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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. Aappl 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.
Cancer risk factors for selecting cohorts for
large-scale chemoprevention trials
Greenwald P.
Dr. P. Greenwald, Dept. of Health and Human Services,
National Institutes of Health, National Cancer Institute,
Bethesda, MD 20892 USA
Journal of Cellular Biochemistry (USA), 1996, 63/SUPPL. 25
(29-36)
Many anticipate that application of findings in molecular
genetics will help to achieve greater precision in defining
high-risk populations that may benefit from chemopreventive
interventions. We must recognize, however, that genetic
susceptibility, environmental factors, and complex
gene-environment interactions are all likely to be risk
determinants for most cancers. Cohort studies of twins and
cancer indicate that having 'identical' genes is generally not
a very accurate predictor of cancer incidence. Data from twin
studies support the suggestion that environmental factors such
as tobacco use significantly influence cancer risk. The
complexities of the genetic contribution to disease risk are
exemplified by the development of Duchenne muscular dystrophy
in only one of monozygotic twin girls, hypothesized to be the
result of X chromosome inactivation, with the distribution
patterns of the X chromosome being skewed to the female X in
the manifesting twin and to the male X in the normal twin.
Evidence from transgenic and genetic- environmental studies in
animals support the possibility of genetic- environmental
interactions. Calorie restriction modifies tumor expression in
p53 knockout mice; a high-fat, low-calcium, low-vitamin D diet
increases prepolyphyperplasia formation in Apc-mutated mice;
and calorie restriction early in life influences development
of obesity in the genetically obese Zucker rat (fata). Such
environmental modulation of gene expression suggests that
chemoprevention has the potential to reduce risk for both
environmentally and genetically determined cancers. In view of
the growing research efforts in chemoprevention, the NCl has
developed a Prevention Trials Decision Network (PTDN) to
formalize the evaluation and approval process for large scale
chemoprevention trials. The PTDN addresses large trial
prioritization and the associated issues of minority
recruitment and retention; identification and validation of
biomarkers as intermediate endpoints for cancer; and
chemopreventive agent selection and development. A
comprehensive database is being established to support the
PTDN's decision making process and will help to determine
which agents investigated in preclinical and early phase
clinical trials should move to large-scale testing. Cohorts
for large-scale chemoprevention trials include individuals who
are determined to be at high risk as a result of genetic
predisposition, carcinogenic exposure, or the presence of
biomarkers indicative of increased risk. Current large scale
trials in well-defined, high-risk populations include the
Breast Cancer Prevention Trial (tamoxifen), the Prostate
Cancer Prevention Trial (finasteride), and the
N-(4-hydroxyphenyl) retinamide (4- HPR) breast cancer
prevention study being conducted in Milan. Biomarker studies
will provide valuable information for refining the design and
facilitating the implementation of future large-scale trials.
For example, potential biomarkers are being assessed at biopsy
in women with ductal carcinoma in situ (DCIS). The women are
then randomized to either placebo, tamoxifen, 4-HPR, or
tamoxifen plus 4-HPR for 2-4 weeks, at which time surgery is
performed and the biomarkers reassessed to determine biomarker
modulation by the interventions. For prostate cancer,
modulation of prostatic intraepithelial neoplasia (PIN) by
4-HPR and difluoromethylornithine is being investigated;
similar studies are being planned for oltipraz,
dehydroepiandrosterone, and vitamin E plus selenomethionine.
The validation of biomarkers as surrogate endpoints for cancer
incidence in high-risk cohorts will allow more agents to be
evaluated in shorter studies that use fewer subjects to
achieve the desired statistical power.
Inhibition of liposomal lipid peroxidation by
isoflavonoid type phyto-oestrogens from soybeans of different
countries of origin
Wiseman H.; Lim P.; O'Reilly J.
Department Nutrition and Dietetics, King's College London,
Campden Hill Road, London W8 7AH United Kingdom
Biochemical Society Transactions (United Kingdom), 1996, 24/3
(392S)
No abstract.
Phytoestrogens: Epidemiology and a possible role in
cancer protection
Adlercreutz H.
Department of Clinical Chemistry, University of Helsinki,
Meilahti Hospital, FIN-00290 Helsinki Finland
Environmental Health Perspectives (USA), 1995, 103/SUPPL. 7
(103-112)
Because many diseases of the Western Hemisphere are
hormone-dependent cancers, we have postulated that the Western
diet, compared to a vegetarian or semivegetarian diet, may
alter hormone production, metabolism or action at the cellular
level by some biochemical mechanisms. Recently, our interest
has been mainly focused on the cancer-protective role of some
hormonelike diphenolic phytoestrogens of dietary origin, the
lignans and the isoflavonoids. The precursors of the
biologically active compounds originate in soybean products
(mainly isoflavonoids), whole grain cereal food, seeds, and
probably berries and nuts (mainly lignans). The plant lignan
and isoflavonoid glycosides are converted by intestinal
bacteria to hormonelike compounds with weak estrogenic but
also antioxidative activity; they have now been shown to
influence not only sex hormone metabolism and biological
activity but also intracellular enzymes, protein synthesis,
growth factor action, malignant cell proliferation,
differentiation, and angiogenesis in a way that makes them
strong candidates for a role as natural cancer-protective
compounds. Epidemiologic investigations strongly support this
hypothesis because the highest levels of these compounds in
the diet are found in countries or regions with low cancer
incidence. This report is a review on recent results
suggesting that the diphenolic, isoflavonoids and lignans are
natural cancer-protective compounds.
Differential sensitivity of human prostatic cancer
cell lines to the effects of protein kinase and phosphatase
inhibitors
Rokhlin O.W.; Cohen M.B.
University of Iowa, Department of Pathology, 118 ML, Iowa
City, IA 52242 USA
Cancer Letters (Ireland), 1995, 98/1 (103-110)
We investigated the effect of protein kinase and
phosphatase inhibitors on the growth of six human prostatic
cancer cell lines: DU145, PC3, ND1, LNCaP, ALVA31 and JCA1. We
studied okadaic acid and sodium orthovanadate as
serine/threonine and tyrosine protein phosphatase inhibitors,
respectively, and staurosporin and genistein as a
serine/threonine and tyrosine protein kinase inhibitors,
respectively. All inhibitors examined exhibited a
dose-dependent growth inhibitory effect on prostatic cancer
cell lines. Our data indicate that prostatic cancer cell lines
express unique biochemical properties since the degree of
growth inhibition varied greatly and was dependent on the
specific cell line and inhibitor studied. In addition, we
found that surface expression of endoglin (CD105) changed by
treatment with all inhibitors in most of the cell lines. These
data also indicate that endoglin appears to be involved both
in protein phosphatase and kinase mediated phosphoprotein
turnover.
Genetic damage and the inhibition of
7,12-dimethylbenz(a)anthracene-induced genetic damage by the
phytoestrogens, genistein and daidzein, in female ICR
mice
Giri A.K.; Lu L.-J.W.
Dept. Prevent. Med. Community Hlth., University of Texas
Medical Branch, 700 Strand, Galveston, TX 77555-1110 USA
Cancer Letters (Ireland), 1995, 95/1-2 (125-133)
Populations consuming soybeans have reduced rates of
breast, colon and prostate cancer possibly due, in part, to
the presence in soybeans of two estrogenic isoflavones,
genistein and daidzein. This study investigated the
genotoxicity of these soya isoflavones and their interactions
with 7,12-dimethylbenz(a)anthracene (DMBA)-induced sister
chromatid exchanges (SCE) in bone marrow cells and DNA adduct
formations in liver and mammary glands of mice. Groups of
female ICR mice were pretreated i.p. with daidzein and/or
genistein (10-20 mg/kg per day for 6 days or 50 mg/kg per 12 h
for 3 days) or with the solvent, dimethylsulfoxide (DMSO). The
mice were implanted with bromodeoxyuridine (BrdU) tablets
s.c., and treated with DMBA (50 mg/kg) i.p. and colchicine (4
mg/kg) i.p. 24, 23, and 2 h before sacrifice, respectively. In
bone marrow cells, DMBA alone induced 11.73 plus or minus 1.42
SCE/cell compared to 4.35 plus or minus 0.83 SCE/cell in the
DMSO treated controls (P = 0.001). DMBA induced 20% fewer SCE
(P < 0.05) in mice pretreated with daidzein, genistein or a
combination of genistein and daidzein (6 x 20 mg/kg per day
for 6 days) when compared to mice that received no
pretreatments. Genistein at 50 mg/kg per 12 h for 3 days also
inhibited DMBA-induced SCE by 20%. However, treatment for 3
days with 50 mg/kg per 12 h of genistein or daidzein alone, or
a combination of daidzein plus genistein (without DMBA
treatment) also induced more SCE than treatment with only the
solvent (DMSO, P < 0.05). Pretreatment with both the low
and the high doses of daidzein plus genistein or the high dose
of genistein reduced the replication index of bone marrow
cells when compared to pretreatment with DMSO (P < 0.05).
Pretreatment with genistein reduced DMBA-induced DNA adduct
formation by 34%, but this was only marginally significant (P
= 0.08) due to the large inter-individual variability in
adduct levels. These results show that genistein and daidzein
suppress SCE and possibly DNA adduct formation induced by the
known carcinogen, DMBA. This response to a low dose isoflavone
exposure may be partly responsible for the protective effect
against endocrine cancers of soya consumption.
Rationale for the use of genistein-containing soy
matrices in chemoprevention trials for breast and prostate
cancer
Barnes S.; Peterson T.G.; Coward L.
Department of Pharmacology, Birmingham Medical Center,
University of Alabama, 1670 University Boulevard, Birmingham,
AL 35294-0019 USA
Journal of Cellular Biochemistry (USA), 1995, 58/SUPPL. 22
(181-187)
Pharmacologists have realized that tyrosine kinase
inhibitors (TKI) have potential as anti-cancer agents, both in
prevention and therapy protocols. Nonetheless, concern about
the risk of toxicity caused by synthetic TKIs restricted their
development as chemoprevention agents. However, a naturally
occurring TKI (the isoflavone genistein) in soy was discovered
in 1987. The concentration of genistein in most soy food
materials ranges from 1-2 mg/g. Oriental populations, who have
low rates of breast and prostate cancer, consume 20-80 mg of
genistein/day, almost entirely derived from soy, whereas the
dietary intake of genistein in the US is only 1-3 mg/day.
Chronic use of genistein as a chemopreventive agent has an
advantage over synthetic TKIs because it is naturally found in
soy foods. It could be delivered either in a purified state as
a pill (to high-risk, motivated patient groups), or in the
form of soy foods or soy-containing foods. Delivery of
genistein in soy foods is more economically viable ($1.50 for
a daily dose of 50 mg) than purified material ($5/day) and
would require no prior approval by the FDA. Accordingly,
investigators at several different sites have begun or are
planning chemoprevention trials using a soy beverage product
based on SUPRO(TM), an isolated soy protein manufactured by
Protein Technologies International of St. Louis, MO. These
investigators are examining the effect of the soy beverage on
surrogate intermediate endpoint biomarkers (SIEBs) in patients
at risk for breast and colon cancer, defining potential SIEBs
in patients at risk for prostate cancer, and determining
whether the soy beverage reduces the incidence of cancer
recurrence. These studies will provide the basis for formal
Phase I, Phase II and Phase III clinical trials of genistein
and soy food products such as SUPRO(TM) for cancer
chemoprevention.
A simplified method to quantify isoflavones in
commercial soybean diets and human urine after legume
consumption
Lu L.-J.W.; Broemeling L.D.; Marshall M.V.; Ramanujam
V.M.S.
Prevent. Med./Community Health Dept., 2.102 Ewing Hall,
University of Texas, 700 Strand, Galveston, TX 77555-1110
USA
Cancer Epidemiology Biomarkers and Prevention (USA), 1995,
4/5 (497-503)
Reliable and economical quantification of micronutrients in
diets and humans is a critical component of successful
epidemiological studies to establish relationships between
dietary constituents and chronic disease. Legumes are one of
the major dietary components consumed by populations
worldwide. Consumption of legumes is thought to play a major
role in lowering breast and prostate cancer risk. In this
study, a simplified method that uses solid-phase extraction
and gas chromatography was developed to measure isoflavones at
levels down to 10 microg/5 ml. With the use of this method,
12.5 g miso (a soybean paste), 12 ounces Isomil, and 12 ounces
soymilk had daidzin/daidzein levels of 2, 5, and 12.4 mg,
respectively, and genistin/genistein levels of 3, 6.5, and
13.7 mg, respectively. In these products, most of the
isoflavones were present as glucosides. With the same method,
urinary levels of isoflavones in six 15-17-year-old subjects
were determined after soymilk ingestion. Each subject was
placed on unrestricted nonsoya diets, and three 12-ounce
portions of soymilk were given at 12-h intervals. Males
excreted 15.02 plus or minus 2.74 (SD) mg of daidzein
glucuronides/sulfates (mean recovery, 40.4 plus or minus 7.4%
(SD)) by 24 h after the third soymilk ingestion, whereas
females excreted 25.56 plus or minus 5.10 mg (68.7 plus or
minus 13.7%) of daidzein conjugates, which was more than males
(P = 0.02). Males and females excreted 7.73 plus or minus 1.95
mg and 9.11 plus or minus 0.84 mg of genistein
glucuronides/sulfates (20% recovery of genistin intake),
respectively, in the urine. Most of the isoflavones were
excreted within 24 h after ingestion. The relative urinary
levels of daidzein to genistein excreted were significantly (P
< 0.05) higher in females than males after the third
ingestion. The observed sex difference requires more study
since two of the females are siblings. Thus, the method
described can be used to measure isoflavones in soya products
and urinary excretion after soya ingestion.
Rapid HPLC analysis of dietary phytoestrogens from
legumes and from human urine
Franke A.A.; Custer L.J.; Cerna C.M.; Narala K.
Molecular Carcinogenesis Program, Cancer Research Center of
Hawaii, 1236 Lauhala Street, Honolulu, HI 96813 USA
Proc. Soc. Exp. Biol. Med. (USA), 1995, 208/1
(18-26)
Due to growing evidence suggesting that phytoestrogens
might protect against various cancers, particularly against
breast and prostate cancer, it is important to measure the
exposure of populations to these compounds by determining
levels in food and in human tissue or body fluids to assess
the possible cancer protective properties of these agents.
Therefore, we developed a simple and fast procedure to extract
and simultaneously hydrolyze phytoestrogens and their
conjugates from food items, and present a fast and selective
high-performance liquid chromatography (HPLC) method for
precise determinations of the most common dietary
phytoestrogens genistein, biochanin-A, daidzein, formononetin,
and coumestrol using flavone as internal standard. For the
first time HPLC was applied to measure these phytoestrogens
and their most abundant metabolites equol and
O-desmethyl-angotensin from human urine. The proposed
methodology has been evaluated for losses due to thermal
degradation during extraction and hydrolysis and due to sample
handling during the entire work-up including solid phase
extraction, and values are given for inter- and intra-assay
variability. We present isoflavonoid levels of most common
peas and beans used in 'western' and 'eastern' diets and
compare isoflavonoid and coumestrol levels of raw, canned, and
cooked foods which can be used in future epidemiological
studies. We also determined human urinary levels with our
methodology comparing values before and after soybean
intake.
Soy intake and cancer risk: A review of the in
vitro and in vivo data
Messina M.J.; Persky V.; Setchell K.D.R.; Barnes S.
Epidemiology/Biostatistics Program, School of Public Health,
University of Illinois, Chicago, IL 60680 USA
Nutr. Cancer (USA), 1994, 21/2 (113-131)
International variations in cancer rates have been
attributed, at least in part, to differences in dietary
intake. Recently, it has been suggested that consumption of
soyfoods may contribute to the relatively low rates of breast,
colon, and prostate cancers in countries such as China and
Japan. Soybeans contain a number of anticarcinogens, and a
recent National Cancer Institute workshop recommended that the
role of soyfoods in cancer prevention be investigated. In this
review, the hypothesis that soy intake reduces cancer risk is
considered by examining relevant in vitro, animal, and
epidemiological data. Soybeans are a unique dietary source of
the isoflavone genistein, which possesses weak estrogenic
activity and has been shown to act in animal models as an
antiestrogen. Genistein is also a specific inhibitor of
protein tyrosine kinases; it also inhibits DNA topoisomerases
and other critical enzymes involved in signal transduction. In
vitro, genistein suppresses the growth of a wide range of
cancer cells, with IC50 values ranging from 5 to 40 microM
(1-10 microg/ml). Of the 26 animal studies of experimental
carcinogenesis in which diets containing soy or soybean
isoflavones were employed, 17 (65%) reported protective
effects. No studies reported soy intake increased tumor
development. The epidemiological data are also inconsistent,
although consumption of nonfermented soy products, such as
soymilk and tofu, tended to be either protective or not
associated with cancer risk; however, no consistent pattern
was evident with the fermented soy products, such as miso.
Protective effects were observed for both hormone- and
nonhormone-related cancers. While a definitive statement that
soy reduces cancer risk cannot be made at this time, there is
sufficient evidence of a protective effect to warrant
continued investigation.
Plasma concentrations of phyto-oestrogens in
Japanese men
Adlercreutz H.; Markkanen H.; Watanabe S.
Department of Clinical Chemistry, University of Helsinki,
Mellahti Hospital, SF-00290 Helsinki Finland
Lancet (United Kingdom), 1993, 342/8881
(1209-1210)
A low mortality from prostatic cancer is found in Japanese
men consuming a low-fat diet with high content of soy
products, a rich source of isoflavonoids. We therefore assayed
four isoflavonoids in plasma of 14 Japanese and 14 Finnish
men. The geometric mean plasma total individual isoflavonoid
levels were 7 to 110 times higher in the Japanese than in the
Finnish men. Genistein, a tyrosine kinase inhibitor, occurred
in the highest concentration (geometric mean 276 nmol/L). We
hypothesise that these high phyto-oestrogen levels may inhibit
the growth of prostatic cancer in Japanese men, which may
explain the low mortality from prostatic cancer in that
country.
Genistein is an effective stimulator of sex
hormone-binding globulin production in hepatocarcinoma human
liver cancer cells and suppresses proliferation of these cells
in culture
Mousavi Y.; Adlercreutz H.
Department of Clinical Chemistry, University of Helsinki,
Meilahti Hospital, SF-00290 Helsinki Finland
Steroids (USA), 1993, 58/7 (301-304)
Studies have indicated a correlation between a high level
of urinary lignans and isoflavonoid phytoestrogens,
particularly genistein, and a low incidence of
hormone-dependent cancers, such as breast and prostate cancer.
Previously it has been observed that a vegetarian diet is
associated with high plasma levels of sex hormone-binding
globulin (SHBG), reducing clearance of sex hormones and
probably risk of breast and prostate cancer. In the present
study we investigated the in vitro effect of genistein on the
production of SHBG by human hepatocarcinoma (Hep-G2) cells in
culture and its effect on cell proliferation. We found that
genistein not only highly significantly increases the SHBG
production by Hep-G2 cells, but also suppresses the
proliferation of these cancer cells already at a stage when
SHBG production continues to be high. We conclude that, in
addition to the lignan enterolactone, the most abundant
urinary isoflavonoid genistein stimulates SHBG production and
inhibits Hep-G2 cancer cell proliferation.
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 Pharmacology, University of Alabama,
Birmingham, AL 35294-0019 USA
Prostate (USA), 1993, 22/4 (335-345)
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 microg/ml for serum and 4.3 to 15 microg/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.
Surrogate endpoint biomarkers for phase II cancer
chemoprevention trials
Kelloff G.J.; Boone C.W.; Crowell J.A.; Steele V.E.; Lubet
R.; Doody L.A.
Chemoprevention Investigat. Studies, Div. of Cancer
Prevention/Control, National Cancer Institute, NIH, Bethesda,
MD 20892 USA
J. Cell. Biochem. (USA), 1994, 56/SUPPL. 19
(1-9)
Three critical aspects govern successful Phase II cancer
chemoprevention trials - well-characterized agents, suitable
cohorts, and reliable intermediate biomarkers for measuring
efficacy. Requirements for the agent are experimental or
epidemiological data showing chemopreventive efficacy, safety
on chronic administration, and a mechanistic rationale for the
chemopreventive activity observed. The cohort should be
suitable for measuring the chemopreventive activity of the
agent and the intermediate biomarkers chosen. Also, many
cohorts proposed for Phase II trials are patients with
previous cancers or premalignant lesions. For such patients,
the trials should be conducted within the context of standard
treatment to avoid unusual risks. The criteria for biomarkers
are that they fit expected biological mechanisms (i.e.,
differential expression in normal and high-risk tissue, on or
closely linked to the causal pathway for the cancer, modulated
by chemopreventive agents, and short latency compared with
cancer), may be assayed reliably and quantitatively, measured
easily, and correlate to decreased cancer incidence. They must
occur in sufficient incidence to allow their biological and
statistical evaluation relevant to cancer. Since
carcinogenesis is a multipath process, single biomarkers are
difficult to validate as surrogate endpoints, as they may
appear on only one or a few of the many possible causal
pathways. Panels of biomarkers, particularly those
representing the range of carcinogenesis pathways, may prove
more useful as surrogate endpoints. It is important to avoid
relying solely on biomarkers representing isolated events that
may or may not be on the causal pathway or otherwise
associated with carcinogenesis. These include markers of
normal cellular processes that may be increased or expressed
during carcinogenesis, but are nonspecific. Chemoprevention
trials should be designed to fully evaluate the two or three
biomarkers that appear to be the best models of the cancer.
Additional biomarkers should be considered only if they can be
analyzed efficiently and the sample size allows the more
important biomarkers to be evaluated completely. Two types of
biomarkers that stand out in regard to their high correlation
to cancer and their ability to be quantified are measures of
intraepithelial neoplasia and indicators of cellular
proliferation. Measurements made by computer-assisted image
analysis that are potentially useful as surrogate endpoint
biomarkers include nuclear pleomorphism comprising nuclear
size, shape (roundness), and texture (DNA distribution
patterns); nucleolar size and number of nucleoli/nucleus; DNA
ploidy; and proliferation biomarkers such as S-phase fraction,
bromodeoxyuridine uptake, Ki-67, and proliferating cell
nuclear antigen. Phase II chemoprevention trials are currently
in progress or planned that will evaluate these biomarkers.
The cohorts include patients scheduled for surgery for ductal
carcinoma in situ in breast or early breast cancer, patients
with previously resected colon tumors or adenomas, patients
with prostatic intraepithelial neoplasia, and patients
scheduled for prostate cancer surgery.
The 16-ene vitamin D analogs
Uskokovic M.R.; Studzinski G.P.; Gardner J.P.; Reddy S.G.;
Campbell M.J.; Koeffler H.P.
M.R. Uskokovic, Hoffmann-La Roche, Inc., Nutley, NJ 07110
USA
Current Pharmaceutical Design (Netherlands), 1997, 3/1
(99-123)
Numerous 16-ene vitamin D analogs were investigated as
potential anticancer agents. Several structural modifications
have been uncovered that contribute to the improvement in the
stimulation of HL-60 cells differentiation, the inhibition of
HL-60 cells proliferation and the reduction of calcemic
properties in vivo. They include the introduction of 16-,
22E-, 23E- and 23Z-double bonds, 23-triple bond or 22R-allene,
and substitution of C26 and C27-hydrogens with fluorine or
methyl groups. The biggest gains have been achieved by
combination of the 16-double bond with 23-double or triple
bond and 26-trifluoro or 26,27-hexafluoro substitution
patterns. Separately, the combination of the 16-double bond
with 22R-allene has produced a highly active analog. In
respect to modifications in the ring A, the high activities in
cell differentiation and inhibition of cell proliferation with
significant reduction of calcemic properties were observed in
the 1alpha-fluoro, 3-desoxy, and 19-nor series. It was also
shown that the lack of the 1alpha-hydroxy group can be
overcome by an optimized modification in the ring D and the
side chain; 25(OH)-16,23E-diene-26,27-F6D3 is fully active in
HL-60 cell differentiation assay with only mimimal effects on
the cellular calcium homeostasis.
Signal transduction inhibitors as modifiers of
radiation therapy in human prostate carcinoma xenografts
Teicher B.A.; Bump E.A.; Palayoor S.; Northey D.; Coleman
C.N.
USA
Radiation Oncology Investigations (USA), 1996, 4/5
(221-230)
Radiation therapy is very useful in the treatment of
prostate cancer; however, local treatment failure still occurs
in the majority of patients with locally advanced disease. The
growth and progression of tumors involve signaling through
protein growth factors and small molecules such as arachidonic
acid cascade products. In order to develop novel agents to
enhance the efficacy of radiation therapy for patients with
prostate cancer, the ability of signal transduction inhibitors
including (1) the antiandrogen, flutamide; (2) the
anti-inflammatory agent, ibuprofen; (3) the growth factor
receptor antagonist, suramin; (4) the retinoid,
all-trans-retinoic acid; and (5) the calcium pump inhibitor,
thapsigargin to enhance the response of the human prostate
carcinoma xenografts DU-145 and LN-CaP, was assessed.
Flutamide acted as a radiation protector of the androgen
independent DU-145 tumor but produced an additive antitumor
effect in combination with fractionated radiation therapy in
the androgen dependent LNCaP tumor. Administration of suramin
or thapsigargin along with radiation therapy provided little
or no tumor growth delay compared with radiation therapy
alone. Treatment with all-trans-retinoic acid did not alter
the response of the DU-145 to radiation therapy but increased
the response of LNCaP tumor to radiation therapy.
Administration of ibuprofen along with radiation therapy was
most effective. The radiation dose modifying factor for
ibuprofen in the DU-145 tumor was 1.8 and 1.7 for a 1-week and
a 2-week fractionated regimen, respectively. Administration of
ibuprofen along with radiation therapy to animals bearing the
LNCaP tumor resulted in a 2-fold increase in tumor growth
delay compared with radiation therapy alone. Further
investigation of inhibitors of the arachidonic acid cascade as
radiation modifiers is warranted.
Calcium regulation of androgen receptor expression
in the human prostate cancer cell line LNCaP
Gong Y.; Blok L.J.; Perry J.E.; Lindzey J.K.; Tindall
D.J.
Department of Urology Research, Mayo Clinic and Foundation,
200 First Street SW, Rochester, MN 55905 USA
Endocrinology (USA), 1995, 136/5 (2172-2178)
Elevation of intracellular calcium levels in the presence
of normal androgen levels has been implicated in apoptotic
prostate cell death. Since the androgen receptor (AR) plays a
critical role in the regulation of growth and differentiation
of the prostate, it was of interest to determine whether Ca2+
would affect the expression of androgen receptor messenger RNA
(mRNA) and protein, thus affecting the ability of androgens to
control prostate function. AR-positive human prostate cancer
cells, LNCaP, were incubated with either the calcium ionophore
A23187 or the intracellular endoplasmic reticulum Ca2+-ATPase
inhibitor thapsigargin. Subsequently, AR mRNA and protein
levels were assessed by Northern and Western blot analysis.
Both A23187 and thapsigargin were found to down-regulate
steady state AR mRNA levels in a time- and dose-dependent
manner. AR mRNA began to decrease after 6-8 h of incubation
with 10-6 M A23187 or 10-7 M thapsigargin, reaching a nadir at
16 and 10 h of incubation, respectively. In contrast, control
mRNA (glyceraldehyde 3-phosphate dehydrogenase) did not change
significantly during the treatments with either A23187 or
thapsigargin. AR protein levels were found to be decreased
after 12 h of incubation with either 10-6 M A23187 or 10-7 M
thapsigargin. The decrease in AR mRNA and protein seemed to
precede apoptosis, since neither A23187 (24 h) nor
thapsigargin (30 h) was found to alter cell morphology within
the treatment time. Cycloheximide and actinomycin D were
unable to change the calcium-mediated decrease in AR mRNA,
ruling out the necessity for de novo protein synthesis or a
change in mRNA stability. Moreover, the decrease in AR mRNA
induced by calcium does not seem to involve protein kinase C-
or calmodulin-dependent pathways, since inhibitors of these
cellular components had no effect. Nuclear run-on assays
demonstrated little or no effects of either A23187 or
thapsigargin treatment on AR gene transcription (8 h and 10
h). In conclusion, these studies show that intracellular
calcium seems to be a potent regulator of AR gene expression
in LNCaP cells.
The role of calcium, pH, and cell proliferation in
the programmed (apoptotic) death of androgen-independent
prostatic cancer cells induced by thapsigarin
Furuya Y.; Lundmo P.; Short A.D.; Gill D.L.; Isaacs
J.T.
Johns Hopkins Oncology Center, 422 N. Bond Street, Baltimore,
MD 21231 USA
Cancer Res. (USA), 1994, 54/23 (6167-6175)
Calcium (Ca2+) accumulates within the endoplasmic reticulum
of cells through function of the sarcoplasmic reticulum and
endoplasmic reticulum Ca2+-dependent ATPase family of
intracellular Ca2+-pumping ATPases. The resulting pools have
important signaling functions. Thapsigargin (TG) is a
sesquiterpene gamma-lactone which selectively inhibits the
sarcoplasmic reticulum and endoplasmic reticulum
Ca2+-dependent ATPase pumps with a 50% inhibitory
concentration of approximately 30 microM. Treatment of
androgen- independent prostate cancer cells of both rat and
human origin with TG inhibits their endoplasmic reticulum
Ca2+-dependent ATPase activity, resulting in a 3-4-fold
elevation in the level of intracellular free Ca2+ (Ca(i))
within minutes of exposure. Due to a secondary influx of
extracellular Ca2+, this increase in Ca(i) is sustained,
resulting in morphological (cell rounding) and biochemical
changes within 6-12 h (enhanced calmodulin, glucose regulated
protein, and tissue transglutaminase expression, and decreased
expression of the G(i) cyclins). Within 24 h of exposure,
androgen-independent prostatic cancer cells stop progression
through the cell cycle, arrest out of cycle in G0, and
irreversibly lose their ability to proliferate with a median
effective concentration value of 31 nM TG. During the next
24-48 h, the genomic DNA of the G0-arrested cells undergoes
double-strand fragmentation. This is followed by the loss of
plasma membrane integrity and fragmentation of the cell into
apoptotic bodies. During this process, there is no
acidification in the intracellular pH. Using cells transfected
with the avian M(r) 28,000 calbindin D Ca2+-buffering protein,
it was demonstrated that the programmed death initiated by TG
is critically dependent upon an adequate (i.e., 3-4-fold)
sustained (>1 h) elevation in Ca(i) and not depletion of
the endoplasmic reticulum pools of Ca2+. These results
demonstrate that TG induces programmed cell in
androgen-independent prostatic cancer cells in a
dose-dependent manner and that this death does not require
proliferation or intracellular acidification but is critically
dependent upon an adequate, sustained (i.e., >1 h)
elevation in Ca(i).
Programmed cell death as a new target for prostatic
cancer therapy
Kyprianou N.; Martikainen P.; Davis L.; English H.F.; Isaacs
J.T.
Johns Hopkins Oncology Center, Baltimore, MD 21205 USA
Cancer Surv. (USA), 1991, 11/- (265-277)
To increase survival of men with metastatic prostatic
cancer, a modality that can effectively eliminate androgen
independent cancer cells is desperately needed. By combining
such an effective modality with androgen ablation, all of the
heterogeneous populations of tumour cells within a prostatic
cancer patient can be affected, thus optimizing the chances of
cure. Unfortunately, such effective therapy for the androgen
independent prostatic cancer cell is not yet available. This
therapy will probably require two types of agents, one having
antiproliferative activity affecting the small number of
dividing androgen independent cells, and the other able to
increase the low rate of cell death among the majority of non-
proliferating (ie interphase) androgen independent prostatic
cancer cells present. Androgen dependent prostatic epithelial
cells can be made to undergo programmed death by means of
androgen ablation, even if the cells are not in the
proliferative cell cycle. Androgen independent prostatic
cancer cells retain the major portion of this programmed cell
death pathway, only there is a defect in the pathway such that
it is no longer activated by androgen ablation. If the
intracellular free Ca2+ is sustained at an elevated level for
a sufficient time, androgen independent cells can be induced
to undergo programmed death. The long term goal is therefore
to develop some type of non-androgen ablative method that can
be used in vivo to induce a sustained elevation in Ca2+ in
androgen independent prostatic cancer cells. To accomplish
this task, a more complete understanding of the biochemical
pathways involved in programmed cell death is urgently needed.
At present, studies are focusing on the mechanism involved in
the Ca2+ elevation in the normal and malignant androgen
dependent cell induced following androgen ablation and the
role of the TRPM-2 protein in this process.
Hyperparathyroidism in metastases of prostatic
carcinoma: A biochemical, hormonal and histomorphometric
study
Rico H.; Uson A.; Hernandez E.R.; Prados P.; Paramo P.;
Cabranes J.A.
Department of Medicine, Medical School, University of Alcala
de Henares, E-28871 Madrid Spain
Eur. Urol. (Switzerland), 1990, 17/1 (35-39)
Secondary hyperparathyroidism can develop as a result of
bone metastases from prostatic cancer, but this has not been
studied from the multiple aspects of biochemistry, hormonal
status and histomorphometry. In 20 patients with stage-D
prostatic cancer, a transiliac bone biopsy was performed for
histomorphometric study. In all of them, molecular
parathormone (PTH-M) and osteocalcin were determined by
radioimmunoassay together with other parameters considered to
be biological markers of bone remodelling. Of these 20
patients, only 2 (10%) had elevated PTH-M (240 plus or minus
20.6 pmol/l), differing significantly from the other 18 (58.6
plus or minus 11.7 pmol/l) and from controls (60.4 plus or
minus 7.2 pmol/l). In the high PTH-M patients, corrected
calcium was low (7.8 plus or minus 0.4 mg/dl) as compared to
normal PTH-M patients (9.2 plus or minus 0.5 mg/dl, p <
0.001), and this was also the case for serum phosphorus (2.2
plus or minus 0.6 vs. 3.2 plus or minus 0.3 and 3.4 plus or
minus 0.4 mg/dl, respectively p < 0.001). Alkaline
phosphatase was raised in the patient groups as compared to
controls (p < 0.001) and was higher in the high PTH-M group
(362 plus or minus 58 vs. 224 plus or minus 62 U/l, p <
0.001). The same pattern of higher values in the
hyperparathyroid patients was repeated for: hydroxyproline/Cr
in fasting urine (3.6 plus or minus 0.2 vs. 2.1 plus or minus
0.4 mg/mg, p < 0.001); Ca/Cr in fasting urine (0.08 plus or
minus 0.02 vs. 0.007 plus or minus 0.01 mg/mg, p < 0.001,
decreased in both patient groups but more so in the high PTH-M
group), and for the 24-hour urinary calcium (128 plus or minus
22 vs. 86 plus or minus 11 mg, p < 0.001) which was only
reduced (p < 0.001) in normals. Serum osteocalcin, although
raised in both groups, did not differ significantly between
patient groups (15.1 plus or minus 2.3 ng/ml for
hyperparathyroid patients and 14.4 plus or minus 5.2 ng/ml for
normals), but was significantly different between patients and
controls (6.8 plus or minus 3.1 ng/ml, p < 0.001).
Histomorphometrically, trabecular bone volume was elevated in
both groups as compared to controls (p < 0.001), and the
resorption surface was increased in hyperparathyroid patients
(9.7 plus or minus 1.1 vs. 4.7 plus or minus 2.8%, p <
0.001), as was the osteoid seam thickness index (31.8 plus or
minus 6.2 vs. 18.6 plus or minus 5.6, p < 0.001). According
to the Pearson test, only effected in the normoparathyroid
group, the only significant and positive correlations were
between osteocalcin and 24-hour urine calcium and between
osteocalcin and Ca/Cr (both p < 0.001). These results
demonstrate the existence of a secondary hyperparathyroidism
in 10% of patients with blastic bone metastases due to stage-D
prostatic cancer and show that osteocalcin is not an adequate
biological bone marker in these patients.
In vitro studies of human prostatic epithelial
cells: Attempts to identify distinguishing features of
malignant cells
Peehl D.M.; Wong S.T.; Bazinet M.; Stamey T.A.
Division of Urology, Stanford Medical Center, Stanford, CA
94305 USA
Growth Factors (United Kingdom), 1989, 1/3
(237-250)
Recent advances in culture techniques have enabled routine
establishment and propagation of epithelial cells derived from
normal and malignant tissues of the human prostate.
Comparative studies of the responses of normal and
cancer-derived cell populations to various growth and
differentiation factors in vitro were undertaken to examine
the possibility that cancer cells might respond
differentially. Clonal growth assays in serum-free medium
demonstrated that optimal proliferation of normal as well as
cancer cell strains was generally dependent on the presence of
cholera toxin, epidermal growth factor, pituitary extract,
hydrocortisone, insulin and high levels of calcium in the
culture medium, and on the use of collagen-coated dishes. Only
one cancer strain responded aberrantly to epidermal growth
factor and hydrocortisone. Putative differentiation factors
(transforming growth factor-beta and vitamin A) inhibited
the growth of all normal and cancer strains. The origin of
a cancer-derived cell strain that responded similarly to
normal strains was verified by positive labeling with a
prostate cancer-specific antibody, validating the conclusion
from these studies that normal and cancer prostatic epithelial
cells are not distinguishable on the basis of responses to the
tested factors.
Hypocalcemia associated with estrogen therapy for
metastatic adenocarcinoma of the prostate
Vogelgesang S.A.; McMillin J.M.
Research Service, Sioux Falls Veterans Administration
Hospital, Sioux Falls, SD USA
J. Urol. (USA), 1988, 140/5 Part I (1025-1027)
We report 2 cases of true hypocalcemia (not caused by
decreased binding protein) associated with metastatic prostate
cancer and review previously reported cases. Hypocalcemia is a
common but frequently unrecognized complication of prostatic
cancer. Estrogen therapy often is associated with the
hypocalcemia, which may be asymptomatic. The hypocalcemia is
always associated with osteoblastic metastases and usually it
is associated with increased serum alkaline phosphatase
activity, acid phosphatase activity and serum parathyroid
hormone concentration. Serum concentrations of magnesium,
phosphorus and vitamin D frequently are decreased.
Patients are in a positive calcium balance. The osteoblastic
metastases seem to act as a calcium sink, creating a 'hungry
tumor phenomenon'. The role of estrogens may be to stop the
resorption of normal bone resulting in lower serum calcium
concentrations.
Hypercalcemia in carcinoma of the prostate: Case
report and review of the literature
George A.L. Jr.; Remler R.B.; Heim C.R.; Warner J.J.
Department of Medicine, Vanderbilt University Medical Center,
Nashville, TN USA
J. Urol. (Baltimore) (USA), 1987, 137/2
(309-311)
Hypercalcemia developed in a man with recurrent
adenocarcinoma of the prostate. Serum calcium became normal
soon after bilateral orchiectomy and the patient was free of
disease 18 months later. The absence of radiographically
detectable bone metastases in this patient suggested a humoral
mechanism for the hypercalcemia. Orchiectomy may be an
effective treatment for hypercalcemia complicating prostatic
carcinoma.
Calcium excretion in metastatic prostatic
carcinoma
Grainger R.; Reda M.; Fitzpatrick J.M.
Department of Urology, Meath Hospital, Dublin 8 Ireland
Br. J. Urol. (England), 1984, 56/6 (687-689)
In 64 men with prostatic carcinoma, calcium excretion per
litre of glomerular filtrate (Ca(e)) was persistently lower in
those with bone secondaries than in those with soft tissue
involvement only, despite a normal range of serum calcium in
both groups. In three patients who showed an improvement in
their bony metastases on bone scan 6 months after starting
treatment, the Ca(e) values had increased slightly but still
remained in the low range. In a further five who showed no
improvement on bone scan, Ca(e) values were lower than before.
In patients with prostatic carcinoma, Ca(e) is an indicator of
early changes in calcium homeostasis. It may also provide an
objective indication of progression of bone secondaries.
Osteomalacia associated with prostatic cancer and
osteoblastic metastases
Kabadi U.M.
Dep. Med., Veterans Adm. Med. Cent., Des Moines, IA 50310
USA
Urology (USA), 1983, 21/1 (65-67)
A patient with carcinoma of the prostate, extensive bony
metastases, and osteomalacia is reported. The diagnosis of
osteomalacia was suspected because of generalized weakness and
bone pains, hypocalcemia, hypophosphatemia, and raised
alkaline phosphatase. It was documented by low
1,25-hydroxyvitamin D level. Furthermore, it was confirmed by
improvement in patient's symptomatology and normalization of
serum calcium and phosphorus after treatment with
1,25-hydroxyvitamin Dsub 3 (Rocaltrol).
Carcinoma of the prostate: The treatment of bone
metastases by radiophosphorus
Glaser M.G.; Howard N.; Waterfall N.
Dept. Radiother., Charing Cross Hosp., London United
Kingdom
Clin. Radiol. (Scotland), 1981, 32/6 (695-697)
Osseous deposits secondary to advanced carcinoma of the
prostate are a common feature of the disease. These deposits
are most often seen in the lumbar spine and pelvis and cause
severe and intractable pain, often requiring large quantities
of strong analgesia for alleviation of pain. Relief of pain
can be achieved by external irradiation of these deposits, but
this relief may not be permanent and the disease may be so
widespread that it is impracticable to treat all the deposits
by irradiation. Deposits from carcinoma of the prostate are
usually multiple and all may cause pain at the same time. A
method of delivering the radiation to all the deposits at the
same time has been sought. Previous studies have shown that
radioactive phosphorus (P32) can be used to obtain this
localisation of radioactivity at sites of osseous activity. In
this study 24 patients with bone metastases from carcinoma of
the prostate were treated with radiophosphorus and methyl
testosterone, or radiophosphorus with parathormone and
calcium. An overall response rate of 58% shows this to be an
effective palliative treatment. The results suggest there is a
greater response when P32 is used in conjunction with
parathormone and calcium, than with methyl testosterone.
Management of cancer of the prostate
Blackard C.E.
VA Hosp., Minneapolis, Minn. USA
Brit.J.Hosp.Med. (England), 1974, 11/3 (357-372)
In this article the management of prostatic cancer is
discussed according to the clinical stage of the tumor.
Ordinarily, treatment of prostatic cancer should not be
started until a positive histological diagnosis has been made
and the patient has been properly staged. Minimal staging
studies include a pretreatment prostatic serum acid
phosphatase test and a skeletal survey.
Intracavitary irradiation of prostate
carcinomas
Dragon V.; Pache G.; Von Niederhausern W.; et al.
Serv. Radiother., CHU Vaudois, Lausanne Switzerland
Rev. Med. Suisse Romande (Switzerland) , 1980, 100/9
(755-762)
A method for the intracavitary irradiation of prostate
carcinomas, used at the Central University Hospital in
Lausanne in 1979 and 1980 on 10 patients is described. The
technique, which is the afterloading type, consists of the
positioning of a Cs 137 source in the proximal ureter. This is
achieved with the aid of a Foley 26 balloon catheter
introduced into the bladder after drainage cystostomy. The
source remains in place for about 26 hours and delivers a dose
of approximately 3800 rads to the prostate to a depth of 4 cm
(NSD=2000 ret) and a maximum of 1700 rads to the rectum
(NSD=700 ret).
Epidemiology of prostatic cancer: A case-control
study
Fincham S.M.; Hill G.B.; Hanson J.; Wijayasinghe C.
Division of Epidemiology and Preventive Oncology, 6th Floor,
9707-110 Street, Edmonton, Alta. T5K 2L9 Canada
Prostate (USA), 1990, 17/3 (189-206)
A population-based case-control study of prostatic cancer
in Alberta was undertaken to determine the risk factors
associated with the disease. Cases were 382 newly diagnosed
prostatic cancer patients and 625 controls, group-matched to
the anticipated age distribution of the cases, chosen at
random from the health insurance roster. Subjects were
interviewed in their homes by using a pre-tested questionnaire
including questions related to ethnic group, education,
puberty, marital history, family history, residence, water
supply, smoking, and diet. Factors significantly related to
the risk of developing prostatic cancer included ethnic group
(British high, Ukrainian low), education (elementary high,
university low), age at first marriage (early high, late low),
family history (high risk for those with relatives with
prostatic cancer), and increased masculinity among the
children of cases. The results with respect to smoking,
occupation, medical history, birthplace, residence, water
supply, and diet were generally negative.
Demonstration of specifically sensitized
lymphocytes in patients treated with an aqueous mistletoe
extract (Viscum album L.)
Schultze J.L.; Stettin A.; Berg P.A.
Medizinische Klinik, Abteilung II, Universitat Tubingen,
W-7400 Tubingen Germany
Klin. Wochenschr. (Germany), 1991, 69/9
(397-403)
Lymphocytes of 25 patients treated with an aqueous
mistletoe extract (Viscum album L.) for up to 6 months (group
1), up to 2 years (group 2), and more than 2 years (group 3)
were examined in 3- and 7-day cultures for specifically
sensitized lymphocytes. The whole extract (HM), the
lectin-polysaccharide fraction (HM-LP), and the 'viscotoxin'
fraction (HM-V) were added at concentrations ranging from 0.5
microg to 12.5 mg extract/ml. Lymphocytes from four of the
nine group 2 patients and five of the ten group 3 patients
reacted specifically with HM and HM-LP at an optimal dose of
5.0 mg/ml, but did not react with HM-V. Stimulation indices
varied between 1.6 and 16. In the patients of group 3 this
effect was observed only when their lymphocytes were
costimulated in the 3-day cultures with phytohemagglutinin
(PHA), in contrast to the four patients of group 2 who reacted
only in the 7-day cultures with HM-LP without PHA
co-stimulation. Patients' lymphocytes had to be protected from
mistletoe lectin-induced cytotoxicity by the addition of their
own sera containing anti-mistletoe lectin antibodies.
Lymphocytes from tumor patients (n = 18) never treated with
mistletoe extracts and healthy individuals (n = 18) showed no
specific proliferative response when tested in 3- and 7-day
cultures. The production of granulocyte-macrophage
colony-stimulating factor (GM-CSF) and interferon-gamma
(IFN-gamma) was measured in the supernatants of lymphocytes
cultures from all 25 patients and 36 controls exposed to HM,
HM-LP, and HM-V in 3- and 7-day cultures.
An urodynamic study of patients with benign
prostatic hypertrophy treated conservatively with phytotherapy
or testosterone
Flamm J.; Kiesswetter H.; Englisch M.
Urol. Abt., Wilhelminenspit., Wien Austria
Wien. Klin. Wochenschr. (Austria), 1979, 91/18
(622-627)
Conservative therapy of benign prostatic hypertrophy
comprises the administration of oestrogens, gestagens,
androgens and anti-androgens. Phytodrugs, which contain an
extract of Sabal serrulatum or Pygeum Africana as active
substance are without side effects and are, therefore, being
used increasingly. 74 patients with irritable or obstructive
bladder symptoms due to benign prostatic hypertrophy were
treated with a phytodrug (Sabal serrulatum) or with
testosterone throughout a period of three months. In group one
(20 patients given phytodrugs and 10 patients given
testosterone) clinical symptoms and measurements of residual
urine, residual urine quotient, bladder capacity, micturition
pressure and maximum urethral closure pressure were recorded
at the beginning and at the end of therapy. In group two 28
patients were treated with the phytodrug in the first and
third months with an intervening placebo trial lasting four
weeks and 16 patients were given testosterone. Clinical
symptoms and uroflow and residual urine only were charted in
this group. None of the patients in either group showed an
improvement in the urodynamic parameters of obstruction, but
all patients felt a subjective alleviation of their
symptoms.
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