739-1741)
No abstract.
Vegetable and fruit consumption in relation to
prostate cancer risk in Hawaii: A reevaluation of the effect
of dietary beta-carotene
Le Marchand L.; Hankin J.H.; Kolonel L.N.; Wilkens L.R.
Epidemiology Program, Cancer Research Center of Hawaii,
University of Hawaii, 1236 Lauhala Street, Honolulu, HI 96813
USA
Am. J. Epidemiol. (USA), 1991, 133/3 (215-219)
This is a further analysis of a case-control study of 452
prostate cancer cases and 899 population controls that was
conducted in 1970-1983 among the multiethnic population of
Hawaii. Because a previous analysis had shown a positive
association with intake of beta-carotene, a nutrient presently
being tested for chemoprevention, the authors reexamined the
data for consistency among the main food sources of
beta-carotene. Vegetables and fruits containing other
phytochemicals suspected to be cancer inhibitors were also
examined. With the exception of papaya, which was positively
associated with risk among men aged 70 years and older,
consumption of other yellow-orange fruits and vegetables,
tomatoes, dark green vegetables, and cruciferous vegetables
was not associated with prostate cancer risk. These results
suggest that: 1) the positive association with beta-carotene
intake among older men that the authors previously reported
was essentially due to the greater papaya consumption of cases
compared with controls; and 2) intake of beta-carotene,
lycopene, lutein, indoles, phenols, or other phytochemicals is
not associated with prostate cancer risk.
Serologic precursors of cancer. Retinol,
carotenoids, and tocopherol and risk of prostate cancer
Hsing A.W.; Comstock G.W.; Abbey H.; Polk B.F.
Training Center for Public Health Research, Box 2067,
Hagerstown, MD 21742-2067 USA
J. Natl. Cancer Inst. (USA), 1990, 82/11
(941-946)
We investigated the associations of serum retinol, the
carotenoids beta-carotene and lycopene, and tocopherol
(vitamin E) with the risk of prostate cancer in a nested
case-control study. For the study, serum obtained in 1974 from
25,802 persons in Washington County, MD, was used. Serum
levels of the nutrients in 103 men who developed prostate
cancer during the subsequent 13 years were compared with
levels in 103 control subjects matched for age and race.
Although no significant associations were observed with
beta-carotene, lycopene, or tocopherol, the data suggested an
inverse relationship between serum retinol and risk of
prostate cancer. We analyzed data on the distribution of serum
retinol by quartiles, using the lowest quartile as the
reference value. Odds ratios were 0.67, 0.39, and 0.40 for the
second, third, and highest quartiles, respectively.
Carcinogenicity of oral cadmium in the male Wistar
(WF/NCr) rat: Effect of chronic dietary zinc deficiency
Waalkes M.P.; Rehm S.
Lab. of Comparative Carcinogenesis, NCI-FCRDC, Frederick, MD
21702-1201 USA
Fundam. Appl. Toxicol. (USA), 1992, 19/4
(512-520)
The effect of chronic dietary zinc deficiency on the
carcinogenic potential of dietary cadmium was assessed in male
Wistar (WF/NCr) rats. Groups (n = 28) of rats were fed diets
adequate (60 ppm) or marginally deficient (7 ppm) in zinc and
containing cadmium at various levels (0, 25, 50, 100, or 200
ppm). Lesions were assessed over the following 77 weeks. Zinc
deficiency alone had no effect on survival, growth, or food
consumption. Cadmium treatment did not reduce survival or food
consumption and only at the highest doses of cadmium (100 and
200 ppm) was body weight reduced (maximum 17%). The incidence
of prostatic proliferative lesions, both hyperplasias and
adenomas, was increased over that seen in controls (1.8%) in
both zinc-adequate (20%) and zinc-deficient rats (14%) fed 50
ppm cadmium. The overall incidence for prostatic lesions for
all cadmium treatment groups was, however, much lower in
zinc-deficient rats, possibly because of a marked increase in
prostatic atrophy that was associated with reduced zinc
intake. Cadmium treatment resulted in an elevated leukemia
incidence (maximum 4.8-fold over control) in both
zinc-adequate and zinc-deficient groups, although zinc
deficiency reduced the potency of cadmium in this respect.
Testicular tumors were significantly elevated only in rats
receiving 200 ppm cadmium and diets adequate in zinc. Both
zinc-deficient and zinc-adequate groups showed significant
positive trends for development of testicular neoplasia with
increasing cadmium dosage. Thus, oral cadmium exposure is
clearly associated with tumors of the prostate, testes, and
hematopoietic system in rats, while dietary zinc deficiency
has complex, apparently inhibitory, effects on cadmium
carcinogenesis by this route.
Nutrition and prostate cancer: A case-control
study
Heshmat M.Y.; Kaul L.; Kovi J.; et al.
Department of Community Health and Family Practice, Howard
University College of Medicine, Washington, DC 20059 USA
Prostate (USA), 1985, 6/1 (7-17)
No abstract.
Zinc, vitamin A and prostatic cancer
Whelan P.; Walker B.E.; Kelleher J.
Dep. Urol., St. James's Univ. Hosp., Leeds LS9 7TF United
Kingdom
Br. J. Urol. (England), 1983, 55/5 (525-528)
The serum zinc, vitamin A, albumin, copper and
retinoid-binding protein content was measured in 27 patients
with benign prostatic hyperplasia and 19 patients with
carcinoma of the prostate. A significantly lower (P = <
0.05) level of serum zinc was found in the cancer group as
well as a significant zinc/vitamin A correlation (P = <
0.05). The possible significance of this in relation to the
pathogenesis of carcinoma of the prostate is discussed.
Influence of isoflavones in soy protein isolates on
development of induced prostate-related cancers in L-W
rats
Pollard M.; Luckert P.H.
M. Pollard, Lobund Lab, University of Notre Dame, Notre Dame,
IN 46556 USA
Nutrition and Cancer (USA), 1997, 28/1 (41-45)
Lobund-Wistar (L-W) rats are inherently susceptible to
spontaneous and induced metastasizing adenocarcinomas in the
prostate-seminal vesicle (P-SV) complex. L-W rats were fed soy
protein isolates containing high isoflavones (genistein and
daidzein) or low isoflavones to determine their effects on
development of induced P-SV tumors in two stages of the
tumorigenic process. In rats fed the
high-isoflavone-supplemented soy diet before initiation by
methylnitrosourea (MNU), the incidence of induced
prostate-related cancer was reduced and the disease-free
period was prolonged by 27% compared with rats fed the same
diet but low in isoflavones. Rats fed the same diets, started
after MNU, manifested suggestive but less consistent results
than those noted above. The incidence rates were of marginal
significance, suggesting that the high intensity of the active
induced disease may not represent the character of the
slower-growing spontaneous (natural) disease. The delay of
disease onset is of clinical significance.
Peptide growth factors: Clinical and therapeutic
strategies
Di Silverio F.; Sciarra A.; Di Nicola S.; Di Chiro C.
F. Di Silverio, Dipartimento 'U. Bracci', Universita 'La
Sapienza', Viale del Policlinico, 00161 Roma Italy
Minerva Urologica e Nefrologica (Italy), 1997, 49/2
(63-72)
The literature contains many accounts of studies in which
tumour growth has been accelerated by administration of a
particular mitogen and the response then inhibited by
co-administration of the corresponding antagonist. Much effort
has been focused on the development of cytokine or growth
factor antagonists. Like most other cancer therapies,
biological therapies will undoubtedly have undesirable
toxicities because the proteins they target may not be unique
to malignant cells. We received the clinical and therapeutic
potential of growth factor agonists and antagonists in some
non urologic and urologic diseases. In a recent report we
demonstrated that both androgen and antiandrogen treatments
enhance the proliferation rate of the hormone-dependent
prostate cancer cell line LNCaP, expressing a mutated androgen
receptor. Simultaneous treatment with 1 nM R1881 and 100 nM
OH-Flutamide, completely counteracted the androgen-induced
increase of Epidermal Growth Factor (EGF) levels. Moreover we
found that Testosterone, DHT and EGF are mainly concentrated
in the periurethral zone in human BPH and long term treatment
with Finasteride and with Flutamide modify the distribution
and concentration of these factors. Some authors analyzed
whether the addition of aurin tricarboxylic acid (ATA) can
reduce the growth rate of basic FGF-dependent cells in a
manner similar to suramin.
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