UROTHERAPY FOR PATIENTS WITH CANCER
Joseph Eldor, MD
Theoretical Medicine Institute
P.O.Box 12142, Jerusalem, 91120,Israel
Abstract
Cancer cells release various antigens, some of which appear
in the urine. Oral auto-urotherapy is suggested as a new
treatment modality for cancer patients. It will provide the
intestinal lymphatic system the many tumor antigens against
which antibodies may be produced. These antibodies may be
transpierced through the blood stream and attack the tumor
and its cells.
The philosophy of cancer
Microbes were known long before the germ theory of disease
was invented. It was not the discovery of germs that
revolutinized medicine, but the invention of a philosophy of
medical explanation that permitted germs to be causative
agents of disease (1).
Burnet and Thomas (2) postulated that specific cell
mediated immunity may have evolved in vertebrates
specially for defense against the "enemy within" rather than
against infecting microorganisms and parasites. Most human
cancers appear to lack truly tumor-specific antigens. The
same neoplastic cell can express several different tumor
antigens. For example, relatively cross-reacting
tumor-specific transplantation antigens have been
demonstrated in many chemically induced tumors (3).
Tumor-associated differentiation antigens are shared by
neoplastic and embryonic cells (4). The extent to which
human patients react immunologically against their cancers
has been a subject of much controversy (5).
Paul Ehrlich, in 1909, said:"I am convinced that during
development and growth malignant cells arise extensively
frequently but that in the majority of people they remain
latent due to the protective action of the host. I am also
convinced that this natural immunity is not due to the
presence of antimicrobial bodies but is determined purely by
cellular factors. These may be weakened in the older age
groups in which cancer is more prevalent" (6).
Tumor antigens in urine
Human melanoma cells express membrane antigens distinct from
those of the normal ectodermal counterparts (7).
Urinary-tumor-associated antigen (U-TAA) is one such
antigen. This high-molecular weight glycoprotein was first
described when melanoma urine was found to react with
autologous antibody (8). The antigen has since been detected
in the urine of 68% of melanoma patients. In addition, high
levels of U-TAA are found to correlate positively with
disease occurrence in surgically treated patients (9).
Prostatic specific antigen (PSA) has become an important
laboratory test in the management of prostate cancer. PSA
levels can be as readily obtained from voided urine as from
serum samples (10).
Quantitative urinary immunocytology with monoclonal antibody
(mab) 486p 3/12 proved to be valuable for diagnostic use in
bladder-cancer patients` urine, especially in the followup
of patients with superficial bladder carcinoma (11).
Quantitative urinary immunocytology is a general tool to
test the diagnostic usefulness of mabs, assuming that normal
and malignant cells differ in their quantitative expression
of a given antigen. Selective criteria for selecting mabs
for diagnostic approaches should ask not for tumor
specificity, but for different quantitative expression of
antigen in the tissues or cells in question.
Gastric juice oncofetal antigen determination, due to direct
shedding of antigens into the fluid around tumor tissues,
appears to accurately indicate the presence and degree of
gastric mucosal damage and to be to a slight extent
influenced by unrelated factors (12). Patients` age, for
example, modifies CEA serum levels (13). A monoclonal
antibody (mab) against a human colorectal adenocarcinoma
cell line has been raised (14), which reacts with
sialosylfucosyllactoteraose (15) corresponding to the
sialylated blood group antigen Lewis (a). The antigen
defined by this antibody, CA50, is elevated in the serum of
many patients with gastrointestinal tumors (16), with a
sensitivity for gastric cancer ranging from 20 (17) to 65%
(18). CA50 (a tumor-associated gangliosidic antigen) levels
have been determined by an RIA test in serum, gastric juice
and urine of patients undergoing upper gastrointestinal
tract endoscopy. Sensitivity and specificity were
respectively 23% and 89% for CA50 determination in urines
(19).
Soluble forms of membrane proteins such as cytokine
receptors or cellular adhesion molecules (CD14, TNF
receptor, CD25, IL-6 receptor, IFN-รง-receptor and CD54) have
been detected in human body fluids. They may have important
functions in immune regulation by blocking receptor/ligand
interactions. The human adhesion receptor CD58 (LFA-3) is
expressed on most cell types. A soluble form of CD58 (sCD58)
was purified from human urine and partially purified from
supernatant of the Hodgkin-derived cell line L428 (20).
Urinary organ-specific neoantigen from colorectal cancer
patients has been used to make a monoclonal antibody, BAC
18.1 (21). Organ-specific neoantigen originates in the colon
and is excreted into the urine, so the BAC 18.1 binding
levels in the urine may be a diagnostic aid for colorectal
cancer.
The polyamines spermidine, spermine and their diamine
precursor putrescine are ubiquitous constituents of
mammalian cells that are fundamentally involved in normal,
malignant and induced proliferative states. The polyamines
and ornithine decarboxylase (ODC), the rate-limiting enzyme
of the polyamine metabolism, were found to play an important
role in tumor promotion (22). The suggestion that polyamines
play an important role in colorectal cancer was confirmed by
studies that found elevated polyamine concentrations in
blood or urine (23) of patients with colon carcinoma.
Sensitivity of urinary polyamines for colon cancer were
highest for total spermidine (92.1%), acetylated putrescine
(84.5%), total putrescine (84.0%), N1-acetylspermidine
(79.3%) and N8-acetylspermidine (78.6%), but in all these
cases specificity was lower than 65% (24). In patients with
successful curative surgical treatment all preoperatively
elevated urinary polyamine concentrations markedly decreased
and returned to normal, whereas they were elevated and
increased further in patients with proven relapse of the
tumor and/or metastases in different organs (24).
The function of the CD44 gene is severely damaged, beginning
with the very early pre-invasive stages of tumor
development. This can be used as a means of tumor detection
and diagnosis both on solid tissue specimens (25) and on
exfoliated cells in clinically obtained excreta and body
fluids (26). Urine cell lysates obtained from patients with
bladder cancer can be discriminated from normal urine
lysates (27) using Western blotting with a monoclonal
antibody against the standard form of the CD44 protein.
Immunotherapy
Zbar and Tanaka (28) first reported on animal immunotherapy
based on the principle that tumor growth is inhibited at
sites of delayed hypersensitivity reactions provoked by
antigens unrelated to the tumor.They injected living
Mycobacterium bovis (strain BCG) into established
intradermal tumors and caused tumor regression and prevented
the development of metastases. For optimum therapeutic
effect contact between BCG and tumor cells was necessary.
The ability of tumor immune lymphocytes to localize
specifically to tumor offers a possibility for therapy which
has been utilized over the past several years (29).
The rejection of murine tumors expressing tumor-specific
transplantation antigens has been shown to be mediated
primarily by immune cells (30). Some 6 to 7% of transplant
recipients may develop cancer as a consequence of iatrogenic
immunosuppression (31).
Studies on the ability of patient lymphocytes to lyse tumor
cells in short term (2-8 hr) isotope release assays have
shown that lymphocytes from cancer patients can generally
destroy only tumor cells from the same patient (32-34),
unless the effector cells are not cytolytic T cells but, for
example, Natural Killer cells or Lymphokine Activated Killer
cells, in which case neoplastic cells representing many
different types are sensitive.
Immunotherapy is believed to be capable of eliminating only
relatively small amounts of neoplastic cells and, therefore,
the failure to induce a regression in patients with
excessive tumor burden is not unexpected (35,36). One
approach of immunotherapy is to "xenogenize" tumor cells by
virus infection. Another is to culture tumor inf
Joseph Eldor, MD
Theoretical Medicine Institute
P.O.Box 12142, Jerusalem, 91120,Israel
Abstract
Cancer cells release various antigens, some of which appear
in the urine. Oral auto-urotherapy is suggested as a new
treatment modality for cancer patients. It will provide the
intestinal lymphatic system the many tumor antigens against
which antibodies may be produced. These antibodies may be
transpierced through the blood stream and attack the tumor
and its cells.
The philosophy of cancer
Microbes were known long before the germ theory of disease
was invented. It was not the discovery of germs that
revolutinized medicine, but the invention of a philosophy of
medical explanation that permitted germs to be causative
agents of disease (1).
Burnet and Thomas (2) postulated that specific cell
mediated immunity may have evolved in vertebrates
specially for defense against the "enemy within" rather than
against infecting microorganisms and parasites. Most human
cancers appear to lack truly tumor-specific antigens. The
same neoplastic cell can express several different tumor
antigens. For example, relatively cross-reacting
tumor-specific transplantation antigens have been
demonstrated in many chemically induced tumors (3).
Tumor-associated differentiation antigens are shared by
neoplastic and embryonic cells (4). The extent to which
human patients react immunologically against their cancers
has been a subject of much controversy (5).
Paul Ehrlich, in 1909, said:"I am convinced that during
development and growth malignant cells arise extensively
frequently but that in the majority of people they remain
latent due to the protective action of the host. I am also
convinced that this natural immunity is not due to the
presence of antimicrobial bodies but is determined purely by
cellular factors. These may be weakened in the older age
groups in which cancer is more prevalent" (6).
Tumor antigens in urine
Human melanoma cells express membrane antigens distinct from
those of the normal ectodermal counterparts (7).
Urinary-tumor-associated antigen (U-TAA) is one such
antigen. This high-molecular weight glycoprotein was first
described when melanoma urine was found to react with
autologous antibody (8). The antigen has since been detected
in the urine of 68% of melanoma patients. In addition, high
levels of U-TAA are found to correlate positively with
disease occurrence in surgically treated patients (9).
Prostatic specific antigen (PSA) has become an important
laboratory test in the management of prostate cancer. PSA
levels can be as readily obtained from voided urine as from
serum samples (10).
Quantitative urinary immunocytology with monoclonal antibody
(mab) 486p 3/12 proved to be valuable for diagnostic use in
bladder-cancer patients` urine, especially in the followup
of patients with superficial bladder carcinoma (11).
Quantitative urinary immunocytology is a general tool to
test the diagnostic usefulness of mabs, assuming that normal
and malignant cells differ in their quantitative expression
of a given antigen. Selective criteria for selecting mabs
for diagnostic approaches should ask not for tumor
specificity, but for different quantitative expression of
antigen in the tissues or cells in question.
Gastric juice oncofetal antigen determination, due to direct
shedding of antigens into the fluid around tumor tissues,
appears to accurately indicate the presence and degree of
gastric mucosal damage and to be to a slight extent
influenced by unrelated factors (12). Patients` age, for
example, modifies CEA serum levels (13). A monoclonal
antibody (mab) against a human colorectal adenocarcinoma
cell line has been raised (14), which reacts with
sialosylfucosyllactoteraose (15) corresponding to the
sialylated blood group antigen Lewis (a). The antigen
defined by this antibody, CA50, is elevated in the serum of
many patients with gastrointestinal tumors (16), with a
sensitivity for gastric cancer ranging from 20 (17) to 65%
(18). CA50 (a tumor-associated gangliosidic antigen) levels
have been determined by an RIA test in serum, gastric juice
and urine of patients undergoing upper gastrointestinal
tract endoscopy. Sensitivity and specificity were
respectively 23% and 89% for CA50 determination in urines
(19).
Soluble forms of membrane proteins such as cytokine
receptors or cellular adhesion molecules (CD14, TNF
receptor, CD25, IL-6 receptor, IFN-รง-receptor and CD54) have
been detected in human body fluids. They may have important
functions in immune regulation by blocking receptor/ligand
interactions. The human adhesion receptor CD58 (LFA-3) is
expressed on most cell types. A soluble form of CD58 (sCD58)
was purified from human urine and partially purified from
supernatant of the Hodgkin-derived cell line L428 (20).
Urinary organ-specific neoantigen from colorectal cancer
patients has been used to make a monoclonal antibody, BAC
18.1 (21). Organ-specific neoantigen originates in the colon
and is excreted into the urine, so the BAC 18.1 binding
levels in the urine may be a diagnostic aid for colorectal
cancer.
The polyamines spermidine, spermine and their diamine
precursor putrescine are ubiquitous constituents of
mammalian cells that are fundamentally involved in normal,
malignant and induced proliferative states. The polyamines
and ornithine decarboxylase (ODC), the rate-limiting enzyme
of the polyamine metabolism, were found to play an important
role in tumor promotion (22). The suggestion that polyamines
play an important role in colorectal cancer was confirmed by
studies that found elevated polyamine concentrations in
blood or urine (23) of patients with colon carcinoma.
Sensitivity of urinary polyamines for colon cancer were
highest for total spermidine (92.1%), acetylated putrescine
(84.5%), total putrescine (84.0%), N1-acetylspermidine
(79.3%) and N8-acetylspermidine (78.6%), but in all these
cases specificity was lower than 65% (24). In patients with
successful curative surgical treatment all preoperatively
elevated urinary polyamine concentrations markedly decreased
and returned to normal, whereas they were elevated and
increased further in patients with proven relapse of the
tumor and/or metastases in different organs (24).
The function of the CD44 gene is severely damaged, beginning
with the very early pre-invasive stages of tumor
development. This can be used as a means of tumor detection
and diagnosis both on solid tissue specimens (25) and on
exfoliated cells in clinically obtained excreta and body
fluids (26). Urine cell lysates obtained from patients with
bladder cancer can be discriminated from normal urine
lysates (27) using Western blotting with a monoclonal
antibody against the standard form of the CD44 protein.
Immunotherapy
Zbar and Tanaka (28) first reported on animal immunotherapy
based on the principle that tumor growth is inhibited at
sites of delayed hypersensitivity reactions provoked by
antigens unrelated to the tumor.They injected living
Mycobacterium bovis (strain BCG) into established
intradermal tumors and caused tumor regression and prevented
the development of metastases. For optimum therapeutic
effect contact between BCG and tumor cells was necessary.
The ability of tumor immune lymphocytes to localize
specifically to tumor offers a possibility for therapy which
has been utilized over the past several years (29).
The rejection of murine tumors expressing tumor-specific
transplantation antigens has been shown to be mediated
primarily by immune cells (30). Some 6 to 7% of transplant
recipients may develop cancer as a consequence of iatrogenic
immunosuppression (31).
Studies on the ability of patient lymphocytes to lyse tumor
cells in short term (2-8 hr) isotope release assays have
shown that lymphocytes from cancer patients can generally
destroy only tumor cells from the same patient (32-34),
unless the effector cells are not cytolytic T cells but, for
example, Natural Killer cells or Lymphokine Activated Killer
cells, in which case neoplastic cells representing many
different types are sensitive.
Immunotherapy is believed to be capable of eliminating only
relatively small amounts of neoplastic cells and, therefore,
the failure to induce a regression in patients with
excessive tumor burden is not unexpected (35,36). One
approach of immunotherapy is to "xenogenize" tumor cells by
virus infection. Another is to culture tumor inf
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