| Magnesium
Ascorbate being a natural neutral salt has significantly higher
gastrointestinal tolerance and hence is more safe and effective in Magnesium
therapy. Knowing the widespread requirements the body has for magnesium,
magnesium is being looked to more and more as adjunct to several medical regimens.
The more magnesium is investigated, the more far reaching are its apparent
benefits. This organically bound form of magnesium is recognized as the natural and more bio-available delivery system for the vital anti-stress mineral. |
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Structure
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Requirements
|
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The
Food and Nutrition Board of the Institute of Medicine of the United States
National Academy of Sciences has recommended the following Adequate Intake
(AI) and Recommended Dietary Allowance (RDA) values for magnesium
|
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Nutritional
significance of Magnesium in cardiovascular treatment
|
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| Magnesium’s
importance to the health of a large number of biological systems is receiving
ever-increasing support. Magnesium has an essential part in hundreds of
biochemical roles, and depending upon the biological systems in the body that
is involved, it may perform its function via different mechanisms. Magnesium’s place in the area of platelet aggregation appears to be crucial to the control or palliation of a number of important health problems. The hyperactivity of platelets that results in their aggregation and the subsequent release of potent vasoconstrictors may be at the base of problems, such as migraine headaches and vascular diseases associated with diabetes, strokes and various cardiovascular diseases. Recent research indicates magnesium deficiency may be a factor in the development of atherosclerosis and coronary artery disease- the major cause of heart attacks. Several clinical studies indicate that maintenance of adequate red blood cell magnesium levels may be key in fighting these health problems. |
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Role of
Ascorbic acid in cardiovascular therapy
|
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| In the early
1990s, several large population studies showed a reduction in cardiovascular
disorder in those who consumed vitamin C (Ascorbic acid). A study, which
evaluated 11,348 participants over a ten-year period of time, showed that
high vitamin C intake extended average life span and reduced mortality due to
cardiovascular disease by 42%. This was again confirmed by a study involving
11,178 participants who took vitamin C and vitamin E supplements. Several studies suggest different mechanism of action by which ascorbic acid protects against cardiovascular disease.
a.
Atherosclerosis is a natural protective mechanism against
the arterial deteriorating effects by a vitamin C deficiency. Thus vitamin C
deficiency leads to atherosclerosis which in turn causes cardiovascular
disease.
b.
Vitamin C enables the arterial system to expand and
contract with youthful elasticity.
c.
Co-administration of nitrate drugs with vitamin C to
coronary artery disease patients prolongs the vasodilating effects of the
nitrate drugs and the energy producing capacity of the cells is maintained.
Otherwise, nitrate drugs alone cause progressive weakening of the heart
muscle’s ability to produce energy and also the vascular system stops
responding to the dilating effects of the drug. Vitamin C thus potentially
helps to prevent the development of nitrate tolerance.
d.
An especially damaging effect of nitrate drugs is that
they cause a decrease in the intracellular product of cGMP. This energy
substrate is required to maintain cellular energy levels. Vitamin C has been
shown to protect against nitrate-induced depletion of cGMP. The use of vitamin
C during pre-treatment with nitrate drugs increased the availability of
nitric oxide, an important precursor to cGMP.
Thus published
research findings suggest that ascorbic acid may reduce mortality in coronary
artery disease patients, increase life span and possibly eliminate the
effects of nitrate tolerance in those taking nitrate drugs.Magnesium Ascorbate, which provides both Magnesium and Ascorbic acid (Vitamin C) appears to be unique and promising product, in that both the components have the potential to reduce the risk of cardiovascular disease. |
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Other
nutritionally important roles of Magnesium and
L- Ascorbic acid |
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| Magnesium is the
fourth most abundant mineral in the body. It is essential to build the bones
and teeth and numerous metabolic functions. Magnesium is also an ingredient in some antacids and laxatives and is used to prevent premature birth and treat certain types of convulsions and rapid heartbeats (tachycardia). Magnesium works with calcium and phosphorous to build strong bones and teeth. It also plays important roles in:
·
Normal metabolism
·
Proper nerve and muscle function
·
Stimulating calcium function
·
Preventing dental cavities
·
Promoting immunity and
·
Boosting the actions of potassium and some of B-vitamins
·
It may also aid in the treatment of asthma, cardiac
arrhythmia, high blood pressure, fibromyalgia and diabetes.
In addition to
its use for the treatment of hypomagnesemia, magnesium is used for the
treatment of certain cardiac arrhythmia’s, in particular torsasde de points
and eclampsia. Magnesium may also have value for the prevention of
osteoporosis and for the management of migraine headaches in some. There is
preliminary evidence that magnesium may help some with premenstrual syndrome,
type 2 diabetes mellitus and hypertension.Ascorbic acid is involved in modulating iron absorption, transport and storage. It aids in the intestinal absorption of iron by reducing ferric iron to ferrous iron and may stimulate ferritin synthesis to promote iron storage in cells. It is involved in the biosynthesis of corticosteroids, aldosterone, the conversion of cholesterol to bile acids and functions as a reducing agent for mixed-function oxidases. For all of this, ascorbic acid is best known for its antioxidant properties and its possible role in the prevention of certain chronic degenerative disorders, such as coronary heart disease and cancer. In fact, ascorbic acid may be the most important water-soluble antioxidant in the body. Ascorbic acid has antioxidant activity. It may also have antiatherogenic, anticarcinogenic, antihypertensive, antiviral, antihistaminic, immunomodulatory, opthalmoprotective and airway-protective actions. It may aid in the detoxification of some heavy metals, such as lead and other toxic chemicals. Ascorbic acid or, more specifically, ascorbate is an excellent reducing agent, and it acts as cofactor in various biochemical reactions to reduce the transition metals, iron and copper. It can be oxidized by most reactive oxygen and nitrogen species thought to play roles in tissue injury associated with various diseases. By virtue of this scavenging activity, ascorbate inhibits lipid peroxidation, oxidative DNA damage and oxidative protein damage. The antioxidant activity of ascorbate is well established and that activity may be helpful in the prevention of some cancers and cardiovascular diseases. It may also be helpful in protecting against some of the lipid oxidation caused by smoking. Ascorbic acid may also be helpful as immune stimulator and modulator in some circumstances. It may help prevent cataract. |
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Efekti tretmana Kancera visokim koncentracijama Askorbata
Izvor: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798917/
The Effects of High Concentrations of Vitamin C on Cancer Cells
This article has been cited by
other articles in PMC.
Abstract
The effect
of high doses of vitamin C for the treatment of cancer has been
controversial. Our previous studies, and studies by others, have reported
that vitamin C at concentrations of 0.25–1.0 mM induced a dose- and
time-dependent inhibition of proliferation in acute myeloid leukemia (AML)
cell lines and in leukemic cells from peripheral blood specimens obtained
from patients with AML. Treatment of cells with high doses of vitamin C
resulted in an immediate increase in intracellular total glutathione content
and glutathione-S transferase activity that was accompanied by the uptake of
cysteine. These results suggest a new role for high concentrations of vitamin
C in modulation of intracellular sulfur containing compounds, such as
glutathione and cysteine. This review, discussing biochemical pharmacologic
studies, including pharmacogenomic and pharmacoproteomic studies, presents
the different pharmacological effects of vitamin C currently under
investigation.
Keywords:
high concentrations of vitamin C, pharmacogenomics, pharmacoproteomics
1. Introduction
There is increasing evidence that vitamin C (ascorbate) is
selectively toxic to some types of tumor cells, functioning as a pro-oxidant
[1,2,3].
Vitamin C at concentrations of 10 nM–1 mM induced apoptosis in neuroblastoma
and melanoma cells [4]
and was shown to be an important modulator for the growth of mouse myeloma
cells in an in vitro colony assay [5].
Studies have established that the growth of leukemic progenitor cells from
patients with acute myeloid leukemia (AML) and myelodysplastic syndromes
(MDS) can be significantly modulated by vitamin C [6,7].
Intravenous (i.v.) administration of sodium 5,6-benzylidene-l-ascorbate (SBA)
to inoperable cancer patients induced a significant reduction in tumor volume
without any adverse side effects [8].
Furthermore, recent clinical studies have reported that manipulation of
vitamin C levels in vivo can result in clinical benefit for patients
with AML and solid tumors [9].
Recent pharmacokinetic studies reported that 10 g of ascorbate given by
i.v. produced plasma concentrations of nearly 6 mM, which were 25-fold higher
than concentrations resulting from the same oral dose [10,11,12].
Depending on the dose, as much as a 70-fold difference in plasma
concentration was found between oral and i.v. administration [13].
Complementary and alternative medicine practitioners worldwide currently use
ascorbate i.v. in patients, in part because there are no apparent harmful
effects [14,15,16].
Physiological concentration of vitamin C is under 0.1 mM, while plasma
vitamin C concentrations that cause toxicity to cancer cells in vitro
(1 mM–10 mM, depending on cell lines) can be achieved clinically by intravenous
administration, which means a high dose of vitamin C.
In this review, in vitro and in vivo studies are
summarized, showing that ascorbate killed cancer cells (Table 1). In addition, the mechanisms and physiologic
relevance under investigation are also described. The results suggest that
doses of vitamin C induce oxidative stress in cancer cells. Our previous
results indicated that treatment of malignant lymphocytic cell lines with
vitamin C (0.25–1 mM) for 24 h led to a marked dose-dependent decrease of
cell proliferation [17].
The responsive cell lines were human myeloid leukemia cell line HL-60,
retinoic acid (RA)-sensitive acute promyelocytic leukemia (APL) cell line NB4
and RA-resistant APL cell line NB4-R1. Different types of leukemia cells,
such as K562 (chronic myelogenous leukemia cell line) [17]
and KG1 (myeloblast cell line) [18],
were also responsive to vitamin C. A similar result was obtained with cells
containing over 90% of blasts from patients with AML. In these cell lines,
induction of apoptosis by vitamin C demonstrated a dose-dependent effect. In
addition, vitamin C weakly induced apoptosis in ovarian cell lines, including
SK-OV-3, OVCAR-3 and 2774 [17].
For many of the cancer cell lines, ascorbate concentrations caused a 50%
decrease in cell survival. The half maximal concentration (IC50)
values were less than 5 mM, and all tested normal cells were insensitive to
20 mM ascorbate [13].
 2. Molecular Mechanisms Induced by Vitamin C
In our previous study, vitamin C at concentrations of
0.25–2.0 mM significantly induced apoptosis in AML cell lines. Vitamin C
induced oxidation of glutathione (GSH) to its oxidized form (GSSG). As a
result, H2O2 accumulated in a concentration-dependent
manner, in parallel with the induction of apoptosis. The direct role of H2O2
in the induction of apoptosis in AML cells was demonstrated by the finding
that catalase could completely abrogate vitamin C-induced apoptosis [17].
A 30-min incubation of NB4 cells with 0–10 mM vitamin C resulted in its
uptake in a concentration-dependent manner [17,19].
In accordance with its proposed pro-oxidant activity, vitamin C treatment
reduced the GSH/GSSG ratio, which correlated with increased intracellular H2O2
in the NB4 cell line. Levine et al. suggested that the effect was
due only to extracellular and not intracellular ascorbate, and that
ascorbate-mediated cell death was probably due to protein-dependent
extracellular H2O2 generation, via ascorbate radical
formation from ascorbate as the electron donor [13].Although H2O2 induced by ascorbate was first generated extracellularly, it is possible that it could diffuse across the plasma membrane into the intracellular space. Although studies in yeast and bacteria have shown that diffusion of H2O2 across membranes is limited, some reports have suggested that selected aquaporin homologues from plants and mammals can channel H2O2 across these membranes [20,21,22,23,24,25]. The susceptibility of cancer cells to ascorbate treatment might therefore be related to the permeability of hydrogen peroxide.
In our studies, vitamin C dramatically increased
intracellular GSH oxidation and reactive oxygen species (ROS) levels within 3
h in a concentration-dependent manner. However, this GSH oxidation and the
ROS accumulation did not last for a long period of time. After 3 h, the
increase in GSH has been observed and hypothesized to be a defense mechanism
[18].
No additional ROS accumulation resulted from the change in GSH. However,
based upon our studies, the dramatic changes of intracellular oxidation state
within 3 h seem to be enough to induce intracellular signaling. The studies
showed that treatment with 1 mM vitamin C for only 30–60 min, followed by
removal when replacing media, could induce apoptosis in both HL-60 and NB4
cells. This observation is consistent with initiation of apoptosis, resulting
from generation of H2O2 after treatment with ascorbate.
However, treatment with As2O3 resulted in less ROS
accumulation than with vitamin C, and it was not in a concentration-dependent
manner. However, ROS accumulation increased up to 24 h, with a long-lasting
effect. Treatment with vitamin C combined with As2O3
increased ROS accumulation, as well as sustained the effect for up to 24 h.
These results are consistent with cellular data showing that apoptosis
induced by As2O3 is evident even at three days [26,27].
3. Proteomics Studies
Proteomics provides important qualitative information on
post-translational modifications to proteins and quantitative data on protein
expression in response to a particular stimulus. This information is
particularly important when it provides data on early cellular events, such
as the stimulus and signaling cascades triggered independently of protein
neosynthesis. In accordance with its proposed pro-oxidant activity, vitamin
C-mediated reduction in the GSH/GSSG ratio correlated with an intracellular H2O2
increase in the NB4 cell line [17,19].
This type of change in regional oxidation state could cause changes in the
cellular milieu that could result in changes in protein structure. This is
especially true of the oxidation state of cysteine sulfur, which is important
for determining the tertiary structure of proteins. The immediate effects of
cell stimuli are associated with protein post-translational modifications,
such as phosphorylation, glutathionylation and cysteine oxidation. To study
these early modifications, NB4 human leukemia cells were treated with 0.5 mM
vitamin C and then analyzed by two-dimensional analysis. Approximately 240
different spots that were focused in a pH range of 4–7 were detected per
sample.
After exposing cells to vitamin C, we observed one new spot, three
intensified spots and five attenuated spots [19].
Each of these spots were excised, digested with trypsin and analyzed by
matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF).
Peptide mass fingerprint analysis and non-redundant sequence database
matching allowed the unambiguous identification of all of the analyzed
species [19].
An important protein identified from the proteomic analysis was a
thiol/disulfide exchange catalyst, protein disulfide isomerase (PDI), which
was a marker of the effect of vitamin C on NB4 cells [19].
PDI belongs to the superfamily of thiol/disulfide exchange catalysts, which
act as protein-thiol-oxidoreductase enzymes, sharing sequence homology with
thioredoxin [28].
PDI is composed of four domains, which have similarities with thioredoxin
folds (i.e., a-b-b′-a′) [29].
In our study [19],
the intensity of the spot corresponding to the PDI b subunit was decreased in
vitamin C-treated cells as compared with control cells. These results
demonstrated that thiol/disulfide exchange proteins are regulated in NB4
cells after vitamin C exposure. This is consistent with our study showing
that intracellular GSH/GSSG exchange occurs shortly after vitamin C exposure
[17].When we measured cysteine uptake in leukemia cell lines exposed to vitamin C by using 35S-labeled-L-Cys in the media, the time-dependent rate of cysteine uptake in the cell culture increased significantly. The rate of uptake, determined under conditions without vitamin C, was very low. The glutathione synthesis inhibitor, buthionine sulfoximine, potently inhibited this increase, suggesting that incorporation of cysteine that corresponded to the amount of increased glutathione was mediated by glutathione synthesis. Overall, our results indicated that vitamin C-induced glutathione synthesis was accompanied by intracellular cysteine uptake. Glutathione-S transferases (GSTs) are enzymes that catalyze the conjugation of electrophilic substitution to GSH, which protects cells by removing reactive oxygen species and regenerating S-thiolated proteins [30]. Intracellular total GSH levels in AML cells incubated with vitamin C peaked around 3 h, then declined, while the increase in incorporated [35S]-L-Cys peaked at 3 h and remained high. These results showed that [35S]-L-Cys transported into cells through cysteine uptake was incorporated and transferred intracellularly, strongly suggesting that the sulfhydryl transfer system is affected by vitamin C [30]. We therefore hypothesize that the biochemical pathway leading to thiol/disulfide redox regulation could be activated by vitamin C. Interestingly, of the proteins whose expressions changed by vitamin C treatment, immunoglobulin heavy chain binding protein (BiP, identical to Hsp70 chaperone) [19], like PDI, is also a multi-domain chaperone. BiP associated with the α-subunit of prolyl 4-hydroxylase (P4-H) by a disulfide bond [31]. P4-H consists of two distinct polypeptides, the catalytically more important α-subunit and the β-subunit, which is identical to the multifunctional enzyme, PDI [31]. Thus, BiP associated with the α-subunit of P4-H, which is another partner of PDI. The interaction of PDI with its substrates was due to a change in disulfide bonds, indicating that intrachain disulfide bonds between domains and substrates had been reduced [19]. Taken together, these results suggested that vitamin C oxidizes intracellular-reduced glutathione and affects disulfide bond formation in proteins [30]. Tropomyosin was also identified as a marker of the oxidative effect of vitamin C in NB4 cells. The spot corresponding to tropomyosin was positioned at an isoelectric point (pI) of approximately 5.0 and was attenuated in vitamin C-treated cells. In addition, a new spot having almost the same molecular weight was detected, which was positioned at a pI of 4.9 [19]. This new spot was also identified as tropomyosin, suggesting that post-translational chemical modification had affected its pI value. This result is consistent with previous data showing that the extracellular signal-regulated kinase (ERK)-mediated phosphorylation of tropomyosin-1 promoted cytoskeleton remodeling in response to oxidative stress [32]. The acidic shift of the spot with pI 5.0 to the phosphorylated tropomyosin spot by treatment with vitamin C was found to be abrogated by co-treatment with PD98059 [19], demonstrating that phosphorylation of tropomyosin was responsible for the observed acidic shift.
The significance of this observation may be related to
differences in the regulation of the actomyosin contractile system in
non-muscle cells as compared with that present in muscle cells. In addition,
proteins that specifically reacted with sera from chronic myeloid leukemia
patients included structural proteins, such as β-tubulin and tropomyosin
isoforms [33].
Although the function of these proteins in myeloid leukemia needs further
investigation, tropomyosin may have value as a leukemia-associated antigen
and as a molecular target in antigen-based immunotherapy. In this regard, it
is important to note that vitamin C causes a tropomyosin isoform to be
modified during the immediate early response.
4. In Vivo Studies
Levine et al. reported that reaction products
obtained from ascorbate in vitro are also found in vivo [34].
They showed that after i.v. injection, ascorbate baseline concentrations of
50–100 µM in blood and extracellular fluids peaked to >8 mM. After
intraperitoneal injection, peaks approached 3 mM in both fluids. They
hypothesized that in vivo, ascorbate was a prodrug for selective
delivery of ascorbate radical and H2O2 to the
extracellular space. Moreover, a regimen of daily pharmacologic ascorbate
treatment significantly decreased growth rates of ovarian (p <
0.005), pancreatic (p < 0.05) and glioblastoma (p <
0.001) tumors established in mice [35].
In addition to inducing oxidative stress, high concentrations of ascorbic
acid inhibited cell migration and the gap filling capacity of endothelial
progenitor cells (EPCs) [36],
and it has been reported that ascorbic acid inhibited corneal
neovascularization in a rat model [37].
High concentrations of ascorbic acid also inhibited tumor
growth in BALB/C mice implanted with sarcoma 180 cancer cells [38].
The survival rate increased by 20% in the group that received high doses of
ascorbic acid, compared to controls. Gene expression studies from biopsy and
wound healing analysis in vivo and in vitro suggested that
the carcinostatic effect induced by high doses of ascorbic acid were related
to inhibition of angiogenesis [39].
In addition, intraperitoneal administration of high doses of ascorbic acid
quantitatively upregulated Raf kinase inhibitory protein (RKIP) and annexin
A5 expression in a group of BALB/C mice implanted with S-180 sarcoma cancer
cells. The increase in RKIP protein levels suggested that these proteins are
involved in the ascorbic acid-mediated suppression of tumor formation [39].
Moreover, high doses of ascorbic acid (~1 mM) enhanced the apoptosis of
cancer cells during co-treatment with paclitaxel, and the combinational
treatment of paclitaxel and ascorbic acid ameliorated the side effects caused
by paclitaxel in BALB/c mice implanted with or without sarcoma 180 cancer
cells [40].
5. Clinical Studies
Cases of apparent responses of malignancies to intravenous
vitamin C therapy have been reported, although they were reported without
sufficient detail [15,41,42,43,44,45,46].
A recent study showed that oral administration of the maximum tolerated dose
of vitamin C (18 g/day) produced peak plasma concentrations of only 0.22 mM,
whereas intravenous administration of the same dose produced plasma
concentrations approximately 25-fold higher. Larger doses (50–100 g) given
intravenously resulted in plasma concentrations of approximately 14 mM [41].
Some case reports stated that high dose i.v. vitamin C has been used by
Complementary and Alternate Medicine (CAM) practitioners [47].
Phase I evaluation of intravenous vitamin C in combination with gemcitabine
and erlotinib in patients with metastatic pancreatic cancer data did not
reveal increased toxicity with the addition of ascorbic acid [48].
No side effects were reported for most patients, while 59 were reported to
have lethargy or fatigue out of 11,233 patients that received intravenous
vitamin C in 2006 and 8876 in 2008 [47].
Overall, it was reported that high dose intravenous vitamin C did not appear
to cause serious side effects in patients.
Another clinical study reported the depletion of L-ascorbic acid alternating with its supplementation
in the treatment of patients with acute myeloid leukemia or myelodysplastic
syndromes [49].
During the supplementation phase, patients received daily i.v. administration
of vitamin C. A pre-therapy in vitro assay was performed for vitamin
C sensitivity of leukemic cells from individual patients. Of the nine
patients with the in vitro assay indicating their leukemic cells
were sensitive to vitamin C, seven exhibited a clinical response, compared
with none of the six patients who were insensitive to vitamin C.
6. Conclusions
Previous studies have shown that vitamin C is involved
in the mechanism of action of the intracellular microenvironment (oxidation)
state changes that improve therapeutic potential, including apoptosis and
necrosis. Although it is difficult to postulate precise vitamin C-specific mechanisms
at this time, identification of genes or proteins that are specifically
regulated by vitamin C in certain cellular phenotypes could improve the
efficacy of therapies.
Conflicts of InterestThe author declares no conflicts of interest.References… |
Anti- Kancer lek
Kombinacija
Magnezijum Askorbata i Vitamina K3 (100:1)
Izvor: US Patent US 8,507,555 B2
(NON-TOXIC ANTI-CANCER DRUG COMBINING
ASCORBATE, MAGNESIUM AND A NAPHTHOQUINONE)
Inventors:
Thomas M. Miller, El Cajon,
CA (US);
James
M. Jamison, Stow, OH (US)
IZVODI IZ
PATENTA:
…by
the Examples
of types of cancers that are successfully treated
present
compositions and methods are presented in the
list
below and in Table 1, which is not intended to be limiting.
Thus
the present invention is directed to the treatment of
pancreatic
carcinomas, renal cell carcinomas, small cell lung
carcinoma,
non-small cell lung carcinoma, prostatic carci
noma,
bladder carcinoma, colorectal carcinomas, breast, ova
rian,
endometrial and cervical cancers, gastric adenocarci
noma,
primary hepatocellular carcinoma, genitourinary
adenocarcinoma,
thyroid adenoma and adenocarcinoma,
melanoma,
retinoblastoma, neuroblastoma, mycosis fun
goides,
pancreatic carcinoma, prostatic carcinoma, bladder
carcinoma,
myeloma, diffuse histiocytic and other lympho
mas,
Wilms’ tumor, Hodgkin’s disease, adrenal tumors
(adrenocortical
or adrenomedullary), osteogenic sarcoma,
soft
tissue sarcoma, EWing’s sarcoma,
rhabdomyosarcoma
and
acute or chronic leukemias, islet cell cancer, cervical,
testicular,
adrenocortical, or adrenomedullary cancers, cho
riocarcinoma,
embryonal rhabdomyosarcoma, Kaposi’s sar
coma,
etc.
TABLE 1
List of
Cancers/Tumors
acoustic
neuroma
adenocarcinoma
angiosarcoma
astrocytoma
basal
cell carcinoma
bile duct
carcinoma
bladder
carcinoma
breast
cancer
bronchogenic
carcinoma
cervical
cancer
chondrosarcoma
choriocarcinoma
colorectal
carcinomas
craniopharyngioma
cystadenocarcinoma
embryonal
carcinoma
endotheliosarcoma
ependymoma
esophageal
carcinoma
EWing’s tumor
?brosarcoma
gastric
carcinoma
Glioma/glioblastoma
Head and
neck cancers
Hemangioblastoma
Hepatocellular
carcinoma
Hepatoma
Kaposi’s
sarcoma
leiomyosarcoma
liposarcoma
lung
carcinoma
lymphangiosarcoma
lymphangioendotheliosarcoma
Lymphoma
Leukemia
medullary
carcinoma
medulloblastoma
Melanoma
meningioma
mesothelioma
Multiple
myeloma
Myxosarcoma
Nasopharyngeal
carcinoma
Neuroblastoma
oligodendroglioma
osteogenic
sarcoma
ovarian
cancer
pancreatic
cancer
papillary
adenocarcinomas
pinealoma
prostate
cancer
renal
cell carcinoma
retinoblastoma
rhabdomyosarcoma
sebaceous
gland carcinoma
seminoma
small cell lung carcinoma
squamous
cell carcinoma
sweat
gland carcinoma
synovioma
testicular
tumor
Thyroid
cancer
Wilms’ tumor
------
Example
III
Formulations
A.
Capsules
The
preferred embodiment of the method utilizes oral
delivery.
Capsules of a combination of MgVC2/V K3 are pre
pared
with the agents in a predetermined ratio. For example,
0.5 g of
Mg ascorbate (L-Ascorbic acid magnesium salt) is
combined
with 0.005 g of water soluble vitamin K3 (mena
dione
sodium bisulfite). Both vitamins are mixed in the pow-
dered
form and placed in capsules without supplementary
ingredients at the predetermined ratio such as is
100:1…
|
Medicinska studija Lečenja raka
prostate sa Apatone® (Magnezijum askorbat +
Vitamin K3 u odnosu 100:1)
Izvor:
http://www.medsci.org/v05p0062.htm
Int J Med Sci 2008; 5(2):62-67. doi:10.7150/ijms.5.62
Research Paper
A 12 Week, Open Label, Phase I/IIa Study Using
Apatone® for the
Treatment of Prostate Cancer
Patients Who Have Failed Standard Therapy
Basir Tareen1, Jack L. Summers1, James M. Jamison1, Deborah R. Neal1,
1. Summa Health System, Department of Urology, Akron, Ohio, USA
2. William Beaumont Hospital,
Department of Urology, Royal Oak,
Michigan, USA
This is an open access article distributed under the terms of
the Creative
Commons Attribution (CC BY-NC) License. See http://ivyspring.com/terms
for full terms and conditions.
How to cite this article:
Tareen B, Summers JL, Jamison JM, Neal DR, McGuire K, Gerson L,
Diokno
A. A 12 Week, Open Label, Phase I/IIa Study Using Apatoneｮ for the
Treatment of Prostate Cancer Patients Who Have Failed Standard
Therapy.
Int J Med Sci 2008; 5(2):62-67. doi:10.7150/ijms.5.62. Available from
Abstract
Purpose: To evaluate the safety and
efficacy of oral Apatone® (Vitamin C and
Vitamin K3)
administration in the treatment of prostate cancer in patients who
failed standard therapy.
Materials and Methods: Seventeen
patients with 2 successive rises in PSA
after failure of standard local therapy were treated with (5,000
mg of VC and
50 mg of VK3 each day)
for a period of 12 weeks. Prostate Specific Antigen
(PSA) levels, PSA velocity (PSAV) and PSA doubling times (PSADT)
were
calculated before and during treatment at 6 week intervals. Following the
initial 12 week trial, 15 of 17 patients opted to continue
treatment for an
additional period ranging from 6 to 24 months. PSA values were
followed for
these patients.
Results: At the conclusion of the 12 week
treatment period, PSAV decreased
and PSADT increased in 13 of 17 patients (p ≤ 0.05). There were
no
dose-limiting adverse effects. Of the 15 patients who continued
on Apatone
after 12 weeks, only 1 death occurred after 14 months of
treatment.
Conclusion: Apatone showed promise in
delaying biochemical progression in
this group of end stage prostate cancer patients.
Keywords: Prostate, Prostate
neoplasms, ascorbic acid, menadione, Vitamin
K3, Apatone, Cancer
Introduction
The PSA era has led to a stage migration in the clinical course
of prostate
cancer. While this success has dramatically lowered the death
rate from
prostate cancer, it remains the most common cancer in men with
234,460 new
cases and 27,350 deaths in the US in 2007.1 While hormonal therapy is
typically initiated when the disease has advanced beyond local
involvement
and delays the time to PSA recurrence, it has not improved
overall survival2 of
patients with metastatic disease and has significant side
effects.3 Newer
chemotherapeutic regimens for metastatic prostate cancer show
promise,4 but
there are few therapy options for androgen independent prostate
cancer
(AIPC) patients. Therefore, there is a substantial need for new
therapeutic
options.
Because of their relatively low systemic toxicity, vitamin C
(VC) and vitamin
K3 (VK3), have been evaluated for their
abilities to prevent and treat cancer.5
VC exhibited selective toxicity against a variety of malignant
cell lines,
prevented the induction of experimental tumors, acted as a
chemosensitizer,
and acted in vivo as a radiosensitizer. However, variable
clinical results were
obtained with VC because of the difficulty of attaining
clinically active doses.6
VK3 exhibited
selective antitumor activity alone and in conjunction with many
chemotherapeutic agents in human cancer cell lines. However,
while
intravenous VK3 acted as a chemosensitizing and radiosensitizing agent in
patients, 30% of the patients exhibited hematologic toxicity (at
higher
doses).7 When VC
and VK3 were combined in a ratio of 100:1
(Apatone) and
administered to human tumor cell lines, including androgen independent
prostate cancer cells (DU145), they exhibited a synergistic
inhibition of cell
growth and induced cell death by apoptosis at concentrations
that were 10 to
50 times lower than for the individual vitamins.8, 9, 10 In
addition, oral
Apatone significantly (P << 0.01) increased the mean
survival time of nude
mice inoculated i.p. with DU145 cells and significantly reduced
the growth rate
of solid tumors in nude mice (P < 0.05) without inducing any
significant bone
marrow toxicity, changes in organ weight or pathologic changes
of these
organs.9
The purpose of this study was to evaluate the safety and
efficacy of oral
Apatone administered throughout the day in prostate cancer in
patients who
failed standard therapy.
Materials and Methods
Patient selection
Prostate cancer patients who had failed standard therapy were
enrolled at
William Beaumont, Royal Oak, MI and Summa Health Systems, Akron, OH.
Standard therapy was defined to include radical prostatectomy,
radiotherapy
and hormonal ablation. We did not include docetaxol chemotherapy
in our
inclusion criteria for failure of standard therapy. A patient
was required to
have a biopsy with proven prostate cancer and 2 successive rises
in PSA to be
included in the study. The patient could not be currently undergoing
chemotherapy, radiotherapy, or androgen deprivation.
All patients exhibited acceptable renal function with blood urea
nitrogen lower
than 40 mg/dl and creatinine levels lower than 3 mg/dl and
lacked clinical
signs of obstructive liver disease as demonstrated by SGOT
levels below 75
U/l; SGPT levels below 80 U/l and Alkaline Phosphatase levels
below 200 U/l.
TPatients using anticoagulants, chemotherapeutic agents, vitamin
K, or
vitamin C were excluded from the study. This protocol was
reviewed and
approved by the Institutional Review Board, and all patients
provided their
voluntary, written informed consent.
Evaluations
Each subject was interviewed by the study coordinator and
examined by an
urologist. Pretreatment evaluation included: a complete history
and physical
examination with a digital rectal examination for prostate
configuration, size
and symmetry; a medication audit; AUA Pain Scale and Symptom
Score
analysis; a complete blood count with differential,
comprehensive chemistry
panel including liver and renal panel, coagulation studies and a
PSA test. We
did not include standard bone scans or other radiographic
studies as part of
our study protocol. Patients were always seen by the study
coordinator and
the same examining urologist.
Treatment
All patients were treated with Vitamin C: K3 (5,000 mg. of VC and 50 mg. of
VK3 each day,
Apatone) for a total of 12 weeks. Apatone in capsular form (500
mg VC as ascorbate and 5mg VK3 as bisulfite) at a dose of 2 capsules on
arising, then 1 capsule every two hours for six doses followed
by two capsules
at bedtime for a total of ten capsules per day. Following the 12
week study,
two of the three “non-responders” in the study who had large
body mass index
values were given double the dose of Apatone by doubling the
number of
capsules in the previous regimen.
Analysis of PSA changes and Statistics
PSA velocity (PSAV) and doubling time (PSADT) were calculated
using the
Prostate Cancer Research Institute Algorithms.12 Successful outcome was
considered a PSADT increase and a PSAV decrease. The binomial
expansion
was used to calculate the exact probability of the number of
successful
outcomes among the enrolled patients. A probability of p
<0.05 was taken as
indicative of an Apatone effect. Matched t-tests were employed
to test for
significant difference in PSA velocity and doubling times before
and after
treatment.13 Linear
spline fit analysis was used to measure and compare PSA
values before, during and after therapy.12
Results
Of thirty-three patients approached for participation, fourteen
were not
eligible; one withdrew; and one did not have two documented PSA
values prior
to enrollment. The characteristics of the remaining seventeen
patients are
detailed in Table 1. The median patient age was 71.5 (range 56 – 85 years),
AUA performance status 6.5 (range 1 – 14) and median number of
prior
chemotherapy regimens was two.
Table 1
Patient Characteristics
N = 17
Age: median (range) 74.5 (56 – 85)
AUA Symptom Score: median (range) 6 (1 – 14)
Race:
Caucasian 15
African American 1
Prior therapies (1 or more treatments):
Hormonal 10
Radiation 8
Surgery 17
Chemotherapy:
None 0
One 0
Two 0
N = 17
Three or more 1
Pre-treatment PSAV ranged from 1.05 to 696 ng/ml/year (median
21.6
ng/ml/yr), while in-trial PSAV ranged from -12 to 256 ng/ml/year
(median
6.39 ng/ml/yr). Conversely, pre-treatment PSADT values ranged
from 2.0 to
54.4 months (median 3.12 months), while in-trial PSADT values
ranged from
-39 to 57.1 months (median 7.88 months).
Linear spline fit analysis was performed using PSA levels before
treatment,
during treatment and following treatment (Figure 1). Representative curves
are shown for a patient with a pre-treatment PSA > 30 ng/ml
(Fig. 1a), a
patient with 30 ng/ml > PSA > 10 ng/ml (Fig. 1b) and for a patient with a PSA
< 10 ng/ml (Fig. 1c). In all 3 cases, the rate of PSA increase is significantly
decreased during Apatone treatment, but increases at a rate
similar to that
seen before treatment once treatment ended (Fig. 1a and 1b). Thirteen of the
17 patients had a successful outcome; a decrease in PSAV and a
lengthening
of PSDT (Table 2). The probability of 13/17 successful outcomes is 0.008
suggesting the 76 % response we observed, was unlikely due to
chance. The 3
“non-responders” each volunteered to have their dose of Apatone
doubled
following the trial. There were no adverse effects and two of
these three
patients subsequently had a decrease in PSA velocity and
increase in PSA
doubling time. No patient had a significant decrease in absolute
PSA.
Figure 1
Natural Log transformations of PSA measurements for patients
with PSA
greater than 30ng/ml (a); between 10-30ng/ml (b) and less than
10ng/ml
(c). Before and after treatment with Apatone plotted against
time in weeks
fitted with a linear spline with knots at -60 weeks, the start
of Apatone
therapy and end of therapy. (→) indicate
where patients went off Apatone or
started alternative therapy.
(Click on the image to enlarge.)
(Click on the image to enlarge.)
(Click on the image to enlarge.)
Table 2
PSA Velocity and Doubling Time in Months
Patient PSA Velocity PSA Doubling Time
Pre-trial In-trial Change Pre-trial In-trial Change
1 1.74 - 12.0 Decreased 54.4 - 5.86 Increased
2 26.1 - 3.01 Decreased 2.51 - 21.2 Increased
3 257 158 Decreased 3.00 6.30 Increased
Patient PSA Velocity PSA Doubling Time
Pre-trial In-trial Change Pre-trial In-trial Change
4 14.6 9.14 Decreased 27.6 57.05 Increased
5 4.38 3.65 Decreased 2.76 9.17 Increased
6 19.3 - 8.11 Decreased 12.1 - 39.5 Increased
7 9.95 2.74 Decreased 2.72 13.7 Increased
8 1.05 0.00 Decreased 10.6 > 60 Increased
9 696 256 Decreased 2.03 9.24 Increased
10 46.5 12.6 Decreased 3.23 20.4 Increased
11 0 0 Unchanged 0 0.00 Unchanged
12 2.09 0.00 Decreased 5.23 > 60 Increased
13 352 163 Decreased 2.79 8.90 Increased
14 21.1 81.7 Increased 7.24 4.30 Decreased
15 54.2 112 Increased 2.91 2.88 Decreased
16 22.0 30.9 Increased 6.54 6.58 Increased
Following the 12 week trial, 15 of 17 patients opted to continue
Apatone
therapy. Any decision to remain on Apatone therapy was left
entirely to the
patient. Anecdotally, most patients reported feeling “better”
and more
“energetic.” This coupled with stabilization of rising PSA along
with no
significant side effects led the men to continue therapy. Four
continued
therapy for 6 months and 11 continued for at least 1 year with
one patient
continuing for more than 2 years. Therapy was not discontinued
in any patient
due to vitamin toxicity or for other safety reasons. The PSA
values of these
patients were checked at various intervals while on treatment
and remained
stable. Patients terminating Apatone therapy experienced sharp
increases in
PSA levels as seen in the linear spline fit analysis (Figure 1). Of the 11
patients on therapy for greater than 1 year, only one (initial
PSA 256, PSADT=
3 months, and PSAV 157ng/ml/yr) passed away after 14 months.
No noteworthy changes were observed in the patient's complete
blood counts,
biochemistry panels or coagulation studies. No dose limiting
toxicity or
adverse events were experienced. Mild intermittent
gastro-esophageal reflux
symptoms was observed in 16 of 17 patients, but was eliminated
when the
Apatone was taken with meals or with antacids. The average AUA
symptom
score prior to beginning therapy was 7.9 (Table 3). This fell to 7.2 upon
completion of the 12 week trial (P = .07). The average pain
score based on
the standard index was 3.2 initially, 2.3 at 6 weeks and
returned to 3.2 at
twelve weeks (Table 4).
Table 3
AUA Symptom Scores
AUA Score In
Points
Number of
Patients
Initial
Visit
Six Week
Visit
Twelve Week
Visit
Mild (0-7) 7 4.14 ｱ
0.40†
4.27 ｱ
0.51
3.43 ｱ 0.53
Moderate (8-19) 9 10.9 ｱ
0.71
12.0 ｱ
0.21
10.0 ｱ 0.80
Severe (20-35) 0 -- -- --
† = Data expressed as the mean ｱ
standard error of the mean
Table 4
Pain Scores
AUA Pain Score In
Points
Initial Visit Six Week
Visit
Twelve Week
Visit
3.19 ｱ
0.79†
2.31 ｱ 0.66 3.19 ｱ 0.70
† = Data expressed as the mean ｱ
standard error of the mean
Discussion
In a previously published, prospective, randomized trial,
patients with
pathologically proven prostate cancer in advanced stages (M1),
osseous
metastasis and resistance to hormone therapy were given two, 7
day courses
of oral Apatone (VC at 5 g/m2/day and VK3 at 50
mg/m2/day), VC alone, VK3
alone, or a placebo.14 The 7day courses of treatment occurred during the first
and fourth week of the study with two weeks of follow up after
each treatment
period. For the vitamin combination, homocysteine (a marker of
tumor cell
death induced by Apatone) assays showed an immediate and
statistically
significant drop (p<<0.01) in tumor cell numbers, while
PSA serum levels rose
in the two initial weeks and then fell to levels that were
significantly different
(p << 0.01) from the control group. For VC and VK3 alone, a non-significant
difference was observed between the serum levels of homocysteine
and PSA
compared to the control group which suggested that the decreased
PSA levels
were due to tumor cell death.14 In this study, Apatone was administered daily
in a single oral dose which was 2.5 to 3 times higher than the
dose employed
during the initial 12 weeks of our study. This dose resulted in
a significant
decrease in patient PSA levels which was ascribed to Apatone-
induced tumor
cell death by autoschizis. Conversely, the lower Apatone doses
employed in
the current study, led to increased PSADT without decreasing
patient PSA
levels.
In the previous study, Apatone was given in a single daily dose.14 However,
Apatone was designed as an adjunctive therapy for existing
treatment
regimens with Apatone being administered intravenously in a
bolus
immediately prior to chemotherapy or radiotherapy and then in
daily oral
maintenance doses between therapies to prevent tumor growth
following
washout of the chemotherapeutic agent. In addition,
pharmacokinetic studies
indicated serum vitamin C levels returned to steady-state values
within 5 to 6
hours of oral administration.15 For these reasons, Apatone was given every 5
to 6 hours in this study. During the 12 week course of the
study, PSADT was
the primary endpoint. Using this criterion, thirteen of 17 patients
had
significant increases in PSA doubling time. Following the
initial 12 week trial,
two of the three “non-responders” in the study who had large
body mass index
values were given increased Apatone doses adjusted to compensate
for their
elevated BMI values. Both patients subsequently became
“responders”. In
addition, 15 of 17 patients opted to continue Apatone therapy
following the 12
week trial. The PSA values of these patients were checked at
various intervals
while on treatment and remained stable. Therapy was not
discontinued in any
patient due to vitamin toxicity or for other safety reasons.
PSADT has been useful in predicting treatment outcome before
definitive
therapy. For example, PSADT significantly correlated with
biochemical
recurrence16,
linearly correlated with the interval to clinical relapse after PSA
failure following radiation therapy for prostate cancer17, and was the most
powerful indicator of disease activity in men under observation
alone.18 When
pretreatment variables in patients with androgen-independent
prostate cancer
were analyzed to determine the effect on PSA response after
initiating
maximum androgen blockade, increased PSADT was the only
significant
predictor of response.19 These results and others have led D'Amico to conclude
that PSADT is sufficiently robust as a surrogate marker of
prostate cancer
survival to serve as a valid endpoint in trials of patients with
hormonerefractory
disease.17
More recently, PSADT has been used as an effective in vivo
method for
screening nontoxic agents, such as dihydroxyvitamin D3
(calcitriol), that
increase PSADT without concomitantly decreasing PSA and yet
become
clinically valuable when used in combination with other
anticancer agents.11
Our results demonstrate that oral Apatone significantly
increased the PSADT of
almost all the patients without concomitantly decreasing PSA,
while
co-administration of Apatone with known chemotherapeutic agents
in other
cancers resulted in a synergistic increase in antitumor
activity.8,20 These
results suggest that Apatone may find use in the clinic as a
co-adjuvant
therapy potentially in addition to docetaxol. Our decision not
to include
patients with alkaline phosphatase over 200 U/l may have
excluded a number
of men with osteoblastic bone lesions from metastases. This
inherent selection
bias does not allow us to examine the potential role of Apatone
as salvage
therapy, potentially after failure of docetaxol chemotherapy in
hormone
refractory patients.
Conclusions
Apatone is safe and effective with thirteen of the 17 prostate
cancer patients
having a statistically significant (P-value < 0.05) increase
in PSADT and a
decrease in PSADV after taking Apatone for 12 weeks. The
long-term impact
of Apatone on disease progression is unknown and remains to be
demonstrated by further clinical study. Additional studies
appear warranted for
the use of Apatone as a co–adjuvant, or for emerging salvage
chemotherapy in
the treatment of late stage prostate cancer.
Acknowledgements
This research was supported by grants from The Beaumont
Foundation, Royal
Oak, Michigan, IC-MedTech, Inc, San Diego, California
and The Summa Health
System Foundation, Akron,
Ohio.
Conflict of interest
The authors have declared that no conflict of interest exists.
References…
Author contact
Correspondence to: Basir Tareen, M.D., Department of Urology, New York
University, 550
First Avenue, New York, NY 10016.
tareen@medicine.nodak.edu
Received 2008-1-27
Accepted 2008-3-23
Published 2008-3-24
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