U.S. patent application number 11/394311 was filed with the patent office on 2006-10-12 for nontoxic potentiation/sensitization of cancer therapy by supplementary treatment with combined vitamins c and k3.
Invention is credited to Jacques Gilloteaux, James M. Jamison, Jack L. Summers, Henryk S. Taper.
Application Number | 20060229360 11/394311 |
Document ID | / |
Family ID | 26856644 |
Filed Date | 2006-10-12 |
United States Patent
Application |
20060229360 |
Kind Code |
A1 |
Gilloteaux; Jacques ; et
al. |
October 12, 2006 |
Nontoxic potentiation/sensitization of cancer therapy by
supplementary treatment with combined Vitamins C and K3
Abstract
A combination of Vitamin C and a quinone used as a supplemental
treatment for a cancer patient. The combination may be administered
before, during and after the patient undergoes a conventional
cancer treatment protocol. The combination may be administered
orally, intravenously, or intraperitoneally. Oral administration
may be in the form of capsules containing a predetermined ratio of
Vitamin C to Vitamin K.sub.3. The supplemental treatment is
effective to inhibit metastases of cancer cells and inhibit tumor
growth. The ratio of Vitamin C to Vitamin K.sub.3 is in the range
of about 50 to 1 to about 250 to 1. A method for evaluating the
effectiveness of the supplemental treatment includes monitoring the
patient's serum DNase activity throughout the course of
treatment.
Inventors: |
Gilloteaux; Jacques; (Kent,
OH) ; Taper; Henryk S.; (Wilsele, BE) ;
Jamison; James M.; (Rootstown, OH) ; Summers; Jack
L.; (Tallmadge, OH) |
Correspondence
Address: |
BROUSE MCDOWELL LPA
388 SOUTH MAIN STREET
SUITE 500
AKRON
OH
44311
US
|
Family ID: |
26856644 |
Appl. No.: |
11/394311 |
Filed: |
March 30, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10160152 |
Jun 3, 2002 |
7091241 |
|
|
11394311 |
Mar 30, 2006 |
|
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60295025 |
Jun 1, 2001 |
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Current U.S.
Class: |
514/474 ;
514/690 |
Current CPC
Class: |
A61K 31/122 20130101;
A61K 31/375 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 31/375 20130101; A61K 31/122 20130101; A61K 45/06
20130101 |
Class at
Publication: |
514/474 ;
514/690 |
International
Class: |
A61K 31/375 20060101
A61K031/375; A61K 31/12 20060101 A61K031/12 |
Claims
1-63. (canceled)
64. A method of inhibiting metastasis of breast cancer cells, colon
cancer cells, prostate cancer cells, or liver cancer cells in a
host in need thereof, the method comprising the step selected from
at least one of: (a) administering orally to said host a first
composition consisting essentially of Vitamin C and benzoquinone in
an amount synergistically effective to inhibit metastasis of said
cancer cells; or, (b) administering intravenously to said host a
second composition consisting essentially of Vitamin C and
benzoquinone in amounts synergistically effective to inhibit
metastasis of said cancer cells; or (c) intraperitoneally
administering said second composition to said host in amounts
synergistically effective to inhibit metastasis of said cancer
cells.
65. The method of claim 64 wherein said benzoquinone is in a
bisulfite form.
66. The method of claim 64 wherein the ratio of Vitamin C to
benzoquinone in the first and the second compositions is in the
range of between about 50:1 and about 250:1
67. The method of claim 66 wherein the ratio of Vitamin C to
benzoquinone in the first composition is about 100:1.
68. The method of claim 64 further comprising prior to said
intravenous administration step, a step of preparing said second
composition by formulating a solution for intravenous delivery that
consists essentially of Vitamin C and benzoquinone.
69. The method of claim 68 wherein said formulating comprises the
steps of: (a) separately formulating (i) a Vitamin C solution and
(ii) a benzoquinone solution; and (b) mixing (i) and (ii), thereby
formulating said second composition.
70. The method of claim 69 wherein the Vitamin C concentration in
said Vitamin C solution (i) is about 16.7 mg/ml sodium
ascorbate.
71. The method of claim 69 wherein the benzoquinone concentration
in said benzoquinone solution (ii) is about 10 mg/ml.
72. The method of claim 68 wherein said second composition
comprises a mixture of about 16.7 mg Vitamin C and about 0.167 mg
benzoquinone per ml of diluent.
73. A method of inhibiting growth of a tumor which tumor is
selected from the group consisting of a breast tumor, a colon
tumor, a prostate tumor, a lymphoma, a bronchogenic carcinoma, a
nonlymphoblastic leukemia, an upper respiratory tract tumor, a
brain tumor, a neck tumor, a lung tumor, and a liver tumor, in a
subject in need thereof, the method comprising the step selected
from at least one of: (a) orally administering to the subject a
first composition consisting essentially of Vitamin C and
benzoquinone in an amount synergistically effective to inhibit said
tumor growth; or, (b) intravenously administering to the subject,
in need thereof, a second composition of Vitamin C and benzoquinone
in an amount synergistically effective to inhibit said tumor
growth.
74. A method for treating a form of cancer selected from the group
consisting of breast cancer, prostate cancer, colon cancer, liver
cancer, lung cancer, lymphoma, bronchogenic carcinoma,
nonlymphoblastic leukemia, upper respiratory tract cancer, brain
cancer, and neck cancer, in a subject in need of such treatment,
the method comprising: (a) orally administering to the subject a
first composition consisting essentially of Vitamin C and
benzoquinone at a ratio of 100:1 formulated for oral
administration; (b) intravenously administering to said subject a
second composition consisting essentially of Vitamin C and
benzoquinone at a ratio of 100:1 formulated for intravenous
administration; (c) orally administering to said subject the first
composition; (d) optionally, intravenously administering to said
subject the second composition; and; (e) optionally, orally
administering to said subject the first composition.
75. A method for treating a form of cancer selected from the group
consisting of breast cancer, prostate cancer, colon cancer, liver
cancer, lung cancer, lymphoma, bronchogenic carcinoma,
nonlymphoblastic leukemia, upper respiratory tract cancer, brain
cancer, and neck cancer, in a subject in need of such treatment who
is also being given conventional cancer treatment, the method
comprising: (i) prior to the conventional cancer treatment, orally
administering to the subject a first composition consisting
essentially of Vitamin C and benzoquinone at a ratio of 100:1
formulated for oral administration; and, (ii) about one day prior
to the conventional cancer treatment, orally administering to the
subject the first composition at a second frequency that is higher
than said first frequency.
76. The method of claim 75, further comprising the steps of: (iii)
on the day of, but prior to, the conventional cancer treatment,
orally administering the first composition at said first frequency;
(iv) on the day of, but prior to, the conventional cancer
treatment, intravenously administering the second composition; and,
(v) administering the conventional cancer treatment.
77. The method of claim 76 further comprising the step of: (vi) on
the day following the conventional cancer treatment, orally
administering, the first composition.
78. The method of claim 76, wherein the first frequency is once
every five hours and the second frequency is once every two
hours.
79. The method of claim 78, wherein on the day of, but prior to,
the conventional cancer treatment the first composition is orally
administered between about 30 minutes and about 180 minutes prior
to the conventional cancer treatment, and the second composition is
intravenously administered between about 30 minutes and about 180
minutes prior to the conventional cancer treatment.
80. The method of claim 74, wherein the cancer is breast cancer or
liver cancer.
81. The method of claim 75, wherein the cancer is breast cancer or
liver cancer.
82. The method of claim 76, wherein the cancer is breast cancer or
liver cancer.
83. The method of claim 77, wherein the cancer is breast cancer or
liver cancer.
84. The method of claim 78, wherein the cancer is breast cancer or
liver cancer.
85. The method of claim 79, wherein the cancer is breast cancer or
liver cancer.
Description
[0001] This application claims priority to U.S. Ser. No.
60/295,025, entitled NONTOXIC POTENTIATION/SENSITIZATION OF CANCER
THERAPY BY SUPPLEMENTARY TREATMENT WITH COMBINED VITAMINS C AND
K.sub.3, filed Jun. 1, 2001.
BACKGROUND OF THE INVENTION
[0002] 1. Field of Invention
[0003] This invention pertains to the art of methods for the
prevention and treatment of human cancer, and more specifically to
methods utilizing a combination of Vitamin C and Vitamin K.sub.3
for the prevention and treatment of human cancer.
[0004] 2. Description of the Related Art
[0005] Metastases are one of the greatest problems in cancer
patients. They appear in almost all cases of this disease and are
the primary cause of mortality in cancer patients. The metastatic
process begins when cancer cells escape from the primary tumor,
invade the basement membrane of regions capillary vessels and
traverse into the blood or lymph and migrate to distant organs or
tissues. There they form vascular emboli from which the cancer
cells cross the basement membrane of capillary vessels for the
second time and colonize the new tissue or organ. Different
mechanisms are involved in the so-called metastatic cascade,
including angiogenesis, cellular adhesion, local proteolysis and
tumor cell migration. Development of chemotherapeutic agents that
target and intervene in one or more processes in the metastatic
cascade should lead to a favorable outcome for a large number of
cancer patients.
[0006] In the art there has been much attention focused on the role
of vitamins in cancer prevention and treatment. For example, it is
known that Sodium Ascorbate, hereafter referred to as Vitamin C,
has been shown to provide improved effects to certain cancer
treatments. Vitamin C potentiates the growth inhibitory effect of
certain agents and increases the cytotoxicity of other agents. It
is considered that Vitamin C may even reverse malignant cell
transformation.
[0007] Similarly, it has been reported in the art that
2-Methyl-1,4-Naphthoquinone, hereafter referred to as Vitamin
K.sub.3, provides improvements in the field of cancer
treatment.
[0008] Research has been conducted on the combination of Vitamin C
and Vitamin K.sub.3 to determine the usefulness of the combination
as a cancer chemotherapy potentiating agent.
[0009] One publication, entitled EFFECTS OF SODIUM ASCORBATE
(VITAMIN C) AND 2-METHYL-1,4-NAPHTHOQUINONE (VITAMIN K.sub.3)
TREATMENT ON PATIENT TUMOR CELL GROWTH IN VITRO (1989), teaches
that Vitamin C tends to accumulate in tumors, may reverse malignant
cell transformation, may demonstrate cytotoxic action toward tumor
cells, and requires high dosages to achieve an inhibiting effect
when administered alone. The article teaches that Vitamin K.sub.3
inhibits growth of mammalian tumor cells in a culture, and requires
high dosages to achieve a desirous effect when administered
alone.
[0010] A second publication, entitled NON-TOXIC POTENTIATION OF
CANCER CHEMOTHERAPY BY COMBINED C AND K.sub.3 VITAMIN PRE-TREATMENT
(1987) discloses in vivo (mice) intraperitoneal injection of
Vitamin C at 1 g/Kg and K.sub.3 at 10 mg/Kg before or after a
single treatment of several cytotoxic drugs.
[0011] POTENTIATION OF RADIOTHERAPY BY NONTOXIC PRETREATMENT WITH
COMBINED VITAMINS C AND K.sub.3 IN MICE BEARING SOLID
TRANSPLANTABLE TUMOR (1996) discusses the use of a Vitamin
C/Vitamin K.sub.3 combination in conjunction with radiotherapy
cancer treatments.
[0012] CANCER CHEMOTHERAPY POTENTIATION INDUCED BY COMBINED VITAMIN
C AND K.sub.3 WITH FERROUS SULFATE PRETREATMENT (1992) teaches
administration of Vitamin C and Vitamin K.sub.3 prior to treatment
with certain chemotherapeutic agents.
[0013] NON-TOXIC SENSITIZATION OF CANCER CHEMOTHERAPY BY COMBINED
VITAMIN C AND K.sub.3 PRETREATMENT IN A MOUSE TUMOR RESISTANT TO
ONCOVIN (1992) discusses the use of an intraperitoneal injection of
Vitamin C and Vitamin K.sub.3 as a pretreatment in order to
increase tumor sensitization to the action of Oncovin.
[0014] EFFECTS OF SODIUM ASCORBATE (VITAMIN C) AND
2-METHYL-1,4-NAPHTHOQUINONE (VITAMIN K.sub.3) TREATMENT ON PATIENT
TUMOR CELL GROWTH IN VITRO. II. SYNERGISM WITH COMBINED
CHEMOTHERAPY ACTION (1993) reports the results of additional in
vitro studies involving simultaneous exposure to Vitamin C and
Vitamin K.sub.3.
[0015] Each of the publications identified above is incorporated in
its entirety by reference into this specification.
[0016] There remains a need in the art for improved methods of
enhancing the efficacy of cancer treatments. The present invention
is directed to a method of treating a patient having cancer by
supplemental treatment with a combination of VC/VK.sub.3. The
supplemental treatment is utilized prior, during, and following the
use of conventional cancer treatments, such as radiology and
chemotherapy. Specifically, the present invention is directed
toward a clinical dosing protocol. Still further, the present
invention is directed to methods of preparation of both oral and
intravenous delivery systems of the VC/VK.sub.3 combination.
[0017] The present invention is further directed to methods of
determining the effectiveness of the supplemental treatments. The
improved methods further provide indications of when additional
supplemental treatments should be administered.
SUMMARY OF THE INVENTION
[0018] In accordance with the present invention, there is provided
a clinical protocol for the administration of a supplemental cancer
treatment utilizing a combination of VC/VK.sub.3.
[0019] In accordance with the invention, there is provided a method
of inhibiting metastasis of cancer cells sensitive to the effects
of a vitamin C/quinone combination which comprises administering to
a host in need of such inhibiting, a combination of Vitamin C and a
quinone wherein the combination is administered in an amount
synergistically effective to inhibit metastasis of cancer
cells.
[0020] In accordance with the invention, the administering step
includes following a predetermined dosing regimen for administering
the combination.
[0021] In accordance with the invention the predetermined dosing
regimen includes providing a first phase of treatment with the
combination; and, providing a subsequent phase of treatment
following the first phase.
[0022] In accordance with the invention, the combination is
administered as a supplemental treatment in conjunction with a
conventional cancer treatment protocol.
[0023] In accordance with the invention, the quinone is Vitamin
K.sub.3.
[0024] In accordance with the invention, there is provided a dosing
regimen for a combination of Vitamin C and a quinone for use in
treating a host in conjunction with a conventional cancer treatment
protocol, the dosing regimen comprising: a first phase wherein a
first amount of the combination is administered to the host each
day from an initial treatment day up until two days prior to
subjecting the host to a conventional treatment according to a
conventional cancer treatment protocol; a second phase wherein a
second amount of the combination is administered to the host for
each of two days prior to subjecting the host to the conventional
cancer treatment protocol; a third phase wherein a third amount of
the combination is administered to the host on a same day as the
host is subjected to the conventional cancer treatment protocol; a
fourth phase wherein a fourth amount of the combination is
administered to the host on the day following the conventional
cancer treatment protocol.
[0025] In accordance with the invention, there is provided a method
for monitoring the effectiveness of a supplemental cancer
treatment, the monitoring method comprising the step of
administering a supplemental cancer treatment to a patient; and,
measuring a serum alkaline DNase activity of the patient before,
during, and after the step of administering the supplemental cancer
treatment.
[0026] In accordance with the invention, there is provided a method
of inhibiting tumor growth in a tumor sensitive to the effects of a
Vitamin C/quinone combination which comprises administering to a
host in need of such inhibiting, a combination of Vitamin C and a
quinone wherein the combination is administered in an amount
synergistically effective to inhibit tumor growth.
[0027] In accordance with the invention, there is provided a cancer
supplemental treatment kit comprising a plurality of capsules, each
of the capsules comprising a combination of Vitamin C and a
quinone.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] The invention may take physical form in certain parts and
arrangement of parts, a preferred embodiment of which will be
described in detail in this specification and illustrated in the
accompanying drawings which form a part hereof and wherein:
[0029] FIG. 1 illustrates the structural formula of Vitamin C.
[0030] FIG. 2 illustrates the structural formula of Vitamin
K.sub.3.
[0031] FIG. 3 is a graph showing the results of a study involving
four groups of male athumic nude mice.
[0032] FIG. 4 illustrates serum alkaline deoxyribonuclease activity
in healthy individuals and in cancer patients.
[0033] FIG. 5 is a schematic representation of serum alkaline DNase
activity verses clinical response in patients with a malignant
tumor.
[0034] FIG. 6 illustrates the variation of serum alkaline DNase
activity in a cancer patient over time.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0035] The following definitions are given to clarify the usage of
terms herein. "Neoplastic" denotes a type of cell exhibiting
uncontrolled proliferation. Generally, mitotic progeny of a
neoplastic cell are also neoplastic in character and do not
terminally differentiate in vivo in response to physiologically
normal (nonpathological) endogenous (not exogenous or invasive)
environmental cues. Neoplastic cells include cancerous and
transformed cells. Neoplastic cells can be isolated in the body (a
metastatic or disseminated neoplastic cell) or aggregated, either
homogeneously or in heterogeneous combination with other cell types
in a tumor or other collection of cells. In this regard, a "tumor"
includes any collection of cells (neoplastic or otherwise) in which
at least some of the member cells are physically associated with at
least some other member cells through a common extracellular
matrix.
[0036] "Autoschizic cell death" is the term used to denote a type
of necrosis characterized by exaggerated membrane damage and
progressive loss of organelle-free cytoplasm through a series of
self-excisions.
[0037] "Synergistic effective amount" denotes an amount of vitamin
C and a quinone in accordance with the invention that is effective
to produce advantageous results when the vitamin C and quinone are
used in combination, rather than results obtained by vitamin C and
a quinone used individually to treat a host.
[0038] The present invention is directed toward cancer treatment
protocols that include a supplemental administration of a Vitamin
C/quinone combination in conjunction with other conventional cancer
treatments. Benzoquinone is an example of a quinone that has been
shown to inhibit the metastasis of several colon cancer lines that
had been implanted into immunocompetent mice. In accordance with
the present invention, a preferred quinone is Vitamin K.sub.3. The
preferred form of Vitamin K.sub.3 is the bisulfite form that is
water soluble, and does not build up in the lipids of the subject.
In this description of the preferred embodiment, reference is made
to a preferred embodiment utilizing Vitamin K.sub.3, however, the
invention is not thereby limited. FIG. 1 illustrates the structural
formula of Vitamin C (10). FIG. 2 is directed to the structural
formula of the bisulfite form of Vitamin K.sub.3 (12).
[0039] It has been discovered that the VC/VK.sub.3 combination
exerts antitumor and antimetastatic activities through a wide array
of mechanisms including: blockage of the cell cycle, modulation of
signal transduction and potentiation of the immune system, and
induction of necrosis characterized by exaggerated membrane damage
and the progressive loss of cytoplasm through a series of
self-excisions. This action is termed "autoschizic cell death" in
this disclosure.
[0040] As a cancer treatment protocol, in its widest scope, the
present invention provides a method of killing a cell with a
neoplastic disorder within a patient by supplemental treatment with
a predetermined regimen of a VC/VK.sub.3 combination, in
conjunction with conventional cancer treatment such as
radiotherapy, chemotherapy, or brachiotherapy. The supplemental
treatment begins prior to an initial conventional cancer treatment,
and continues into the interval between subsequent conventional
treatments.
[0041] This approach is effective in treating patients having
intact tumors. For example, it is known in the art that when a
tumor grows to a certain size, then eventual metastases becomes
predictable. Use of the present invention retards or inhibits tumor
growth. Therefore, the inventive method reduces the likelihood that
cells from such tumors will eventually metastasize or
disseminate.
[0042] The inventive method can reduce or substantially eliminate
the potential for further spread of neoplastic cells throughout the
patient, thereby also reducing or minimizing the probability that
such cells will proliferate to form novel tumors within the
patient. In the event that the preventive method achieves
substantial reduction or elimination of the tumor, then the
pathogenic effects of such tumors within the patient are
attenuated.
[0043] In the preferred vitamin combination of the present
invention, the preferred ratio of the amount of Vitamin C to
Vitamin K.sub.3 is 100 to 1. This preferred ratio will be
referenced in this specification as exemplary only and not by way
of limiting the invention. However, in its widest scope, the
present invention has been shown to be an effective cancer
treatment protocol when the ratio of the amount of Vitamin C to the
amount of Vitamin K ranges between 50 to 1 and 250 to 1.
[0044] In the dosing regimen, the maximum dosage of the combination
is limited by the Vitamin K.sub.3 dose, since Vitamin K.sub.3 is
believed to be toxic at high concentrations.
[0045] Where both vitamins are delivered orally, the dosage of
Vitamin C may range from about 33.3 mg/Kg (body weight)/day to a
maximal amount of about 1 g/Kg/day. The dosage of Vitamin K.sub.3
may range from about 0.17 mg/Kg/day to a maximal amount of about
200 mg/Kg/day. In a preferred embodiment, the ratio of vitamin C to
vitamin K.sub.3 is about 50 to 1. In another preferred embodiment,
the ratio of vitamin C to vitamin K.sub.3 is about 250 to 1. In yet
another preferred embodiment, the ratio of vitamin C to vitamin
K.sub.3 is about 100 to 1. In the preferred embodiment, the ratio
of vitamin C to vitamin K.sub.3 is preferably in the range of 50 to
1 to 250 to 1, respectively.
[0046] In the case where both vitamins are delivered intravenously
or intraperitoneally, the dosage of Vitamin C may be is as low as 1
g/Kg/day. In a preferred embodiment, the dosage of Vitamin C may be
about 100 g/Kg/day. In another preferred embodiment, the dosage of
Vitamin C may be up to about 625 g/Kg/day. In another preferred
embodiment, the dosage of Vitamin C may be in the range of about
1/g/Kg/day to up to about 625/g/Kg/day.
[0047] The dosage of Vitamin K.sub.3 may be as low as about 20
mg/Kg/day. In a preferred embodiment, the dosage of Vitamin K.sub.3
may be 1 g/Kg/day. In another preferred embodiment, the Vitamin
K.sub.3 may be up to about 2.5 g/Kg/day. In another preferred
embodiment, the dosage of Vitamin K.sub.3 may be in the range of
about 20 mg/Kg/day to about 2.5 g/Kg/day.
[0048] In the practice of the present invention, the vitamin
combination can be administered by any suitable manner, i.e.,
orally, intravenously, or intraperitoneally. The vitamins can also
be delivered, for example, by injection of vitamin K.sub.3, and
administration of Vitamin C in drinking water. In a preferred
embodiment, both oral and intravenous administration is
utilized.
EXAMPLE I
Capsule Formulation
[0049] The preferred embodiment of the invention utilizes an oral
delivery system for a portion of the supplemental treatment
regimen. In the preferred embodiment, capsules of a combination of
VC/VK.sub.3 are prepared. Each capsule according to the invention
contains the vitamins in a predetermined ratio. For example, 0.5 g
of sodium ascorbate (L-Ascorbic acid sodium salt) is combined with
0.005 g of water soluble vitamin K.sub.3 (menadione sodium
bisulfite). In the preferred embodiment, both vitamins are mixed in
the powdered form and placed in capsules without any supplementary
ingredients. In this example, the predetermined ratio is 100 to
1.
EXAMPLE II
IV Preparation
[0050] The preferred embodiment of the invention further utilizes
intravenous delivery for another portion of the supplemental
treatment regimen. In the preferred embodiment, solutions of
vitamin C and vitamin K.sub.3 are prepared and stored separately
and mixed directly before intravenous infusion. Exemplary
intravenous solutions are prepared as follows:
[0051] Solution of Vitamin C: 5 g Sodium ascorbate; 1.2 g NaCl; 300
ml Sterile, apyrogenic water for injection.
[0052] Solution of Vitamin K.sub.3: 50 mg Menadione sodium
bisulfite; 5 ml Sterile, apyrogenic water for injection.
[0053] These solutions must be oxygen-free (e.g. perfused with
gaseous nitrogen); sterilized by filtration (millipore filters of
pore diameter approximately 0.22 nm); and introduced into sterile
and devoid of oxygen pockets for the vitamin C solution or glass
vials for vitamin K.sub.3 solution. Each series of prepared pockets
or vials must be examined for apyrogenicity and sterility by
methods known in the art. Since both vitamins are oxygen, light,
and temperature sensitive, the solutions should be stored in anoxic
conditions at approximately 4.degree. C. in darkness to insure
their effectiveness.
[0054] Alternately, the intravenous solution may be prepared by
mixing 5 grams of Vitamin C and 50 mg of Vitamin K.sub.3 in 300 ml
of sterile non-pyrogenic normal saline in an IV bag immediately
prior to use.
EXAMPLE III
Treatment Regimen
[0055] In the preferred embodiment, the treatment regimen is
divided into distinct phases. Phase I includes the period of time
prior to treatment with conventional cancer treatment (e.g.
radiotherapy, chemotherapy, brachiotherapy), ending with two days
prior to conventional treatment. Phase I is designated -t.sub.x.
Phase II comprises the day before the convention treatment and is
designated -t.sub.1. Phase III comprises the day of the
conventional cancer treatment and is designated t.sub.0. Phase IV
comprises the day following the conventional cancer treatment and
is designated +t.sub.1. Phase V is the period of time following
Phase IV and is designated +t.sub.x. If additional conventional
treatments are to be used on the patient, then the cycle repeats so
that Phase V melds into Phase I of the next cycle.
[0056] In the preferred embodiment, Phase I includes at least two
weeks and more preferably includes four weeks. Additionally, Phase
V preferably includes the entire period of time prior to a next
conventional treatment, if any, which are generally spaced from
four to six weeks apart.
[0057] The preferred supplemental treatment regimen is as follows:
[0058] Phase I: 4 capsules per day taken at 5-hour intervals;
[0059] Phase II: 10 capsules per day taken at 2-hour intervals;
[0060] Phase III: 10 capsules per day taken at 2 hour intervals,
plus intravenous delivery of up to 5 g Vitamin C and 50 mg Vitamin
K.sub.3, prepared as above, at least approximately 30 minutes, but
less than approximately 3 hours prior to the conventional
treatment; [0061] Phase IV: 10 capsules per day taken at 2-hour
intervals; [0062] Phase V: 4 capsules per day taken at 5-hour
intervals.
[0063] The preceding dosing regimen is provided for exemplary
purposes only and not by way of limiting the invention.
EXAMPLE IV
Case Study I
[0064] The following example demonstrates the efficacy of the
present invention. In particular the example demonstrates that
pretreatment of neoplastic cells with a VC/VK.sub.3 combination
increases the efficiency of conventional cancer treatments. This
example is included here merely for illustrative purposes and
should not be construed so as to limit any aspect of the claimed
invention.
[0065] This case study concerns a woman with recurrent breast
cancer with pea-size metastases to the vertebral column. After the
primary tumor had been surgically removed, she was subjected to
four cycles of traditional chemotherapy. However, new metastases
were observed and existing metastases were seen to grow following
each of the four cycles of chemotherapy. Immediately following the
last of these four chemotherapy sessions, the patient took 2 g of
Vitamin C and 20 mg of Vitamin K.sub.3 (4 capsules total) orally at
approximately five-hour intervals. On the day proceeding, the day
of, and the day following chemotherapy, the patient received 5 g of
Vitamin C and 50 mg of Vitamin K.sub.3 (10 capsules total) orally
at approximately two-hour intervals. In addition to the oral
dosage, approximately thirty minutes prior to another chemotherapy
treatment, the patient received an intravenous solution of 4.5 g
Vitamin C and 45 mg of Vitamin K.sub.3. On the second day following
chemotherapy, she resumed taking 2 g of Vitamin C and 20 mg of
Vitamin K.sub.3 (4 capsules total) orally at approximately
five-hour intervals until the day prior to the next chemotherapy.
Following one cycle of this regimen, no new metastases were
observed and existing metastases were observed to decrease in size.
The metastases continued to be diminished with each subsequent
cycle of chemotherapy. After 5 cycles of chemotherapy, the
patient's cancer went into remission and she has been cancer free
for over four years.
EXAMPLE V
Case Study II
[0066] This case study involves a man with colon cancer who had
large and abundant metastases to the liver. This end-stage cancer
patient had been undergoing chemotherapy with 5-fluorouracil and
other chemotherapeutic agents and was suffering many side effects
from the treatment. In addition, he was bloated with ascites fluid
and was expected to die within 2 months. The patient received oral
dosages of a vitamin C (2.0 g/day)/vitamin K.sub.3 (0,020 g/day)
combination in conjunction with the chemotherapy. While the vitamin
combination was not curative, it did substantially ameliorate the
side effects of the chemotherapy. In addition, he survived
relatively pain free and was lucid until his death nearly two years
later.
EXAMPLE VI
Evaluation Of Vitamin-Induced Changes In Life Span Of Nude Mice
[0067] Male athymic nude mice (NCCr-nu/nu; 4 weeks old) were
purchased from Taconic Farms (Germantown, N.Y.) and maintained in
microinsulator cages (within the AALAC accredited NEOUCOM
Comparative Medicine Unit) in a pathogen-free isolation facility.
After a one-week isolation period, the nude mice were divided into
four groups of eight animals. Group I received the vitamin
combination daily for one week by oral gavage prior to tumor
injection. Group II received a single intraperitoneal injection of
the vitamin combination 48 hours after tumor inoculation. Group III
received both oral and intraperitoneal vitamin combination at the
dosages and regimen described for Groups I & II. Group IV
received a single intraperitoneal injection of the administration
vector. All mice were inoculated with 5.0.times.10.sup.6 DU145
cells and the date of death was recorded. Mice surviving 90 days
post tumor inoculation were considered long term survivors. FIG. 3
illustrates the % mortality vs. days for this study.
[0068] The mean survival days and percentages of long term
survivors are summarized in TABLE I below: TABLE-US-00001 TABLE I
Group Number Mean Survival Days Long Term Survivors I 71 .+-. 15
25% II 66 .+-. 12 0% III 69 .+-. 4.6 12% IV 60 .+-. 4.7 0%
[0069] One month after the death of the last control mouse,
surviving mice were sacrificed and autopsied. These mice showed
little if any tumor burden (4-6 tumors vs. 40-60 tumors for control
mice.) The similarity in mean survival days for Groups I & III
suggest that the oral vitamin administration may be the most
effective route of delivery.
[0070] With reference to TABLE 1, the mortality rates of the test
groups are shown. In Group III, the first mouse died on day 45,
however, an autopsy revealed a low amount of tumor burden. Liver
necrosis and signs of infection suggested that the mouse died from
infection, not tumor load. Therefore, the first tumor-related death
of mice in Group III occurred four days after the death of the last
control mouse.
EXAMPLE VII
Measurement of Vitamin-Induced Changes in Solid Tumor Volume
[0071] Four week old male athymic nude mice were held in isolation
for one week. Subsequently, 1.times.10.sup.6 DU145 cells suspended
in 0.1 ml of matrigel were injected subcutaneusly into the
interscapular region. After tumors of sufficient size had developed
(a minimum of 3 mm in the smallest dimension), the mice were
weighed, randomized, and divided into four groups of eight animals.
Group A received the vitamins ad libitum in their drinking water
for the duration of the study. Group B received the vitamins twice
per week by subcutaneous injection near the tumor. Group C received
vitamins in their drinking water and by subcutaneous injection at
the doses and regimen described in Groups A and B. Group D received
only water. The weight and tumor size of individual mice were
determined weekly. Tumor volume was calculated using the formula:
V=(L.times.W.sup.2)/2, where V=volume, L=length, and W=width. After
3 weeks of vitamin exposure, the mice were sacrificed and major
organs were removed, weighed and histologically examined.
[0072] The change in the volume of the tumors is given for each
group in Table II below: TABLE-US-00002 TABLE II TIME IN WEEKS
GROUP 0 1 2 3 A 0.098 .+-. 0.047 0.313 .+-. 0.147 0.657 .+-. 0.222
0.918 .+-. 0.308 B 0.086 .+-. 0.032 0.511 .+-. 0.293 1.186 .+-.
0.579 1.207 .+-. 0.308 C 0.077 .+-. 0.032 0.320 .+-. 0.122 0.541
.+-. 0.228 0.963 .+-. 0.400 D 0.073 .+-. 0.035 0.498 .+-. 0.169
0.959 .+-. 0.346 1.420 .+-. 0.492 Volume given in cm.sup.3
[0073] In this example, oral vitamin administration resulted in
statistically significant slowing of tumor growth, while
subcutaneous vitamin administration had no effect on the rate of
tumor growth. The fact that the oral vitamins were administered ad
libitum in the drinking water suggests that the continuous presence
(of even small doses) or periodic introduction of small doses of
the vitamins may be more effective in controlling the growth of the
tumor than gavage of a larger dose of the vitamins.
[0074] The results of the histological examination of major organs
for Group A and Group D (control) is given in Table III below:
TABLE-US-00003 TABLE III GROUP Heart Kidney Liver Lungs Spleen A
0.166 .+-. 0.020 0.616 .+-. 0.057 2.294 .+-. 0.263 0.206 .+-. 0.008
0.227 .+-. 0.027 D 0.198 .+-. 0.010 0.703 .+-. 0.069 2.883 .+-.
0.245 0.235 .+-. 0.026 0.245 .+-. 0.088
[0075] None of the organs of the vitamin treated mice exhibited a
weight that was significantly different from the control mice.
Histological examination for signs of vitamin-induced pathology to
the heart, kidneys, liver, lungs, spleen, the epithelial lining of
the intestinal tract, and bone marrow revealed that vitamin
treatment at these doses did not produce any apparent non-specific
toxicity to the host mice.
EXAMPLE VIII
Influence of Orally Administered VC/VK.sub.3 on the Metastasis of
Mouse Liver Tumor (T.L.T) Cells Implanted in C3H Mice
[0076] Young adult male C3h mice were given water, containing
VC/VK.sub.3 (15 g//0.15 g dissolved in 1000 ml) beginning two weeks
before tumor transplantation until the end of the experiment.
Control mice received water ad libitum. T.L.T. cells (10.sup.6)
were implanted intramuscularly in the right thigh of the mice. All
mice were sacrificed 42 days after tumor transplantation. Primary
tumor, lungs, lymph nodes and other organs or tissues suspected of
harboring metastases were examined macroscopically. Samples of
primary tumors, their local lymph nodes, lungs and main organs such
as liver, kidneys, spleen were taken for detailed histological
examination.
[0077] 42% of control mice exhibited lung metastases and 27%
possessed metastases in local lymph nodes metastases whereas 24% of
vitamin-treated mice exhibited lung metastases and 10% possessed
local lymph nodes metastases. Furthermore, the total number of lung
metastases was 19 in control group and 10 in vitamin C and
K.sub.3-treated mice. Histopathological examination of the metastic
tumors from the vitamin-treated mice revealed the presence of many
tumor cells undergoing autoschizic cell death.
[0078] Oral vitamin C and K.sub.3 significantly inhibited the
development of metastases of T.L.T. tumors in C3H mice. It is
believed that at least a portion of this inhibition was due to the
ability of the vitamin combination to induce autoschizic cell
death.
EXAMPLE IX
Patient Monitoring
[0079] The effectiveness of the supplemental treatment according to
the invention can be monitored for any given patient utilizing a
method for cancer therapy prognosis based on the variations of
serum alkaline DNase activity ("SADA").
[0080] The concept of serum alkaline DNase activity (SADA)
measuring as a means for cancer therapy prediction and
post-therapeutic monitoring of cancer patients is based on
histochemical observations that the DNase was deficient in
nonnecrotic cancer cells and was reactivated in early states of
cancer cells necrosis both that of spontaneous origin as that
induced by efficient treatment.
[0081] Due to the great inter-individual differences of SADA levels
between the cancer bearing patients before treatment, as well as
due to the lack of distinct differences of SADA levels between
cancer bearing patents and normal individuals the test based on
SADA measuring cannot be utilized as a diagnostic means for cancer
detection. For example, FIG. 4 illustrates the serum alkaline
deoxyribonuclease activity in (a) healthy individuals and in (b)
cancer patients. However, multiple measuring of SADA in cancer
patients during and after the treatment is certainly useful and
valuable means for therapeutic prognosis and post-therapeutic
monitoring of cancer patients.
[0082] The curves of this sensitive prognostic marker have 3 stages
as illustrated in FIG. 5: Stage I (days after treatment) presents a
decrease of SADA in good responders to the treatment and unchanged
levels in non-responders. Stage II (weeks after treatment)
demonstrates an increase of SADA higher than the initial value
before treatment in complete remissions, lower increase in partial
remissions and no SADA increase in tumor progression. Stage III
(months after treatment) is characterized by the maintenance of
post-therapeutic higher level in cases with the maintenance of
remission and by the successive decrease of SADA values without any
simultaneous treatment which precedes several weeks the clinical
detection of recurrence. T.sub.o indicates the serum alkaline
deoxyribonuclease activity level of the patient at the time of
initial diagnosis, before therapy.
[0083] Above described SADA variations were investigated and
compared to the clinical evolution of cancer in more than 600
patients with lymphomas; bronchogenic carcinomas, nonlymphoblastic
leukemias, upper respiratory tract cancers, head and neck cancers
and in various types of cancers. The results observed in human
patients were confirmed in tumor bearing rats. SADA variations were
also investigated in normal humans. An exemplary curve showing
variations of alkaline DNase activity in the serum of an acute
non-lymphoblastic leukemia patient during therapeutic monitoring is
shown in FIG. 6.
[0084] Preferably, the SADA measurements are obtained using the
following procedures: [0085] 1) Temperature of incubation:
50.degree. C. [0086] 2) Time and incubation: 60 minutes. [0087] 3)
Volume of investigated serum: 100 .mu.l. in 900 .mu.l of tris
buffer at pH 8 with substrate 500 .mu.g (DNA sodium salt from calf
thymus). [0088] 4) The presence of CaCl.sub.2 and MgCl.sub.2 in the
incubator medium. [0089] 5) Precipitation procedure in ice bath by:
addition of saturated solution of MgSO.sub.4.7H.sub.2O, vortex,
addition of 25 N PCA, vortex, 20 min.; centrifugation at 2000
g.
EXAMPLE X
Determination Of Serum Alkaline DNase Activity
[0090] Blood is obtained by venipuncture (.+-.5 ml), collected in
dry tubes without any anticoagulant, maintained at 4.degree. C.
maximum 24 h before serum separation. Frozen serum samples at
-20.degree. C. do not lose alkaline DNase activity up to several
weeks.
[0091] Composition of solutions: TABLE-US-00004 Solution A (test)
Tris(-hydroxymethtyl)aminomethane 12.114 g CaCl.sub.2.2H.sub.20
0.0367 g MgCl.sub.2.6H.sub.20 1.0165 g H.sub.20 dist. ad 500 ml pH
adjusted to 8 with concentrated HCl. Solution B (blank)
Tris(-hydroxymethyl)aminomethane 12.114 g EDTA 2.7224 g H.sub.20
dist. ad 500 ml pH adjusted to 8 with concentrated HCl.
Solution C (Substrate)
[0092] DNA sodium salt, highly polymerized from calf thymus (Sigma
product D 1501) is cut with scissors and dissolved in proportions;
DNA 500 .mu.g/dist H.sub.2O 400 .mu.l, by using magnetic stirrer in
cold room overnight.
Solution D
[0093] Saturated aqueous solution of MgSO.sub.4.7H.sub.2O
Solution E (Precipitating Agent)
2.25 N PCA
[0094] Solutions A, B, C are stored at 4.degree. C. and heated up
to room temperature before use. PCA is used at ice temperature.
[0095] Test Procedure: TABLE-US-00005 Incubation medium (test)
Solution A 500 .mu.l Solution C 400 .mu.l tested serum 100 .mu.l
Incubation medium (blank) Solution B 500 .mu.l Solution C 400 .mu.l
tested serum 100 .mu.l
[0096] Tested serum is added directly before the incubation which
is performed at the temperature 50.degree. C. during 60 minutes.
The incubation is stopped by the following procedure: Add to each
tube 500 .mu.l of the solution D, vortex, then add 1.5 ml of cold
solution E, vortex and place the tubes in ice bath at least for 30
minutes. Tubes are centrifuged at 2000 g for 20 minutes.
Supernatant is separated immediately after centrifugation.
[0097] The optical density of the supernatants is measured in a
quartz cell (1 cm pathway) at 260 nm after zeroing the
spectrophotometer on distilled water.
[0098] The absorbance of the blank is deduced from the absorbance
of the test. The results are expressed in international kilounits
per liter of serum.
[0099] If the measurement of the absorbance of the supernatant is
not realized within a couple of hours, the supernatants must be
stored at 4.degree. C. overnight. Assays should be done at room
temperature.
[0100] If absorbance of a sample is higher than the limit of
linearity of the spectrophotometer, repeat the assay with the same
volume of diluted serum (in distilled water) and correct the
calculations by multiplying the results by the dilution factor.
[0101] Valid results depend on an accurately calibrated instrument,
timing and temperature control.
Tabulation of Results
[0102] Units used are defined as follows: (Abs test-Abs
blank).times.total vol (ml).times.1 E(8.8 10.sup.-3).times.sample
vol (ml).times.time (min).times.pathway (cm) or (Abs test-Abs
blank).times.10.sup.3.times.56.8=IU/L
[0103] For practical reasons, the following units should be used:
(Abs test-Abs blank).times.56.8=kilo IU/L or KIU/L
[0104] The preferred embodiments have been described, hereinabove.
It will be apparent to those skilled in the art that the above
methods may incorporate changes and modifications without departing
from the general scope of this invention. It is intended to include
all such modifications and alterations in so far as they come
within the scope of the appended claims or the equivalents
thereof.
* * * * *