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Deuterium Depletion May Delay the Progression of Prostate Cancer

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Deuterium-depleted water (DDW) is a new promising agent in cancer therapy. The efficiency of the method is based on the discovery, that cancer cells are extremely sensitive to depletion of deuterium (D) and might cause necrosis of the tumour. The purpose of this study was to show the efficacy of D-depletion in prostate cancer (PC) patients. In the dou-ble blind, four-month-long, randomized Phase II clinical trial the daily water intake was replaced with DDW in 22 PC patients. Other 22 PC patients took normal water while both groups received the same forms of conventional treatment. In the retrospective study, 91 DDW-treated PC patients were evaluated and median survival time (MST) in the sub-groups was calculated. The time course of changes in DDW dose and PSA is presented in two cases. In the prospective trial seven patients in the treated group and one patient in the placebo group achieved partial response (p = 0.046). In the treated group, the net decrease in the prostate volume was three times higher (160.3 cm3 vs. 54.0 cm3; p = 0.0019), urination complaints ceased at a higher rate (8 vs. 0 patients, p = 0.0041), and the one-year survival rate was also higher (2 vs. 9 deaths; p = 0.034). The 91 retrospectively evaluated patients achieved an MST of 11.02 years, despite the fact that 46 of them suffered from distant metastasis. In the two monitored patients, drop of PSA level correlated with the DDW intake. In summary, D-depletion prolonged MST in patients with PC. The method proved to be safe thus its integration in the PC cure as an adjuvant or complementary therapy would be considered.
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Journal of Cancer Therapy, 2011, 2, 548-556
doi:10.4236/jct.2011.24075 Published Online October 2011 (http://www.SciRP.org/journal/jct)
Copyright © 2011 SciRes. JCT
Deuterium Depletion May Delay the Progression of
Prostate Cancer
András Kovács1, Imre Guller1, Krisztina Krempels2, Ildikó Somlyai2, István Jánosi3, Zoltán Gyöngyi4,
István Szabó4, István Ember4, Gábor Somlyai2*
1Saint John’s Hospital, Budapest, Hungary; 2HYD LLC. for Cancer Research and Drug Development, Budapest, Hungary; 3Planimeter
Ltd., Budapest, Hungary; 4University of Pécs, Medical School, Institute of Public Health, Pécs, Hungary.
Email: ad.kovacs@mail.janoskorhaz.hu, gullerimre@yahoo.com, {krempels, isomlyai, *gsomlyai}@hyd.hu, janosi@planimeter.hu,
{zoltan.gyongyi, istvan.ember}@aok.pte.hu, bokor28@yahoo.co.uk
Received July 7th, 2011; revised August 10th, 2011; accepted August 19th, 2011.
ABSTRACT
Deuterium-depleted water (DDW) is a new promising agent in cancer therapy. The efficiency of the method is based on
the discovery, that cancer cells are extremely sensitive to depletion of deuterium (D) and might cause necrosis of the
tumour. The purpose of this study was to show the efficacy of D-depletion in prostate cancer (PC) patients. In the dou-
ble blind, four-month-long, randomized Phase II clinical trial the daily water intake was replaced with DDW in 22 PC
patients. Other 22 PC patients took normal water while both groups received the same forms of conventional treatment.
In the retrospective study, 91 DDW-treated PC patients were evaluated and median survival time (MST) in the sub-
groups was calculated. The time course of changes in DDW dose and PSA is presented in two cases. In the prospective
trial seven patients in the treated group and one patient in the placebo group achieved partial response (p = 0.046). In
the treated group, the net decrease in the prostate volume was three times higher (160.3 cm3 vs. 54.0 cm3; p = 0.0019),
urination complaints ceased at a higher rate (8 vs. 0 patients, p = 0.0041), and the one-year survival rate was also
higher (2 vs. 9 deaths; p = 0.034). The 91 retrospectively evaluated patients achieved an MST of 11.02 years, despite
the fact that 46 of them suffered from distant metastasis. In the two monitored patients, drop of PSA level correlated
with the DDW intake. In summary, D-depletion prolonged MST in patients with PC. The method proved to be safe thus
its integration in the PC cure as an adjuvant or complementary therapy would be considered.
Keywords: DeuteriumDepletion, DDW, Prostate Cancer, Phase II Clinical Trial, Retrospective Evaluation, Median
Survival
1. Introduction
Hydrogen has a naturally occurring stable isotope, deute-
rium (D), with a mass number of 2. It is present in sur-
face waters mainly in the form of HDO at a concentra-
tion of appr. 16.8 mmol/L. The two isotopes, hydrogen
(1H) and deuterium (2D) have the largest mass difference
among stable isotopes of the same element, resulting in
significantly different chemical and physical properties
[1-3].
Although the effect of D at an elevated concentration
in biological systems has been investigated in several
experiments [4-5], these studies ignored the significance
of natural D-concentration. The first paper, suggesting
that reduced D-concentration has an impact on living
organisms, was published in 1993 [6]. Since then, nu-
merous studies have been conducted on different cell
lines using culture media prepared with deuterium-de-
pleted water (DDW) [6-7]. The growth rate of different
cancer cell lines significantly decreased in DDW-con-
taining media in vitro. In mice xenotransplanted with
MDA-MB-231, MCF-7 human breast adenocarcinomas
or PC-3 human prostate tumors, DDW resulted in com-
plete or partial tumour regression [7-8]. The apoptosis-
triggering effect of DDW was observed both in vitro [7]
and in vivo [8]. D-depletion exerts an influence on proto-
oncogenes and tumor suppressor genes, such as c-myc,
Ha-ras and p53. Expression of these genes, induced by
carcinogen exposure, was significantly lower when the
animals received DDW as drinking water [9]. The most
striking discovery was that cancer cells proved to be ex-
tremely sensitive to D-depletion which might even cause
the necrosis of tumours, while non-cancer cells are able
to tolerate the decreasing D-concentration. This finding
Deuterium Depletion May Delay the Progression of Prostate Cancer 549
raised the possibility that DDW might be one of the
agents which can reduce the risk of cancer and acts as an
effective modality in cancer therapy [10].
Prostate cancer (PC) is placed third in cancer mortality
among men in Europe. The estimated mortality rate in
2011 is between 12.6 and 8.1/100,000 men [11]. In the
years 2001-2005 the mean deaths of prostate cancer was
1265 in Hungary [12]. PC is the most frequently screened
out malignant transformation; the incidence is 214 out of
1000 men. PC often lies behind the cases that are catego-
rized as “died from other tumour” [13,14].
Decline in PC mortality is expected through Europe
likely due to the attributable improvement in screening,
diagnosis and predominantly treatment of the disease
[11]. Treatment options for PC may have severe side
effects, therefore an optimal choice attains a balance be-
tween deteriorations in quality of life and therapeutic
benefit [15-17].
Hormonal therapy is a mainstay of treatment for pa-
tients with advanced PC [18]. The recently published
clinical trials indicate a median survival time (MST) of
15 to 21 months in patients suffering from advanced
hormone refractory PC [19-22].
In order to investigate whether DDW might exert an
anticancer effect in humans and improve the results of
conventional treatments, a four-month-long double-blind
phase II placebo controlled clinical trial was conducted
on PC patients. The primary outcome was the best re-
sponse, and the agent’s safety was also assessed. In addi-
tion, the course of the disease was retrospectively evalu-
ated in 91 DDW-treated patients.
2. Patients and Methods
DDW was produced from normal tap water using frac-
tional distillation [23] as described earlier [24].
2.1. Prospective Study
The four-month-long phase II clinical trial was con-
ducted (under the permission of the Hungarian Institute
of Pharmacology: No. 5621/40/95) in four Hungarian
trial sites in a double blind, randomized, placebo con-
trolled setting according to GCP principles. The daily
water intake of PC patients was replaced with DDW of
85 ppm D concentration (treated group), or remained
normal with 150 ppm D (placebo group). The protocol
contained no restrictive requirements with respect to the
conventional treatments. The endpoints were the best
overall response and the change in prostate size. Urina-
tion complaints, PSA value and safety were also evalu-
ated. All patients were followed after closing their files
for years, and the impact of DDW on survival was de-
termined as well. Eligible patients had histologically
confirmed primary or relapsed PC and their life expec-
tancy was longer than six months. Forty-four patients
were evaluated in the Intention-to-Treat analysis (ITT
Population), 22 patients were involved in the treated and
22 patients in the placebo group. Thirty-three patients
completed the trial in full accordance with the protocol
requirements (PP Population), 17 of them (51.5%) were
treated with the agent and 16 patients (48.5%) were tak-
ing the placebo. Here we present the evaluation of the
ITT population alone, since the analysis of the ITT and
PP population showed no substantive difference in the
outcome. There was no statistical difference between the
test groups in staging, histological diagnosis and the
conventional treatments applied, so these factors were
irrelevant in the statistical analysis.
The volume of the prostate gland was calculated with
the formula
3
π
62
ab
V



where a and b were the two diameters (cm) determined
by transrectal ultrasonography. The prostate volume at
the first visit (baseline) and the value calculated at the
last (6th) visit were compared in both groups. Urination
problems were also categorized. The PSA value at the
last visit was compared to the baseline PSA level. During
the extended follow-up, the mortality rates were com-
pared in the test groups with Fisher’s Exact test.
Adverse events were to be also reported and charac-
terized. At the time of involvement and the last visit he-
matologic values and serum chemical parameters were
measured for screening liver- and renal function accord-
ing to GLP requirements.
2.2. Retrospective Study
Ninety-one PC patients were evaluated retrospectively.
Eligible patient was who: 1) was histologically diagnosed
with PC; 2) started consuming DDW at the time of the
diagnosis or after that; 3) was taking DDW for at least 90
days in addition to the conventional forms of treatment.
Patients were provided with all the available information
regarding DDW-treatment. In this study a) D concentra-
tion of DDW was gradually decreased from 105 to 25
ppm; b) duration was longer than a year in most cases; c)
the cure was interrupted and then continued several times.
In order to gain comparable data a new rate, deuterium
depletion unit (DdU), was introduced:


150 ppm D concentration of DDW ppm
Dose DdU body weight kg

daily volume of DDW L
The time pattern of PSA changes and DDW dose was
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Deuterium Depletion May Delay the Progression of Prostate Cancer
550
evaluated in detail in two patients.
The statistical analysis were performed using the SAS
statistical package. The result was considered statistically
significant at p < 0.05. The graphs were generated in R.
Survival curves were created using the method of Kaplan
and Meier.
Based on the presence or absence of distant metastasis,
homogenous groups were made up. Forty-five patients
had no metastasis. Among patients with metastasis (46
subjects) there were 32 patients who had exclusively
bone metastasis and made up two homogenous sub-
groups; 20 of them developed bone metastasis within a
year and 12 other patients later than one year after the
diagnosis of PC. Fourteen patients were not involved in
the evaluation due to the heterogeneity of metastases.
3. Results
3.1. Prospective Study
Seven patients in the treated group, and one patient in the
placebo group achieved partial response (PR) (significant
difference, p = 0.046). No change (NC) was verified in
11 patients in the treated, and in 13 patients in the pla-
cebo group (non-significant difference). Progression of
disease (PD) was diagnosed in 4 cases in the treated
group and in 8 patients of the control group. Because of
the duration of the clinical trial (only 4 months), com-
plete response (CR) was not verified in any of the pa-
tients during the study.
Prostate volume decreased in 18 out of 22 patients in
the treated arm. No change was detected in one patient
while the prostate volume increased in two subjects.
There was no available data on the prostate size in one
patient. In the placebo group, prostate size decreased in
11 patients, no change was recorded in 5 patients, and
increased prostate size was found in another 5. One pa-
tient was excluded because the decrease in prostate size
was not in connection with the improvement of the dis-
ease (the patient died after the 2nd visit). In the treated
group, the cumulated decrease of prostate size was 171.6
cm3 and the increase was 11.3 cm3, while in the placebo
group 108.1 cm3 decrease and 54.1 cm3 increase were
found. The net decrease was 160.3 cm3 in the treated, and
54 cm3 in the control group (p = 0.0019). Furthermore, in
those 7 patients who achieved PR, the prostate volume
became smaller by 125.2 cm3 in total. One patient in the
control group showing PR achieved 13.4 cm3 decrease in
prostate volume.
Urination complaints ceased in 8 patients of the treated
group, but in the placebo group none of the patients ex-
perienced changes in their complaints (p = 0.0041).
Changes in the PSA values are summarized in Table 1.
It became evident that the PSA and prostate size were
changing concomitantly in numerous cases. Cumulative
PSA showed decrease in the test groups in the four-
month-long study. The baseline value was 406.4 ng/mL
and 521 ng/mL in the treated and placebo group, respec-
tively. By the end of the trial the cumulative PSA value
decreased to 80.3 ng/mL in the treated and 277.4 ng/mL
in the placebo group.
Survival data were obtained during the three-year-long
extended follow-up: in the first year 2 patients (9.1%)
died in the treated group and 9 patients (40.9%) in the
placebo group (p = 0.034, Fisher’s exact test). After two-
year follow-up, 7 patients died in the treated, and 12 in
the placebo group, by the end of the third year the ratio
was 8:12.
3.2. Retrospective Study
The cumulative time period that elapsed from the diag-
nosis of PC till the start of DDW treatment was 142.5
years (52,003 days) in the 91 DDW-treated PC patients.
The cumulative duration of DDW treatment was 139.2
years (50,808 days), and the follow-up period from the
initial diagnosis was 350.1 years (127,800 days).
The MST was 11.02 years (4022 days), and 19 deaths
(21 %) were detected (Figure 1(a)).
The Kaplan Meier curve of the 45 patients having no
metastasis (Figure 1(b)) showed that only 4 patients (9%)
died.
Due to the extremely long survival, the data were not
suitable for calculating MST. Out of the 46 patients hav-
ing distant metastasis, the subgroup of 20 patients whose
bone metastasis was verified within one year from the
diagnosis of PC was separated. On this subgroup, we
addressed the question whether DDW extended MST;
considering the poor prognosis at this stage. During the
Table 1. Distribution of changes in PSA values during the
four-month-long clinical trial in the DDW treated and pla-
cebo group.
TEST GROUP
CHANGES IN PSA Treated
group Placebo
group Total
Marked improvement
(decrease > 50%) 15 9 24
(p = 0.089)
Mild improvement
(decrease of 10% - 50%) 1 1 2
Unchanged
(decrease or increase < 10%) 0 4 4
Mild deterioration
(increase of 10% - 50%) 0 2 2
Marked deterioration
(increase > 50%) 6 6
12
Total 22 22 44
Copyright © 2011 SciRes. JCT
Deuterium Depletion May Delay the Progression of Prostate Cancer
Copyright © 2011 SciRes. JCT
551
(a)
(b)
Deuterium Depletion May Delay the Progression of Prostate Cancer
552
(c)
(d)
Figure 1. (a) Kaplan Meier survival curves in the retrospectively evaluated 91 DDW-treated PC patients. Days from the di-
agnosis of prostate cancer to the end of the follow-up. MST was 11.02 years (4022 days). (b) Survival curve of the 45 DDW-
treated PC patients with no metastasis during the follow-up. Days from the diagnosis of prostate cancer to the end of the fol-
low-up. MST cannot be calculated due to the long survival. (c) Survival curve of 20 DDW-treated PC patients, who developed
bone metastasis within one year from the diagnosis of PC. Days from the diagnosis of prostate cancer to the end of the follow-
up. MST was 65.27 months (1958 days). (d) Survival curve of 12 DDW-treated patients, who developed bone metastasis later
than one year from the diagnosis. Days from the diagnosis of prostate cancer to the end of the follow-up. MST could not be
alculated because of the low number of incidences (2 deaths). c
Copyright © 2011 SciRes. JCT
Deuterium Depletion May Delay the Progression of Prostate Cancer
Copyright © 2011 SciRes. JCT
553
follow-up, 8 patients (40%) died. MST from the diagno-
sis of PC was 1958 days (65.27 months), with individual
values varying between 989 days (32.97 months) and
3396 days (113.2 months) (Figure 1(c)). In another sub-
group, consisting of 12 patients who developed bone
metastasis later than one year after the diagnosis of PC,
MST could not be calculated because of the low inci-
dence rate (2 deaths) and the small number of subjects
(Figure 1(d)). The remaining 14 patients were not evalu-
ated as a subgroup because of the heterogeneity, metas-
tases in different organs or other type of cancer diag-
nosed beside PC.
The time pattern of PSA changes in relation to DDW
dose is exemplified on the data of two patients. Patient 1.
started DDW at a relatively low PSA level following
prostatectomy. Patient 2. started the cure with bone me-
tastasis and highly elevated PSA level (over 1.000 ng/mL).
Patient 1. (53 years old; Figure 2(a)): Elevated PSA
(11.9 ng/mL) and no bone metastasis were present at the
time of diagnosis. The patient underwent prostatectomy
followed by antiandrogen therapy, PSA still remained
elevated (6 ng/mL). DDW treatment resulted in a de-
crease in PSA level. The patient repeated 12 - 16 weeks
long DDW cures with interruptions of 8 weeks, whereby
DDW dose was increased gradually during each cure but
the DdU value was kept steady close to 1.0 which was
sufficient to keep PSA close to 0.0 ng/mL. Four years
later progression was detected therefore the DDW dose
was increased up to 1.45 DdU that resulted in regression
again. Five years after the initial diagnosis, PSA level is
still steady below 1.0 ng/mL.
Patient 2. (61 years old; Figure 2(b)): Bone metastasis
was confirmed at the diagnosis of PC; PSA level was
over 1.000 ng/mL at that time. The conventional treat-
ment plus DDWthe latter was initiated 21 months after
the diagnosisresulted in a striking decrease in PSA.
The patient interrupted DDW consumption for six months
that resulted in a slight increase of PSA. Then, the re-
peated cures with DDW resulted in a decrease of PSA
again and the low level remained steady for years. De-
spite the potentially poor initial prognosis, the patient
remained in regression for 7.5 years.
3.3. Safety of DDW Treatment
During the prospective trial, 16 adverse events were re-
ported in 9 patients: three of them received the agent and
six patients belonged to the placebo group. In a single
case the detected symptoms (i.e. nausea, fatigue and
weakness) were classified as treatment-related, in the
other patients no causality was provable. In the treated
group there was no significant change in the examined
laboratory parameters.
During the 17-year-long history of the DDW treated
PC patients, there were absolutely no adverse events re-
lated to DDW, apart from the concomitant phenomena of
the healing process such as general weakness, despon-
dency, drowsiness, flush, occasional high temperature,
temporary increase of pain, alleviation and cessation of
pain, and warming of the affected area. Those patients
who started to use DDW in remission did not experience
the above symptoms. There was no significant change in
blood count even if the patient had taken high dose of
DDW during the years.
4. Discussion
Application of DDW is a new opportunity in cancer
therapy. Growing evidence suggests that D-depletion
might play a role both in treatment and prevention of
cancer. In vitro and in vivo experiments confirmed the
inhibition of proliferation of cancer cells [25] and the
possible cancer preventive effect [26]. Numerous other
experiments, including the study had been conducted on
mice xenotransplanted with PC-3 cells, proved the anti-
cancer effect of D-depletion induced by the application
of DDW [8]. Because of the novelty of this research area
there are still a limited number of publications concern-
ing D-depletion and first of all the human clinical appli-
cation of DDW. In 2008 a case series of four lung cancer
patients have been published [24]. The present study is
the first evaluation of the effects of D-depletion in hu-
mans that was conducted on a substantially higher popu-
lation of cancer patients. A human phase II clinical trial
was launched to evaluate the possible anticancer effect of
DDW in humans. Forty-four patients—a homogenous
groups with respect to staging and the applied conven-
tional forms of treatment—were evaluated in the treated
and the placebo group. The only (non-significant) dif-
ference was that anaplastic adenocarcinoma was diag-
nosed in a single patient in the treated, and in four pa-
tients in the placebo group and therefore the final out-
come of the trial could have been slightly altered. While
the four patients in the control group, expectedly, did not
show any improvement, the patient in the treated group
with anaplastic adenocarcinoma achieved PR. These data
suggest that D-depletion might be effective even in those
cases where histological diagnosis predicts poor progno-
sis. The distribution of the best response (PR) to treat-
ments differed significantly after four-month-long DDW
or placebo treatment in the test groups (7 subjects vs. 1
subject).
The three times higher net decrease in prostate volume
in the DDW treated group explains why the urination
complaints ceased at a significantly higher rate (8 pa-
tients vs. 0 patients, p = 0.0041) in the treated group.
urthermore, this was in line with the fact that 15 out of F
Deuterium Depletion May Delay the Progression of Prostate Cancer
554
(a)
(b)
Figure 2. a-b The time course of DDW dose (DdU) and PSA levels (ng/mL) in two patients. The Y axis shows the DDW dose
(right side) and the PSA value (left side). The pecked line depicts the timeline of PSA values, while the solid line represents
the DDW dose. Notes: DdU = deuterium depletion unit, that was calculated considering the difference in D-concentration
between plain tap water and the DDW used, the daily volume of the DDW, and body weight. (a) Patient 1: Five-years follow
up of a 53 years old PC patient, who underwent prostatectomy followed by antiandrogen therapy. Further decrease in PSA
was achieved, when DDW treatment was introduced. Repeated, 12 - 16 weeks long DDW cures kept PSA close to 0.0 ng/mL,
and after the detection of an increase in PSA value the higher DDW dose ensured further reduction of PSA again. (b) Patient
2: Follow-up of a 61 years old PC patient with bone metastasis and highly elevated PSA (1000 ng/mL). DDW treatment was
introduced in addition to the conventional forms of treatment. Despite the potentially poor prognosis the patient remained in
regression for 7.5 years.
22 patients showed over 50% decrease in PSA level in
the treated group while in the placebo group only 9 pa-
tients showed such result. All these results clarify the
impressive difference in the death rate in the two groups
(2:9, treated vs. placebo group) within the first year.
In addition to the prospective study, we had the possi-
Copyright © 2011 SciRes. JCT
Deuterium Depletion May Delay the Progression of Prostate Cancer 555
bility to follow 91 PC patients after the diagnosis for a
cumulative time of 350 years. Patients without distant
metastasis showed extremely low death rate during the
cumulative follow-up period of 157 years (Figure 1(b)).
In patients who suffered from early developing distant
metastasis, D-depletion was able to extend MST to 64.8
months (Figure 1(c)), while other studies indicated a 15 -
20 month-long MST for progressive metastatic PC [22].
Considering also the MST in all prostate cancer patients
that was published in the Hungarian National Cancer
Registry [27] we suggest that D-depletion contributed to
the long overall MST of 11 years calculated in the pre-
sent study (Figure 1(a)).
Examining the PSA values in certain patients’ causal-
ity was observed between DDW cures and the time pat-
tern of PSA-changes (Figures 2(a) and (b)). DDW-con-
sumption could also prolong the progression-free interval
in the early stages of PC.
Based upon the preclinical toxicological investigations
[28], the prospective and retrospective clinical studies,
the application of DDW at a concentration of 25 to 105
ppm D seems to be completely innocuous, and can act as
a highly effective tool in cancer therapy which can be
easily integrated in the treatment regimens. Consequently,
the application of DDW in the most affected population
might reduce the mortality of PC, since it is able to delay
progression as well as to prolong MST in patients with
histologically confirmed PC.
5. Acknowledgements
The authors wish to acknowledge the valuable contribu-
tion of the following clinicians: Gábor Árpási, Béla Böc-
skei, Gábor Csúsz, Tibor Kázmér, Jorgosz Szapanidisz
(St. Johns Hospital, Budapest, Hungary); Dénes Répássy
(St. István Hospital, Budapest, Hungary); Barnabás Rusz-
inkó, György Sára (Uzsoki Hospital, Budapest, Hungary).
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... The possible role of naturally occurring deuterium (16.8 mmol/L in natural waters) was investigated in different studies, which revealed that deuterium depletion inhibited tumor cell growth in vitro and caused tumor regression in vivo [7][8][9][10][11][12]-apparently due to the significantly different chemical and physical properties of hydrogen (H) and deuterium (D) [13,14], and because changing the D/H ratio exerts a significant impact on cell physiology [15,16]. Numerous studies conducted on different cell lines in culture media containing deuterium-depleted water (DDW) verified the determinative role of D in cell cycle regulation and tumor growth [12,[17][18][19][20]. D depletion influences protooncogenes and tumor suppressor genes. ...
... The clinical outcome of D depletion was investigated in prospective, phase 2, double blind [10], and retrospective human clinical studies [10,11,25,26]. For retrospective studies, clinical data on the test results of the conventional therapies in patients consuming DDW were collected. ...
... The clinical outcome of D depletion was investigated in prospective, phase 2, double blind [10], and retrospective human clinical studies [10,11,25,26]. For retrospective studies, clinical data on the test results of the conventional therapies in patients consuming DDW were collected. ...
Article
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Glioblastoma multiforme (GBM) and malignant gliomas are the most common primary malignant brain tumors. Temozolomide (TMZ) chemotherapy plus radiation therapy (RT), admi-mistered after debulking surgery, increased the median survival time (MST) from 12.1 months with RT alone merely to 14.6 months, respectively. In this study, the actions of deuterium-depleted water (DDW) on the survival of GBM patients who also received conventional therapies was investigated. Without changing the conventional treatment, the daily fluid intake of the patients was wholly replaced with DDW in 1.5-2 L per day volume to reduce the D concentration in their bodies. The primary endpoint was the MST. The 55 patients involved in this study, who received conventional treatment and consumed DDW, showed a longer MST (30 months) compared to the historical control (12.1-14.6 months). There was a massive difference between the two genders in the calculated MST values; it was 25 months in the male subgroup (n = 33) and 42 months in the female subgroup (n = 22), respectively. The MST was 27 months without TMZ treatment (38 patients) and 42 months in the TMZ-treated group (17 patients), respectively. For the selected 31 patients, who consumed DDW in the correct way in addition to their conventional treatments, their MST was calculated as 30 months. Within this group, the 20 subjects who had relapsed before DDW treatment had 30 months of MST, but in those 10 subjects who were in remission when DDW treatment started, their MST was 47 months. In the subgroup of patients who began their DDW treatment parallel with radiotherapy, their MST was again 47 months, and it was 25 months when their DDW treatment was started at 8 weeks or later after the completion of radiotherapy. Altogether, these survival times were substantially prolonged compared to the prospective clinical data of patients with primary GBM. Consequently, if conventional therapies are supplemented with D depletion, better survival can be achieved in the advanced stage of GBM than with the known targeted or combination therapies. Application of DDW is recommended in all stages of the disease before surgery and in parallel with radiotherapy, and repeated DDW courses are advised when remission has been achieved.
... Of the included studies, two were conducted in China [28,29], five in Hungary [19,[30][31][32][33], three in Iran [15,17,21], two in Romania [16,34], one in Sweden [18], one in Turkey [20], and one in Russia [35]. The studies identified were categorized into two types based on their subject: fourteen studies of the effect of DDW on cancer cell lines and animal cancer models [15][16][17][18][19][20][21][28][29][30][31][32]34,35] and one clinical study in humans [35]. ...
... Furthermore, both the number of patients with cessation of urination complaints and the one-year survival rate in the treated group were higher than in the placebo group. The decrease in net prostate-specific antigen (PSA) value was 326.1 ng/mL in the treated group compared with 243.6 ng/mL in the placebo group, with an initial PSA value of 406.4 ng/mL in the treated group and 521 ng/mL in the placebo group [33]. ...
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Chemotherapy exhibits numerous side effects in anti-tumour therapy. The clinical experiments indicated that deuterium-depleted water (DDW) monotherapy or in combination with chemotherapy was beneficial in inhibiting cancer development. To further understand the potential mechanism of DDW in cancer therapy, we performed a systematic review. The data from experiments published over the past 15 years were included. PubMed, Cochrane and Web of Science (January 2008 to November 2023) were systemically searched. Fifteen studies qualified for review, including fourteen in vivo and in vitro trials and one interventional trial. The results showed that DDW alone or in combination with chemotherapy effectively inhibited cancer progression in most experiments. The combination treatment enhances the therapeutic effect on cancer compared with chemotherapeutic monotherapy. The inhibitory role of DDW in tumours is through regulating the reactive oxygen species (ROS)-related genes in Kelch-like ECH-associated protein 1 (Keap 1) and Nuclear erythroid 2-related factor 2 (Nrf2) signalling pathways, further controlling ROS production. An abnormal amount of ROS can inhibit the tumour progression. More extensive randomized controlled trials should be conducted to evaluate the accurate effect of DDW in Keap1-Nrf2 signalling pathways.
... In a 4-month randomized doubleblind clinical trial conducted by Kovacs et al. [7], 91 prostate cancer (PC) patients treated with DDW were evaluated and the median survival time (MST) was calculated in the subgroups. The 91 patients evaluated achieved an MST of 11.02 years, despite the fact that 46 of them had metastases. ...
... The 91 patients evaluated achieved an MST of 11.02 years, despite the fact that 46 of them had metastases. The authors demonstrated that the administration of DDW should be implemented in the treatment of CP as an adjunctive therapy [7]. ...
Article
Full-text available
Drinking water has a deuterium (2 H) concentration of 150 ppm. The intake of deuterium-depleted water (DDW) provides a series of effects on the improvement of the state of health, contributing to the prevention of various diseases, as well as the delay in the evolution of certain types of cancer. The objective of this review is to verify the influence of DDW intake on the regression and survival rate of different types of cancer in living beings. The intake of DDW in patients with chronic lymphocytic leukemia, lung, prostate and breast cancer, as well as the antitumor effects of the intake of DDW in living beings, were analyzed. In conclusion, commenting that the intake of DDW has beneficial effects on the increase in the average survival time of cancer patients, favors the inhibition of cancer cell growth, increases the probability of total or partial regression of malignant tumors, as well as the delay in the multiplication of various types of tumor cells (PC-3, MDA, HT-29 and M14) and contributes to the decrease in PSA values in patients with prostate cancer.
... In the prospective trial, in the treated group (deuterium-depleted water at 85 ppm) versus placebo group (normal water at 150 ppm), they achieved the following: partial response (p = 0.046), net decrease in prostate volume was three times higher (p = 0.0019), urination complaints stopped at a higher rate (p = 0.0041), and 1-year survival rate was higher (p = 0.034). (Kovács et al., 2011). ...
Article
Full-text available
Introduction Large variations in fatty and amino acid natural ²H/¹H ratios in reference with solvent water point to the active involvement of compartmental, inter- and intramolecular deuterium disequilibrium in adaptive biology. Yet, the human deutenome is an untapped area of energy metabolism and health in humans. Objectives The purpose of this scoping review is to examine health effects through deuterium homeostasis using deuterium-depleted water and/or a deuterium-depleted diet. We also aim to reveal health effects of nutritional, metabolic and exercise ketosis, i.e. complete mitochondrial fatty acid oxidation with the production of deuterium depleted (deupleted) metabolic water. Methods A protocol process approach was used to retrieve current research in deuterium depletion according to the preferred reporting items protocol for systematic reviews and meta-analyses, extension for scoping reviews with checklist (PRISMA-ScR). Results Fifteen research articles were used. All retrieved articles were heterogenous in nature and additional themes did not evolve. Deuterium depletion was found to have beneficial health effects in the following conditions: cancer prevention, cancer treatment, depression, diabetes, long-term memory, anti-aging, and sports performance. Deutenomics is actively pursued in drug research and there are biomarker roles attributed to large natural variations with adaptive significance in biology. Conclusion Even with limited data, consistent deuterium depletion can be seen across all conditions reviewed. More randomized control trials are recommended to confirm cause and effect for translationally and clinically informed integrative nutrition-based medical interventions.
... The DDW intake in the prostate cancer patients matched with the low concentrations of their prostate serum antigen (PSA). Moreover, DDW treatment prolonged significantly the MST of patients who suffered from distant metastasis [138]. ...
Preprint
Full-text available
Deuterium is a non-radioactive isotope of hydrogen, containing a neutron as well as a proton, which makes it twice as heavy as hydrogen. Deuterium is a natural element found at 156 parts per million in seawater. Human metabolism employs clever strategies to minimize the amount of deuterium in mitochondrial water, because it causes a stutter in ATPase pumps, introducing excess reactive oxygen species and inefficiencies in ATP production. Gut microbes produce hydrogen gas that is 80% depleted in deuterium (deupleted), and this gas is recycled into organic matter that supplies deupleted nutrients to the host, such as acetate, butyrate, formate, methionine, and choline. Mitochondrial dysfunction is associated with many chronic diseases, most notably, cancer. Dehydrogenases are flavoproteins that typically have a high deuterium kinetic isotope effect, and they supply deupleted protons to NAD+ to produce NADH, which supplies protons to the ATPase pumps. Here, we examine the unique metabolic policies of cancer cells in a new light, and we propose that a tumor may arise as a strategy to help repair the mitochondria of tumor-resident immune cells overburdened with deuterium. While lactate accumulation in the tumor microenvironment promotes tumor growth, it also provides a valuable deuterium depleted nutrient to the tumor-resident immune cells. We provide strong evidence that deuterium depleted water (DDW) is a promising treatment for cancer.
... Specifically, it has become clear that high deuterium concentrations promote the growth of cancer cells, whereas low deuterium concentrations inhibit the growth of cancer cells and cause tumor regression [1][2][3]. As an application for cancer treatment, various animal experiments and clinical studies have reported that drinking deuterium-depleted water (DDW) suppresses the expression of cancer genes and causes tumor regression, indicating the possibility that DDW can be used as a safe anticancer drug [4][5][6][7]. ...
Article
Full-text available
Deuterium-depleted water (DDW) is used in the treatment of many diseases, including cancer and diabetes. To detect the effect of DDW on gene expression and activation of the insulin-responsive transporter GLUT4 as a mechanism for improving the pathology of diabetes, we investigated the GLUT4 expression and glucose uptake at various concentrations of DDW using the myoblast cell line C2C12 differentiated into myotubes. GLUT4 gene expression significantly increased under deuterium depletion, reaching a maximum value at a deuterium concentration of approximately 50 ppm, which was approximately nine times that of natural water with a deuterium concentration of 150 ppm. GLUT4 protein also showed an increase at similar DDW concentrations. The membrane translocation of GLUT4 by insulin stimulation reached a maximum value at a deuterium concentration of approximately 50–75 ppm, which was approximately 2.2 times that in natural water. Accordingly, glucose uptake also increased by up to 2.2 times at a deuterium concentration of approximately 50 ppm. Drug-induced insulin resistance was attenuated, and the glucose uptake was four times higher in the presence of 10 ng/mL TNF-α and three times higher in the presence of 1 μg/mL resistin at a deuterium concentration of approximately 50 ppm relative to natural water. These results suggest that DDW promotes GLUT4 expression and insulin-stimulated activation in muscle cells and reduces insulin resistance, making it an effective treatment for diabetes.
... Beyond that, D depletion impedes tumor cell growth by causing oxidative stress [10,11] and reduces their migration [13]. The anticancer effect of D depletion was confirmed, among others, in a 4-month-long, double-blind, randomized human phase 2 clinical trial on prostate cancer [14]. The clinical data of over 500 DDW-consuming cancer patients, collected, evaluated, and published [1,8,15,16,] indicated that the combination of D depletion with the existing therapies (surgery, radio-, chemo-, and hormonal therapy) achieved severalfold increase of Median Survival Time (MST). ...
Article
Full-text available
The anticancer effect of deuterium depletion has been proved in various types of cancer, either in combination with conventional therapies or as a single treatment. Here we present 3 case studies illustrating 3 different cancer types. The first patient was diagnosed with spinal astrocytic glioma, a very rare cancer type. In her case, conventional therapy was and could not be used, but she consumed Deuterium-Depleted Water (DDW). Her follow-up time was 21 years. The second one was diagnosed with carcinoma mammae, worldwide the second most common cause of cancer-related death in women. She was operated, left side mastectomy was done, and metastases were found in 8 out of the 9 removed lymph nodes. She received chemo-and radiotherapy and started DDW consumption one month after the surgery. Her follow-up time was 24 years. The third patient was diagnosed with malignant melanoma, a highly aggressive skin cancer, currently the fifth most common cancer in men and seventh in women. He was operated, then 3 years later liver metastasis was detected, and chemoembolization was done. Afterwards, the patient started a one-year DDW cure, then repeated several cures of various durations, in the subsequent 26 years. These cases confirm that deuterium depletion is effective both as a single treatment and in parallel or subsequent use with conventional therapies. DDW causes regression of the tumors and is an efficient therapeutic modality to achieve better patient outcomes.
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Since its discovery by Harold Urey in 1932, deuterium has attracted increased amounts of attention from the scientific community, with many previous works aimed to uncover its biological effects on living organisms. Existing studies indicate that deuterium, as a relatively rare isotope, is indispensable for maintaining normal cellular function, while its enrichment and depletion can affect living systems at multiple levels, including but not limited to molecules, organelles, cells, organs, and organisms. As an important compound of deuterium, deuterium-depleted water (DDW) possess various special effects, including but not limited to altering cellular metabolism and potentially inhibiting the growth of cancer cells, demonstrating anxiolytic-like behavior, enhancing long-term memory in rats, reducing free radical oxidation, regulating lipid metabolism, harmonizing indices related to diabetes and metabolic syndrome, and alleviating toxic effects caused by cadmium, manganese, and other harmful substances, implying its tremendous potential in anticancer, neuroprotective, antiaging, antioxidant, obesity alleviation, diabetes and metabolic syndrome treatment, anti-inflammatory, and detoxification, thereby drawing extensive attention from researchers. This review comprehensively summarizes the latest progress in deuterium acting on living organisms. We start by providing a snapshot of the distribution of deuterium in nature and the tolerance of various organisms to it. Then, we discussed the impact of deuterium excess and deprivation, in the form of deuterium-enriched water (DEW) and deuterium-depleted water (DDW), on living organisms at different levels. Finally, we focused on the potential of DDW as an adjuvant therapeutic agent for various diseases and disorders.
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Inorganic materials depleted of heavy stable isotopes are known to deviate strongly in some physicochemical properties from their isotopically natural counterparts. Here we explored for the first time the effect of simultaneous depletion of the heavy carbon, hydrogen, oxygen and nitrogen isotopes on the bacterium E. coli and the enzymes expressed in it. Bacteria showed faster growth, with most proteins exhibiting higher thermal stability, while for recombinant enzymes expressed in depleted media, faster kinetics was discovered. At room temperature, luciferase, thioredoxin and dihydrofolate reductase and Pfu DNA polymerase showed up to a 250 % increase in activity compared to the native counterparts, with an additional ∼50 % increase at 10 °C. Diminished conformational and vibrational entropy is hypothesized to be the cause of the accelerated kinetics. Ultralight enzymes may find an application where extreme reaction rates are required.
Article
Inorganic materials depleted of heavy stable isotopes are known to deviate strongly in some physicochemical properties from their isotopically natural counterparts. Here we explored for the first time the effect of simultaneous depletion of the heavy carbon, hydrogen, oxygen and nitrogen isotopes on the bacterium E. coli and the enzymes expressed in it. Bacteria showed faster growth, with most proteins exhibiting higher thermal stability, while for recombinant enzymes expressed in depleted media, faster kinetics was discovered. At room temperature, luciferase, thioredoxin and dihydrofolate reductase and Pfu DNA polymerase showed up to a 250% increase in activity compared to the native counterparts, with an additional ~50% increase at 10 °C. Diminished conformational and vibrational entropy is hypothesized to be the cause of the accelerated kinetics. Ultralight enzymes may find an application where extreme reaction rates are required.
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It is known that the mass difference between hydrogen and deuterium leads to differences in the physical and chemical behaviour between the two stable isotopes. In spite of the fact that the concentration of D is about 150 ppm (over 16 mM) in surface water and more than 10 mM in living organisms the possible role of the naturally occurring deuterium in biological systems was never investigated before 1993. The first experiments with deuterium- depleted water (DDW) revealed that due to the D-depletion the non-tumorous L929 fibroblast cells required longer time to multiply in vitro and DDW caused human breast tumor regression in mice. In this communication we present additional evidence demonstrating that DDW i) inhibits cell proliferation of A4 cell line in vitro; ii) as drinking water inhibits the PC-3 human prostate tumor growth in mice, induces apoptosis in vivo, iii) can induce complete or partial tumor regression in dogs and cats with different tumors. Based upon the observations gained with DDW we suppose that the cells are able to regulate the D/H ratio and the changes in the D/H ratio can trigger certain molecular mechanisms. We suggest that the application of DDW may open new possibilities in cancer therapy by offering a direct intervention into the mechanism playing a central role in cell cycle regulation.
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The role of naturally occurring D in living organisms has been examined by using deuterium-depleted water (30–40 ppm D) instead of water containing the natural abundance of D (150 ppm). The deuterium-depleted water significantly decreased the growth rate of the L929 fibroblast cell line, and also inhibited the tumor growth in xenotransplanted mice. Eighty days after transplantation in 10 (59%) out of 17 tumorous mice the tumor, after having grown, regressed and then disappeared. We suggest that the naturally occurring D has a central role in signal transduction involved in cell cycle regulation.
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Mortality figures become available after some years. Using the World Health Organization mortality and population data, we estimated numbers of deaths in 2011 from all cancers and selected sites for the European Union (EU) and six major countries, by fitting a joinpoint model to 5-year age-specific numbers of deaths. Age-standardized rates were computed using EUROSTAT population estimates. The predicted number of cancer deaths in the EU in 2011 was 1,281,436, with standardized rates of 143/100,000 men and 85/100,000 women. Poland had the highest rates, with smaller falls over recent periods. Declines in mortality for major sites including stomach, colorectum, breast, uterus, prostate and leukemias, plus male lung cancer, will continue until 2011, and a trend reversal or a leveling off is predicted where upward trends were previously observed. Female lung cancer rates are increasing in all major EU countries except the UK, where it is the first cause of cancer death, as now in Poland. The increasing pancreatic cancer trends in women observed up to 2004 have likely leveled off. Despite falls in rates, absolute numbers of cancer deaths are stable in Europe. The gap between Western and former nonmarket economy countries will likely persist.
Book
The analysis of stable isotope ratios represents one of the most exciting new technical advances in environmental sciences. In this book, leading experts offer the first survey of applications of stable isotope analysis to ecological research. Central topics are - plant physiology studies - food webs and animal metabolism - biogeochemical fluxes. Extensive coverage is given to natural isotopes of carbon, hydrogen, oxygen, nitrogen, sulfur, and strontium in both terrestrial and marine ecosystems. Ecologists of diverse research interests, as well as agronomists, anthropologists, and geochemists will value this overview for its wealth of information on theoretical background, experimental approaches, and technical design of studies utilizing stable isotope ratios.
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Summary A Summer School in Nuclear Chemistry sponsored by the U. S. Department of Energy and the American Chemical Society has been held at San José State University for the past 20 years. The intent of the program is to introduce outstanding college students to the field of nuclear and radiochemistry with the goal that some of these students will consider careers on nuclear science. The program features radiochemistry experiments along with radiation safety training, guest lectures by well known nuclear scientists and field trips to nuclear chemistry facilities in the San Francisco area.
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To investigate the in vivo and in vitro inhibitory effects of deuterium-depleted water (DDW) on human lung cancer and the possible mechanisms underlying these effects, we cultured and treated human lung carcinoma cell line A549 and human embryonic lung fibroblasts HLF-1 with various concentrations of DDW from 2 to 72 h. Cellular growth inhibition rates were determined using the 3-(4, 5-dimethyldiazol-2-yl)-2, 5-diphenyltetrazolium-bromide) (MTT) proliferation assay. A549 cells were treated with 50±5 ppm DDW, and the morphology and structure of cells were observed by scanning electron microscopy (SEM). We observed alterations in the cellular skeleton by transmission electron microscopy (TEM) and changes in cell cycle by flow cytometry. Our data showed that DDW significantly inhibited the proliferation of A549 cells at a specific time point, and cells demonstrated the characteristic morphological changes of apoptosis under SEM and TEM. The length of the S phase increased significantly in cells treated with 50 ppm DDW, whereas the G0 to G1 phase and G2 to M phase were decreased. We observed DDW-induced cellular apoptosis using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and DNA fragment analyses. In addition, we established a tumor transplantion model by injecting H460 tumor cells into subcutaneous tissue of BALB/c mice treated with DDW for 60 days. We determined the tumor inhibition rate of treated and control groups and found that the tumor weight was significantly decreased and the tumor inhibition rate was approximately 30% in the DDW group. We conclude that DDW is a promising new anticancer agent with potential for future clinical application.
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Prostate cancer has emerged as the most frequent cancer amongst men in Europe, with incidence increasing rapidly over the past two decades. Incidence has been uniformly increasing in the 24 countries with comparable data available, although in a few countries with very high rates (Sweden, Finland and The Netherlands), incidence has begun to fall during the last 3-4 years. The highest prostate cancer mortality rates are in the Baltic region (Estonia, Latvia and Lithuania) and in Denmark, Norway and Sweden. Prostate cancer mortality has been decreasing in 13 of the 37 European countries considered - predominantly in higher-resource countries within each region - beginning in England and Wales (1992) and more recently in the Czech Republic (2004). There was considerable variability in the magnitude of the annual declines, varying from approximately 1% in Scotland (from 1994) to over 4% for the more recent declines in Hungary, France and the Czech Republic. There appears little relation between the extent of the increases in incidence (in the late 1990s) and the recent mortality declines. It remains unclear to what extent the increasing trends in incidence indicate true risk and how much is due to detection of latent disease. The decreasing mortality after 1990 may be attributable to improvements in treatment and to an effect of prostate specific antigen (PSA) testing. The increase in mortality observed in the Baltic region and in several Central and Eastern European countries appear to reflect a real increase in risk and requires further monitoring.