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Experimental Therapeutics, Preclinical Pharmacology |
Departments of Radiation Oncology [G. G. H., J. D. F., M. Y., R. L. M., J. R., A. L., S. T-M.], Internal Medicine [O. K.], Integrated Biostatistics Unit [S. T-M., J. A.], and Pathology [F. H. S.], Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, and Harper Hospital, Detroit, Michigan 48201
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2-fold
lower than photon doses required to observe the same efficacy. These
studies suggest a potential of combining genistein with radiation for
the treatment of localized prostate carcinoma. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The interest in genistein stems from observations that increased soy
consumption in Asian diets, resulting in increased serum isoflavone
levels, has been associated with a decreased risk for prostate
adenocarcinoma. Epidemiology studies have shown that Japanese and
Chinese men have the lowest incidence of prostate carcinoma in the
world (13)
. Genistein has an heterocyclic diphenolic
structure similar to estrogen (14)
and has demonstrated
antitumor and antiangiogenic activities (15
, 16)
.
Genistein was found to inhibit tyrosine protein kinases (except p40
protein-tyrosine kinase; Ref. 17
), topoisomerases I and II
(18)
, protein histidine kinase, and 5
-reductase
(19)
. Genistein has been shown to inhibit cell growth of
tumor cell lines from various malignancies including breast, lung,
melanoma, prostate, head and neck squamous cell carcinoma, leukemia,
and lymphoma (10
, 20, 21, 22, 23, 24, 25, 26)
. We have shown previously that
genistein inhibited the cell growth of androgen-dependent (LNCaP) and
androgen-independent (PC-3) human prostate carcinoma cell lines
(10)
. We found that genistein induced a
G2-M cell cycle arrest leading to cell growth
inhibition (10)
. Cell growth inhibition was observed with
concomitant down-regulation of cyclin B, up-regulation of the
p21WAF1 growth-inhibitory protein, and induction
of apoptosis (10)
. This effect of genistein on disruption
of the cell cycle, resulting in the inhibition of cell growth of
prostate cancer cells, suggests that genistein can be used to augment
the cell killing induced by radiation. The goal of our study was to
investigate in vitro the effect of photon and neutron
radiation on PC-3 cells and test whether genistein pretreatment of PC-3
cells could augment the cell growth inhibition induced by either form
of radiation. This study shows that genistein potentiates the effect of
low doses of photon or neutron radiation, resulting in a significant
increase in cell killing of human prostate cancer cells in
vitro.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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[3
H]Thymidine Uptake Assay.
Cells were seeded in six replicates in 96-well flat-bottomed
microplates at 3000 cells/well/0.1 ml in CM. After 24 h, genistein
was added in 0.05 ml of CM, resulting in a final concentration of 1–90
µM. After 24 h exposure to genistein, cells in the
microplates were irradiated with various doses of photons or neutrons.
In all wells, the volume was adjusted to 0.2 ml with CM. After 3 days
incubation at 37°C in a 5% CO2 incubator,
cells were labeled with 1 µCi of
[3
H]thymidine (Amersham) for 18 h
(27
, 28)
. Plates were harvested onto a glass fiber filter
with a micromate 196 harvester (Packard Instrument, Meriden, CT).
Filters were counted in the ß direct Matrix 96 counter (Packard
Instrument, Meriden, CT; Refs. 27
and 28
).
The percentage of inhibition was calculated as follows:
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Tumor Cell Growth and Colony Assays.
Cells were plated in T25 flasks at 0.5 x
106
cells/flask in CM. Three days later, cells
were treated with genistein at a final concentration of 1–90
µM. After 24 h exposure to genistein, cells were
removed by trypsinization using trypsin-EDTA (Life Technologies, Inc.),
counted, and transferred to 15-ml conical tubes at about 2 x
106
cells/5 ml in CM for irradiation with various
doses of photons or neutrons. After radiation, cells were either plated
for a cell count or for colony assay (29)
. For a cell
count, cells were plated in duplicates in T25 flasks at 0.5 x
106
cells/flask and supplemented with genistein
at a final concentration of 5–30 µM. On day 3 of
incubation at 37°C in a 5% CO2 incubator,
cells were removed by trypsinization and counted using eosin exclusion
dye. The mean cell number of duplicates was used for data analysis. To
set up the colony assay after radiation, cells were plated in
triplicates in six-well plates at 250 cells/well and supplemented with
genistein at a final concentration of 5–30 µM. After 10
days incubation at 37°C in a 5% CO2 incubator,
colonies were fixed in 10% buffered formalin, stained with eosin and
hematoxylin, and counted (29)
. The percentage of
inhibition of the cell number or colonies was calculated as follows:
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Radiation.
Cells, in 96-well microplates or 15-ml tubes, were either irradiated
with neutrons or photons. For neutron irradiation, the beam was
produced by bombarding a thick beryllium target with 48.5 MeV deuterons
[d(48.5)+Be] from a superconducting cyclotron (6
, 7)
.
The microplates were irradiated from above with a vertical beam. They
were covered with 1 cm of A150 tissue-equivalent plastic (Exradin,
Inc., Lisle, IL) to provide adequate build-up and to flatten the
25 x 25-cm field. The distance between the target and the surface
of the plastic was 170 cm. The total dose rate with this arrangement
was 51 cGy min-1 with 12.5 µA of deuteron
beam. Tubes were irradiated with a horizontal 25 x 25-cm neutron
beam. Tubes of 15-ml capacity were placed at a depth of 3.1 cm in a
specially machined Lucite block of dimensions 10 x 20.3 x
12.8 cm, which was positioned on the central axis of the neutron beam
with the its surface at a distance of 142 cm from the target. At this
position with a 25 x 25-cm field size, the dose rate was 70
cGy min-1 with 12.5 µA of deuteron beam. For
both arrangements, there was an approximately 3–5% 
-ray dose
component.
Photon irradiation was performed with a 60Co unit
(AECL Theratron 780). Arrangements similar to those used for neutron
irradiation were used for 60Co irradiation.
Microplates were irradiated from above with a vertical beam, 2.5 mm of
polystyrene build-up material was placed on top of the flasks, and the
surface of the build-up material was at a distance of 76 cm from the
source. The dose rate was 32 cGy min-1. For
tube irradiation, a Lucite block similar to that used for neutron
irradiation was used with a horizontal beam. The surface of the block
was positioned at 46 cm from the source, the tubes were at a depth of
2.6 cm, and the dose rate was 92 cGy min-1.
Statistical Analysis.
Statistical analysis of the data was carried out using the BMDP
Statistical Software version 7.0. For the thymidine assay, outcome
values (cpm) were evaluated using a two-way ANOVA. Multiple comparisons
were conducted using the Bonferroni procedure. For the colony assay,
preliminary data analysis indicated that two-way ANOVA models were
inappropriate because of substantial statistical interaction between
radiation and genistein. An additional problem was heterogeneity of
variances. Consequently, we used one-way ANOVA to compare the effects
of different radiation and genistein doses. When Bartlett’s test
indicated significant heterogeneity of variance, the analyses were
repeated on square root transformed data. In the case where there was
still significant heterogeneity of variances, two-sample t
tests were performed using Satterthwaite’s method for unequal
variances. Bonferroni’s procedure was used to correct for multiple
comparisons.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. However, neutrons used at lower doses than photons were more
effective than photons. A significant inhibition of 50% was
obtained at 100 cGy neutrons and at 200–300 cGy photons. The RBE
calculated as the ratio of photon dose to neutron dose causing 50%
inhibition was found to be 2.6 for PC-3 cells.
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. After radiation, the cells in
microplates were further incubated for 3 days, and DNA synthesis of
untreated and treated PC-3 cells was monitored by
[3
H]thymidine incorporation. In this assay,
cells were continuously exposed to genistein, even after radiation for
the duration of the experiment (4 days). Data from a representative
experiment are presented in Fig. 2
. A dose-dependent decrease in [3
H]thymidine
counts was measured with increasing concentrations of genistein from 5
to 60 µM, indicative of inhibition of DNA synthesis (Fig. 2
A). The extent of DNA inhibition induced by genistein was
further enhanced by increasing doses of photons (Fig. 2
A).
The percentage of DNA inhibition relative to control untreated cells
was calculated to compare between the combinations of various doses of
genistein and radiation (Fig. 2
B). Photon irradiation caused
a gradual and significant increase in DNA inhibition from 28 to 72% at
doses of 100–500 cGy compared with untreated control cells
(P < 0.01). At lower concentrations of genistein of 1
and 5 µM, the effect of genistein alone was
minimal (P > 0.01), and no significant increase in DNA
inhibition was observed with radiation above that induced by radiation
alone (Fig. 2
B). At concentrations of 30
µM genistein and higher, the effect of
genistein alone was >90% DNA inhibition (P < 0.01),
and only a slight further increase to 96% was seen by adding
radiation. However, genistein at a concentration of 15
µM caused a significant 46% inhibition of DNA
synthesis compared with untreated cells (P < 0.01)
that was further augmented by radiation at each dose of radiation
tested in a radiation dose-dependent manner (Fig. 2
B). The
DNA inhibition induced by 15 µM genistein
combined with photon radiation at doses of 100–500 cGy (67–91%) was
significantly greater than that induced by genistein alone (46%;
P < 0.01) and radiation alone (28–72% at 100–500
cGy; P < 0.01). This effect was marked at intermediate
doses of radiation of 200 and 300 cGy inducing 78 and 83% DNA
inhibition, respectively, compared with 37 and 53% inhibition induced
by 200 and 300 cGy photons alone (P < 0.01).
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. In this experiment, the dose range of genistein was selected to
include concentrations between 15 and 35 µM based on data
shown in Fig. 2
. The dose-dependent decrease in
[3
H]thymidine counts induced by genistein was
comparable with that seen in the independent experiment shown in Fig. 2
showing the reproducibility of the genistein effect on DNA synthesis.
This effect was also consistently increased by additional exposure of
the cells to increasing doses of neutrons (Fig. 3
A).
Genistein at concentrations of 15 and 25 µM,
respectively, induced 47 and 78% DNA inhibition compared with
untreated cells (P < 0.01; Fig. 3
mdit>B). This
DNA inhibition was significantly increased to 66–93% inhibition by
combination with low doses of 50–200 cGy neutron radiation compared
with genistein alone (P < 0.01) and to the 47–68%
inhibition induced by 50–200 cGy neutrons alone (P <
0.01; Fig. 3
B). These data indicate that genistein can also
augment the effect of neutrons at doses 2-fold lower than photon
doses required to observe the same efficacy. This experiment also shows
that concentrations of genistein >30 µM have
an optimal effect alone, as seen previously in Fig. 2
B.
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Cell Growth Inhibition by Genistein and Radiation.
To study the effect of DNA synthesis inhibition induced by genistein
and radiation on cell growth, cells were pretreated with genistein for
24 h and then irradiated and incubated in the presence of
genistein. The short-term effects of the combined treatment on cell
growth were assessed by counting viable cells 3 days after radiation,
whereas the long-term effects on cell division were assessed in a
colony assay on day 10 after radiation. On day 3, the cell count showed
the same trend observed in DNA synthesis with the combined treatment of
15 µM genistein and 300 cGy photons causing 69%
inhibition in cell growth compared with 50% with each treatment alone
(Table 1)
. This extent in cell growth inhibition was lower than the 83%
observed in DNA inhibition using the same doses of genistein and
radiation and indicates that cell death is a slower event than DNA
synthesis inhibition. Cell growth inhibition was not enhanced further
by radiation combined with 30 µM genistein. With low
doses of neutrons combined with genistein, the effect on cell growth
was comparable with that observed with genistein and photons; however,
an increased inhibition in cell growth was also observed at 5
µM genistein combined with 100 or 150 cGy neutrons (Table 1)
. Although variations in cell growth inhibition by genistein is
observed in the two representative experiments presented in Table 1
,
the trend of increased cell growth inhibition by genistein combined
with radiation remains.
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. Genistein alone at 30 µM caused a complete inhibition
of 97–100% in colony formation (data not shown). In the
photon/genistein experiment (Fig. 4
A), a minimal effect was
observed at 5 µM (P = 1.00),
whereas a significant inhibition of 67% in colony formation was seen
at 15 µM genistein (P <
0.001). Photons at 200 and 300 cGy caused a significant inhibition of
38 and 55%, respectively, in colony formation (P <
0.001). A slight increase in colony inhibition was obtained by
combination of 5 µM genistein and 200 or 300
cGy photons, which was not significant compared with radiation alone
(P > 0.2). However, when these radiation doses were
combined with 15 µM genistein, a significant
increase in colony inhibition was observed up to 75–84% with 200 and
300 cGy photons that was significantly greater than with radiation
alone (P < 0.002). This effect on cell division
corroborates the effect observed in DNA synthesis.
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B), the effect of
50 cGy neutrons alone on colony formation was not significant
(P = 1.00), whereas a significant inhibition in colony
formation was observed at 100 and 150 cGy neutrons (P < 0.05). In this experiment, some inhibition in colony formation
(26%) was observed with 5 µM genistein alone,
indicating variations between experiments when compared with the
photon/genistein experiment (Fig. 4
A). The combination of 5
µM genistein with radiation at doses of 50 and
100 cGy neutrons showed a further decrease in the number of colonies
that was significant to genistein alone (P < 0.001)
and to radiation alone (P < 0.05). The effect of 15
µM genistein alone was more reproducible and
more significant (59% inhibition; P = 0.001). At
neutron doses of 100 and 150 cGy combined with 15
µM genistein, a significant increase in colony
inhibition to 86 and 95% was observed compared with 60% with
genistein alone (P < 0.001) and compared with 49 and
77% with 100 and 150 cGy neutrons alone, respectively
(P < 0.001; Fig. 4
B). This effect was
greater than that observed in DNA division. The effect of 15
µM genistein and 100 cGy neutrons was
comparable with 15 µM genistein combined with
300 cGy photons, resulting in >80% inhibition in colony formation.
These data show that much lower doses of neutrons than photons are
sufficient for a genistein potentiation effect. The effect of genistein
combined with neutrons seems more pronounced on cell division than that
obtained with genistein and photons because the combination of
genistein and neutrons was significantly better than genistein alone or
neutrons alone.
Microscopic observation of the colonies in the combined treatment
showed that cells failed to form colonies, and remaining cells were
enlarged, showing intense cytoplasmic vacuolization and disintegrating
nuclei compared with the morphology of untreated cells (Fig. 5)
. These findings are similar to the effect of genistein alone on the
cell morphology (10)
and to the effect of radiation alone
on the cell
morphology.4
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Optimal Conditions for Genistein and Radiation Interaction.
We have demonstrated that the effect of a low dose of 15
µM genistein is sufficient to induce about 50–60%
growth inhibition of PC-3 cells. This dose was found to be optimal for
combination with low doses of radiation of 100–300 cGy photons or
100–150 cGy neutron radiation and resulted in up to 80% inhibition in
DNA synthesis and 84–95% inhibition in cell division. Fig. 6
emphasizes these findings by comparing the inhibitory effect of the
combined treatment on DNA synthesis and cell division. These data show
a good correlation between both [3
H]thymidine
and colony assays and indicate that the DNA synthesis inhibition
observed after 4 days exposure to genistein with and without radiation
is irreversible and does lead to cell division inhibition measured by
the colony assay.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Radiation of PC-3 cells either with neutrons or photons induced a dose-dependent inhibition of colony formation. However, we demonstrated that neutrons were more effective than photons with an RBE of 2.6 for PC-3 cells. We determined a dose range of photons (100–500 cGy) and neutrons (50–200 cGy) causing a significant effect on cell division (30–70% inhibition) but not a complete inhibition that is adequate for a combination with genistein.
We have shown previously that genistein significantly inhibited the growth of PC-3 cells at concentrations >10 µM when cells were counted after 3 days in culture (10) . In this study, similar findings were obtained. We found that 15 µM genistein also inhibited PC-3 cell growth, in the range of 30–50%, after continuous exposure for 3 days. In addition, we showed that the decrease in cell growth was attributable to DNA synthesis inhibition (>45%), as measured in a 4-day assay leading to cell division inhibition of 60–70% in the 10-day colony assay. These data confirm our previous findings that genistein causes cell cycle arrest leading to cell killing (10) . Therefore, the dose of genistein selected for combination with radiation was 15 µM because it induced a significant and median inhibition in DNA synthesis, cell growth, and colony formation in the range of 40–60%. A lower dose of 5 µM genistein was not as effective, and doses higher than 30 µM were toxic to the tumor cells, as measured in the three assays.
Pretreatment of PC-3 cells with genistein for 24 h, followed by
radiation with photons and continuous exposure to genistein for 3 more
days, caused a significant increase in DNA synthesis inhibition that
was greater than that induced by genistein or radiation alone. This
effect was particularly observed at 15 µM genistein
combined with intermediate doses of radiation of 200 and 300 cGy
inducing 78 and 83% DNA inhibition, respectively, compared with 37 and
53% inhibition induced by 200 and 300 cGy photons alone and with 46%
inhibition caused by genistein alone. This augmentation of DNA
inhibition by genistein and photon radiation was also induced by
pretreatment with genistein followed by neutron radiation. This DNA
inhibition was significantly increased to 66–93% inhibition by
combination with low doses of 50–200 cGy neutron radiation compared
with genistein alone (47%) and with the inhibition induced by 50–200
cGy neutrons alone (47–68%). These data indicate that genistein can
also augment the effect of neutrons at doses 2-fold lower than
photon doses required to observe the same efficacy. Both for photons +
genistein and neutrons + genistein, the effect on DNA synthesis
inhibition does not follow an additive pattern when compared with each
treatment separately but rather follows a pattern indicating
potentiation of radiation effect by pretreatment with genistein. Thus,
we believe that genistein may function as a radiosensitizer for PC-3
cells.
When cell growth was measured after treatment with genistein and radiation, a further decrease in the cell number was observed compared with genistein alone and radiation alone. These data showed that a trend in cell growth inhibition comparable with that observed in DNA synthesis inhibition was obtained, indicating that inhibition of DNA synthesis may have resulted in decreased cell growth. The long-term effects of the combined treatment on cell division as measured by colony formation on day 10 after treatment were markedly increased compared with those observed on day 3. The increased inhibition of colony formation was particularly pronounced at 15 µM combined with 300 cGy photons or 100–150 cGy neutrons, causing up to 80–95% inhibition. This effect on cell division corroborates the effect observed in DNA synthesis but shows that cell death may be a late event, as observed previously for genistein alone (10) and radiation alone.5 These data show a good correlation between both [3 H]thymidine and colony assays and indicate that the DNA synthesis inhibition observed after 4 days exposure to genistein and radiation is irreversible and does lead to cell division inhibition measured by the colony assay. This effect was dependent on continuous exposure of the cells to genistein.
We have demonstrated previously that genistein caused the PC-3 cells to
arrest at the G2-M phase of the cell cycle
(10)
. Ongoing studies on the mechanism of PC-3 cell
killing by photons and neutrons in our laboratory show that radiation
also causes accumulation of cells in the G2-M
phase of the cell cycle, but this effect was more pronounced with
photons than neutrons.5
Whether the combination
of genistein with radiation causes a greater accumulation of cells in
G2-M phase remains to be clarified. The molecular
events leading to G2-M arrest may be the same or
may differ for each modality alone and the combined modalities. The
interaction of genistein and radiation may lead to new alterations in
earlier events of the cell cycle, which ultimately will result in cell
death. For example, the investigation of the effects of these two
modalities on the transcription factor NF-
B may be warranted based
on our previous observations that genistein can inhibit NF-B DNA
binding in PC-3 and LNCaP human prostate carcinoma cells
(30)
. Moreover, genistein inhibited NF-B activation by
DNA-damaging agents, including
H2O2 and tumor necrosis
factor-, resulting in cell apoptosis in these cell lines
(30)
. In contrast to genistein, ionizing radiation was
shown to activate NF-B as an immediate-early response that functions
to protect cells from apoptosis, a mechanism that could be implicated
in cell survival to radiation, although it is still controversial
(31
, 32)
. We hypothesize that pretreatment of the cells
with genistein may block NF-B activation by radiation, inducing a
cascade of molecular events driving the cells to an apoptotic pathway
and, thus, increasing cell killing as shown in the present study.
Further studies are under way to investigate the mechanism of
interaction between genistein and radiation, both at the cellular and
molecular levels by studying the genes involved in cell killing.
It should be noted that concentrations of genistein in the range of 5–15 µM are considered as mild doses and have shown no toxic effect on normal breast epithelial cells in vitro.6 In vivo, in human volunteers consuming 50 mg of isoflavone consisting of 40 mg of genistein and daidzein, the serum level of genistein was in the range of 15 µM, and no apparent toxicity was observed.7 Other studies have reported measurements of physiological concentrations of genistein in the range of 276 nM to 6 µM, depending on the study subjects and the isoflavone source (33 , 34) . Also, the doses of photon (200–300 cGy) or neutron (100–150 cGy) radiation, showing an optimal augmentation of cell killing when combined with 15 µM genistein, are low and nontoxic doses of radiation. These findings suggest that genistein may potentiate the effect of radiation therapy for localized prostate carcinoma and can be translated into the design of clinical protocols for prostate cancer patients with locally advanced disease to improve the outcome of radiation therapy.
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FOOTNOTES |
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1 These studies were generously supported by the
Patricia and E. Jan Hartmann Cancer Fund. 
2 To whom requests for reprints should be
addressed, at Department of Radiation Oncology, Karmanos Cancer
Institute, Hudson-Weber Bldg., Rm. 515, HWRC Cancer Center, 4100 John
R., Detroit, MI 48201. Phone: (313) 966-7652; Fax: (313) 966-0605;
E-mail: hillmang{at}karmanos.org
3 The abbreviations used are: RBE, relative
biological effectiveness; CM, culture medium; NF-B, nuclear
factor-B.
5 G. G. Hillman, personal communication.
6 F. H. Sarkar, personal communication.
Received 7/31/00; revised 11/28/00; accepted 11/29/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and tumor necrosis factor on human renal cell carcinoma tumor cell lines.. Clin. Exp. Immunol., 96: 476-483, 1994.[Medline]
B activation in prostate cancer cells.. Nutr. Cancer, 35: 167-174, 1999.[CrossRef][Medline]
B inhibition–progress and pitfalls.. J. Natl. Cancer Inst., 91: 1910-1911, 1999.B, clonogenicity, and radiosensitivity of human cancer cells.. J. Natl. Cancer Inst., 91: 1956-1960, 1999.This article has been cited by other articles:
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  L. Rice, R. Handayani, Y. Cui, T. Medrano, V. Samedi, H. Baker, N. J. Szabo, C. J. Rosser, S. Goodison, and K. T. Shiverick Soy Isoflavones Exert Differential Effects on Androgen Responsive Genes in LNCaP Human Prostate Cancer Cells J. Nutr., April 1, 2007; 137(4): 964 - 972. [Abstract] [Full Text] [PDF]
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 J. J. Raffoul, S. Banerjee, V. Singh-Gupta, Z. E. Knoll, A. Fite, H. Zhang, J. Abrams, F. H. Sarkar, and G. G. Hillman Down-regulation of Apurinic/Apyrimidinic Endonuclease 1/Redox Factor-1 Expression by Soy Isoflavones Enhances Prostate Cancer Radiotherapy In vitro and In vivo Cancer Res., March 1, 2007; 67(5): 2141 - 2149. [Abstract] [Full Text] [PDF]
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F. H. Sarkar and Y. Li Using chemopreventive agents to enhance the efficacy of cancer therapy. Cancer Res., April 1, 2006; 66(7): 3347 - 3350. [Abstract] [Full Text] [PDF]
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R. Handayani, L. Rice, Y. Cui, T. A. Medrano, V. G. Samedi, H. V. Baker, N. J. Szabo, and K. T. Shiverick Soy Isoflavones Alter Expression of Genes Associated with Cancer Progression, Including Interleukin-8, in Androgen-Independent PC-3 Human Prostate Cancer Cells J. Nutr., January 1, 2006; 136(1): 75 - 82. [Abstract] [Full Text] [PDF]
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 G. G. Hillman, Y. Wang, O. Kucuk, M. Che, D. R. Doerge, M. Yudelev, M. C. Joiner, B. Marples, J. D. Forman, and F. H. Sarkar Genistein potentiates inhibition of tumor growth by radiation in a prostate cancer orthotopic model Mol. Cancer Ther., October 1, 2004; 3(10): 1271 - 1279. [Abstract] [Full Text] [PDF]
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