Note: Descriptions are shown in the official language in which they were submitted.
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FIEI D OF TNVENTION
This invention relates to the treatment of cancer ancl
particularly relates to new rnethods for the treatment of cancer, new
formulations suitable for use in the treatment of cancer and the use of
5 the new formul~tions in the treatment of cancer.
BACKGROUND OF THE INVENTION
Cancer cells require sugar (glucose) in order to survive.
Under stressful conditions (for example hyperthermia, radiation and
chemotherapy), the cancer cells require more sugar (glucose).
U.S. Patent 4,684,627 claims a method for the treatment of
lung cancer which comprises administering lonidamine and one or more
compounds selected from the group consisting of phlorizin, phlorizin
glucoronide and 4-deoxy-phoretin-2-D-glucoside in an amount effective
to inhibit glucose transport in the cancer cells while subjecting the
15 cancer cells to additional therapy in the forrm of chemotherapy, thermal
or radiation therapy.
U.S. Patent 3,523,937 purports to teach phlorizin analogues
useful for eliminating glucose from humans and animals. In fact the
patent states at column 1, line 58 that "the phlorizin analogues would be
20 useful for any condition where the reduction of sugar is beneficial.
U.S. Patent 4,~g4,627 teaches that phlorizin "has now been
found to be able to block glucose entry into cancer cells as well. The
said patent further provides that "Cancer cells unlike normal cells
require both glucose and oxygen to satisfy energy needs. The blocking
2 5 of glucose entry impedes vital processes of the cancer cell and at
elevated temperatures becomes lethal for cancer cells. By contrast, heat
and the reduction of its glucose supply is well tolerated by normal
tissues."
In tissue culture, the administration of the phlorizin, its
3 0 glucoronide or 4d deoxyphloretin-2D glucoside can readily and
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effectively inhibit glucose transport into cancer cells. Each one of these
molecules effectively inhibit the growth of cancer cells in culture wllich
can be demonstrated by decreased 1 4C radioactive thymidine uptake.
This effect is much greater on cancer cells compared to normal cells.
5 Furthermore, the addition of other nutrients such as short chain fatty
acids, restores the prvliferation of normal cells but does not enhance
proliferation of cancer cells in the presence of the molecules which block
glucose transport.
In the large mammals such as the human, cancer cells grow
10 in a group mass - tumors. When examined microscopically tumors
consist of cellular elements with a vascular blood supply without
smooth muscle present and a frequently dense collagen or fibrous tissue
surrounding the various cellular elements, known as scar tissue or
fibrous reaction around the tumor.
In the center of many tumors there is always partially
necrotic or marginally viable cellular tissue since the tumor growth has
"outstripped" its blood supply and is hypoxic, receiving insufficient
oxygen.
While the teachings of U.S. Patent 4,684,627 (LeVeen)
2 0 appear to suggest the use of compounds which inhibit glucose transport
in the cancer cells to kill the cancer cells, in practice the results clearly
are not the breakthrough being sought after. The reason may in part
reside in the nature of the tumor itself - the scar tissue surrounding the
various cellular elements and the necrotic or marginally viable cellular
25 tissue at the center of many tumors. The compounds may not be able to
penetrate into the center of tumor.
It is therefore an object of this invention to provide new
methods for the treatment of cancer, new formulations suitable for use
in the treatment of cancer and the use of the new formulations in the
3 0 treatment of cancer.
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Further and other objects of this invention will be realized
by those skilled in the art from the following summary of the invention,
embodiments of the invention and case studies.
SUMMARY OF T~IE INVENTION
According to one aspect of the invention, there is provided a
new formulation suitable for use for treating cancer (for use in
conjunction with at least thermotherapy (hyperthermia) and if desired,
other modalities (such as chemotherapy or radiation)), the formulation
comprising (for example in a pharmaceutically acceptable carrier):
(a) a glucose inhibiting (non-toxic) amount of an agent that
blocks the glucose transport protein (active transport
molecule in the membrane) of a cell from transporting
glucose into the cell, and
tb) an effective (non-toxic) amount of an agent which
(i) enhances penetration and transport of agent (a)
through the tissue surrounding the various cellular
elements, generally known as scar ~issue or fibrous
reaction arownd the cancerous tumor, and
(ii) alters the penetration characteristics of the tissue
- 2 0 surrounding the tumor to permit agent (a) to be
transported to the center of the tumor.
According to another aspect of the invention, there is
provided a combination formulation suitable for use for treating cancer,
the combination comprising:
2 5 (a) a glucose inhibiting (non-toxic) amount of an agent that
blocks the glucose transport protein (active transport
molecule in the membrane) of a cell from transporting
glucose into the cell, and
(b) an effective (non-toxic) amount of an agent which
3 0 (i) enhances peneeration and transport of agent (a)
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through the tissue surrounding the Yarious cellular
elements, generally known as scar tissue or fibrous
reaction around the cancerous tumor, and
tii) alters the penetration characteristics of the tissue
S surrounding the tumor to permit agent (a) to be
transported to the center of the tumor.
After the introduction of the fo~mulation or combination
comprising agents (a) and (b) to the patient which have the effect of
metabolically compromising the cancer cells of the tumor, the tumor and
the cancer cells making up the tumor are stressed by at least
thermotherapy (hyperthermia). In this regard, when agent ~a) is
transported into the tumor cells and the tumor cells are stressed, there
is an inadequate amount of glucose available to the tumor cell for it to
continue to function metabolically. Thus the tumor cell is impaired in
its energy supply and dies. Therefore according to another aspect of the
invention, a method for the treatment of cancer comprises
administering (for example in a pharmaceu~ically acceptable carrier):
(a) a glucose inhibiting (non-toxic) amount of an agent that
blocks the glucose transport protein (active transport
2 0 molecule in the membrane) of a cell from transporting
glucose into the cell, and
(b) an effective (non-toxic) amount of an agent which
(i) enhances penetration and transport of agent (a)
through the tissue surrounding the various cellular
2 5 elements, generally known as scar tissue or fibrous
reaction around the cancerous tumor, and
(ii) alters the penetration characteristics of the tissue
surrounding the tumor to permit agent (a) to be
transported to the center of the tumor, 0 and subjecting the cancer cells to hyperthermia (thermotherapy)
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therapy. In some instances other modalities (for example
chemotherapy and/oT radiation therapy) may also be employed.
The glucose inhibiting (non-toxic~ ar,nount of an agent that
blocks the glucose transport protein of a cell from transporting glucose
5 into the cell (in cancer cells there appear to be more than in normal
cells) may comprise:
Phlorizin
ON
HO~
~
1 0 O-e--D-zlucoL~
Phloretin
HO~
or their analogues including phlorizin glucoronide; 4-deoxy-phoretin-2-
D-glucoside and the like.
The effective (non-toxic) amount of the agent which
(i) enhances penetration and transport of agent (a) through the
tissue surrounding the various cellular elements, generally
2 0 known as scar tissue or fibrous reaction around the
cancerous tumor, and
(ii) alters the penetration characteristics of the tissue
surrounding the tumor to permit agent ~a) to be transported
to the center of the tumor
2 5 may comprise dimethyl sulfoxide (DMSO), methylsulfonylmethane
(MSM) (also called methylsulfone methane) or other carrier transport-
type molecules having the characteristics which
(i) enhances penetration and transport of agent (a) through the
tissue surrounding the various cellular elements, generally
3 0 known as scar tissue or fibrous reaction around the
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cancerous tumor, and
(ii) alters the penetration characteristics of the tissue
surrounding the tumor to permit agent (a) to be transported
to the center of the tumor.
With respect to the tissue cultures previously referred to to
which one of the phlorizin, i~s glucoronide, and 4d-deoxyphloretin-2-D-
glucoside were added, DMSO and MSM were added individually and the
addition of DMSO or MSM (methylsulfone methane) enhanced the
inhibition of cancer cell growth and allowed for a lower dose of the
glucose blocking molecules (agent (a)). Because the cancer cell has a
membrane which is less permeable than a normal cell it is believed the
the carrier transport-type molecules such as DMSO arld MSM enhance
penetration of the glucose blocking molecules to the active transport
molecule in the membrane. Preferred agents (a) are phlorizin and
1 5 phloretin.
Irrespective of the agent however non-toxic amounts of the
agents must be selected. Thus where amounts may be toxic, their
introduction must be reduced to lower non-toxic levels over a prolonged
peliod .
2 0 Phlorizin is preferably utilized at a dose of 70-350
mgm/kgm body weight given over a time period of 4-24 hours. If
prepared without DMSO or MSM it may be given as solution of 10 gm
phlorizin/litre of normal saline with 5 gm of sodium bicarbonate added
to enhance solubility. D~SO is then administered. If phlorizin is used
2 5 with DMSO it may be prepared using 500 ml normal saline, 2.5 gm
sodium bicarbonate, 25 gm DMSO and 10 gms phlorizin. When utilizing
~ISM the preparation comprises 250 ml D/W5% (dextrose/water), 5 gm
phlorizin, 20 gm MSM, and 1 gm sodium bicarbonate. When using non-
alcohol based phlorizin, the preparation used may be ~00 ml normal
3 0 saline with 10 gm phlorizin. If using in combina~ion with DMSO~ 25 cc
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may be added, or if adding MSM, 20 gm may be used per 500 ml bag.
Phloretin is preferably administered at a dose of 7-70
mgm/kgm body weight administered over 2-24 hours intravenously.
Phloretin may be administered using a solution of 500 cc normal saline,
500 mg phloretin and 2.5 gm sodium bicarbonate. When used in
combination with DMSO, the preparation may comprise of 500 cc normal
saline, 1 gm phloretin, 2.5 gm sodium lbicarbonate and 25 gm DMSO
(100% solution). If using MSM rather than DMSO, the solution may
comprise of 2 gm phloretin (250 ml D/VV 5%) (dextrose/water), 1 gm
sodium bicarbonate and 20 gm MSM.
Various cases are cited to illustrate the enhanced effect of
tumor destruction produced clinically when agent (b) for example DMSO,
MSM or other carrier transport-type molecules are administered in
conjunction with agent (a), the molecules that block the glucose
receptor, for example: phlorizin, phloretin, the glucoronide or phlorizin,
etc:
CASE #1
A man with undifferentiated small cell carcinoma of the lung had
metastasized to the liver. Neithcr the plimary lung tumor nor the
2 0 metastatic tumor in the liver showed more than a marginal
response to chemotherapy by itself. The areas of the lung and the
liver were treated wi~h thermotherapy and phloretin was
administered intravenously dissolved in bicarbonate and alcohol.
This produced an effective response with complete regression of
2 5 tumor in both instances demonstrating that there is activity of this
glucose blocking molecule in conjunction with heat and
chemotherapy. Subsequently the patient developed five
metastatic tumors in the brain. These were treated with
thermotherapy, chemotherapy and phloretin and showed a partial
3 0 regression. When phloretin was dissolved in DMSO and
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administered to the patient in combination with thermotherapy
and a reduced dose of chemotherapy a marked and rapid
regression was induced with all tumors disappearing within two
weeks as demonstrated by computerized tomographic scanning.
CASE #2
A patient with carcinoma of the colon metastatic to the liver was
treated for four sessions with combination of chemotherapy,
thermotherapy and phloretin in a bicarbonate-alcohol solution. In
addition the tumors were injected directly with alcohol. The
patients tumors showed a partial response but without
disappearance of all tumors. After one session of treatment with
thermotherapy, chemotherapy, phloretin in DMSO there was
complete regression of all tumors as demonstrated by sonographic
assessment of the liver five weeks after treatment. The patients
liver function tests had returned to normal and the circulating
carcinoembryonic antigen had dropped substantially.
CASE #3
A female patient with a primary nonsecretory islet cell tumor of
the pancreas metastatic to the lymph nodes and the liver was
2 0 treated for three years with a combination of phloretin,
chemotherapy and hyperthermia. The tumor remained stable and
then in the past six months began to grow. She was treated with
additional chemotherapy with some regression of the disease.
Subsequently she was treated Wit}l one course with
2 5 thermotherapy, chemotherapy and phloretin in 5% DMSO with a
dramatic reduction in tumor size albeit not a complete remission
as yet.
CASE #4
~ man with carcinoma of the pancreas metastatic to the liver and
3 0 with local tumor not surgically resectable developec3 a pancreatic
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fistula through tumor tissue after treatment with thermotherapy,
phloretin and chemotherapy. After one collrse of thermotherapy,
chemotherapy, phloretin in DMSO, a marked improvement in the
tumor status occurred. The pancreatic fistula through malignant
tissue healed (this has never been demonstrated before) and the
patient is showing steady impro vement with tumor regression.
CAS~ ~5
A man with adenocarcinoma of the lung metastatic to the Iymph
nodes not previously treated but demonstrated to be not
surgically resectable was treated with chemotherapy,
thermotherapy and phloretin in 5% DMSO. On assessment four
weeks later the adenocarcinoma of the lung (considered to be a
nonresponsive tumor) had decreased in size by over 50%. Further
treatment is in progress.
CASE #6
A female with cancer of the breast metastatic to the bone treated
previously with hormone blocking agents, chemotherapy and
subsequently hyperthermia, chemotherapy and phlorizin and
phloretin was maintained in a stable position but still with
2 0 multiple metastases demonstrable to the skull. After three
courses of treatment with combination hyper~hermia and
phloretin in 5% DMSO there was marked regression of the tumor
in the skull with total relief of symptoms and improvement in
clinical status.
2 5 CASE ~7
A male with cancer of the embryonic bladder remnant with
diffuse intra-abdominal metastases treated for 1.5 years with
hyperthermia, chemotherapy and phlorizin developed further
disease progression as demonstrated by computerized
3 0 tomographic sc~mning of the abdomen and clinical symptoms. He
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was treated with a combination of thermotherapy, chemotherapy
and phlorizin ;n DMSO. After one month of treatment there was
marked regression of tumor as demonstrated by computerized
tomographic Tadiography of tumor in the abdomen.
CASE #8
A female with cancer of the stomach-linitus plastica type was
operated on and found to have perforated through the tumor into
the abdomen with diffuse tumor throughout the abdomen. There
was local resection in the area of the stomach and the patient was
referred for further tllerapy. She was treated with one course of
thermotherapy, chemotherapy and phloretin in 5% DMSO. On
computerized tomographic scanning of the abdomen four weeks
later there was greater than 50% regression of the disease with
restoration of normal gastrointestinal passage. After a second
course of treatment there was complete regression of the disease.
CASE #9
A patient with malignant glioblastoma present in the left frontal
lobe found not to be operable was referred for therapy and
treated with hyperthermia, phlorizin, phloretin and
2 0 chemotherapy. There was substantial but incomplete regression
of the tumor after three courses of treatment. He was treated
with one additional course of thermotherapy, chemotherapy and
phloretin in 5% DMSO with marked further regression of the
tumor.
2 5 For comparison purposes, in the period of February-March,
1988, I treated in excess of 250 patients in Canada with agent (a) and
hyperthermia treatment (in some cases with other rnodalities). These
patients were considered to be at the end stage. Of those treated, 15%
died before the end of March, 1988.
3 0 In the period April-May, 1988, I treated 185 patients in
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accordance with the teachings of my invention. Only 4.5% of the
patients died. In both periods the cancer from which the patients were
suffering was of the same types and the patients had been referred to
me believing they were terminal. I can only account for the significant
5 difference with the conclusion that my invention was the cause of the
substantial difference in the number of deaths.
It appears that in all of the different neoplastic situations
treated, although there may have been some response with the drugs
that block glucose uptake in conjunction with thermal and
10 chemotherapy there is a much greater and accelerated response when
the glucose blocking drugs are given in conjunction with transport
facilitating molecules. Indeed, in some instances the response has been
so rapid that a reduced treatment schedule was necessary to prevent
excessively rapid tumor necrosis and breakdown to avoid toxicity.
As many changes can be made to the various formulations
employed without departing from the scope of the invention, it is
intended that all material contained herein be interpre~ed as illustrative
o~ the invention and not in a limi~ing sense.
