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-ç-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 infiltrating
lymphocytes with interleukin-2 and reinoculate them into the
host with cytokines (37). The introduction of recombinant
vectors expressing cytokine genes into tumor infiltrating
lymphocyte cells (38) or into the tumor cells themselves
(39) may enhance the migration of effector immune cells into
the tumor with consequent immunomediated control. The
considerable heterogeneity in the expression of tumor
associated differentiation antigens by cells within the same
tumor constitutes a problem for any immunotherapy, since it
facilitates the escape of antigen-negative tumor variants.
An alternative approach toward increasing the immune
response to tumor-associated differentiation antigens is to
treat the host to be immunized so as to abolish a
"suppressor" response. Such treatment can be provided in the
form of sublethal whole body x-irradiation (40), injection
of a drug such as cyclophosphamide (41), or by the
administration of certain anti-idiotypic antibodies (42).
Anergy is defined as a state of T lymphocyte
unresponsiveness characterized by absence of
proliferation,IL-2 production and diminished expression of
IL-2R (43,44). Most available data support suppression as a
mechanism of oral tolerance (45,46). Immunological
suppression is classically demonstrated by the suppression
of antigen-specific immune responses by T lymphocytes
(47,48).
Autoantigens
Oral administration of S-antigen (S-Ag), a retinal
autoantigen that induces experimental autoimmune uveitis,
prevented or markedly diminished the clinical appearance of
S-Ag-induced disease as measured by ocular inflammation
(49,50).
Gut associated lymphoid tissue has the capacity to generate
potent immune responses on one hand, and to induce
peripheral tolerance to external antigens on the other
(51-53). Both processes require antigen stimulation (53),
involve cytokine production (51) and might occur at the same
time - the first leading to potent local and systemic immune
responses, while the latter leads to systemic
antigen-specific nonresponsiveness (54). The generation of
acquired immune responses in the small intestine is believed
to occur in Peyer`s patches (51,55).
Orally fed protein antigens are found in the blood within 1
hr of feeding (56). Peripheral tolerance is not induced
locally, but rather is induced systemically upon transfer of
intact antigen, or its peptides, into the circulation
(57-59).Oral tolerance may be induced by a single feeding of
a protein antigen (60,61) or by several intermittent
feedings (46,62). In order to test whether feeding on
autoantigen could suppress an experimental autoimmune
disease, the Lewis rat model of experimental autoimmune
encephalomyelitis was studied (63). With increasing dosages
of GP-MBP, the incidence and severity of disease was
suppressed, as well as proliferative responses of lymph node
cells to MBP. Antibody responses to MBP were decreased but
not as dramatically as proliferative responses. Thus it
appears that oral tolerance to MBP, as to other non-self
antigens (45), preferentially suppress cellular immune
responses. It appears that homologous MBP is a more potent
oral tolerogen for experimental autoimmune encephalomyelitis
than heterologous MBP (64).
Tumor cells may escape immune recognition in immunocompetent
hosts by clonal evolution.Attention could be directed to
activate the resident immune effectors to break the anergy
or tolerance.
Urotherapy
Subcutaneous urine injections was practiced in 1912 by
Duncan (65) from New York under the name of auto-pyotherapy
for urinary infections, and in 1919 by Wildbolz (65) from
Bern for diagnostic purposes. Cimino (66) from Palermo
reported in 1927 on the use of auto uro-therapy for urinary
infections. Rabinowitch (67) in 1931 described this
auto-urine therapy for gonarthritis. Jausion et al. (68)
used this kind of therapy in 1933 for desensitization and
endocrinological problems. They treated with auto urotherapy
injections patients who suffered from migraine, pruritus,
asthma, urticaria, eczema, psoriasis, etc. Day (69)in 1936
treated patients with acute and subacute glomerulonephritis
by injection of an autogenous urinary extract. Sandweiss,
Saltzstein and Farbman (70) reported in 1938 that an extract
from urine of pregnant women has a prophylactic and
therapeutic effect on experimental ulcers in dogs. Shortly
thereafter the same group noted that an extract from urine
of normal women has a similar beneficial effect (71).
In 1926 Seiffert first described the construction of ileal
loop conduits for urinary diversion (72). Bricker in the
1950s popularized the use of the ileal loop as a means of
supravesical urinary diversion following exenteration for
pelvic malignancy in adults (73). Ureterosigmoidostomy as a
means of urinary diversion was used widely from 1920 to
1955. It was this type of implant which Hammer first
reported in 1929 associated with tumor (74).
Peyer`s patches are immunocompetent lymphoid organs which
participate in intestinal immune responses (75). Epithelial
cells within the crypts of the small bowel are one of the
fastest dividing cells in the body and yet they show one of
the lowest rate of malignant transformation (76). Stem cells
in the mucosa of the small bowel can divide every 8 to 12
hours (77). Tapper and Folkman (78) demonstrated that
exposure of intestinal segments to urine causes marked
lymphoid depletion in the segments. These studies give
additional support to the idea that a lymphocyte suppressive
factor exist in urine (79). The continued presence of urine
bathing the intestinal mucosa appears to locally inhibit
regeneration of the Peyer`s patches.
Starkey et al. (80) detected in human urine a material that
is biologically and immunologically similar to epidermal
growth factor that causes proliferation and keratinization
of epidermal tissues.
The increased susceptibility of the colon to cancer
associated with the existence of an implanted ureter has
been theorized to relate to 3 factore: 1. The role of the
urine in the colon (81,82). 2. The mechanical effect of the
fecal stream on the stoma (83). 3. The age of the
anastomosis (84). Adenocarcinoma of the colon mucosa is a
recognized complication of ureterosigmoidostomy. The tumor,
which develops adjacent to the junction of the ureter with
the bowel, occurs 500 times as often as in the population at
large and, in children so operated , 7,000 times as often as
in all persons under age 25. The latency period is 5 to 50
years (81,85-87).
It is common knowledge that malignant tumors may disappear
spontaneously although very infrequently (88-90). Usually it
is accepted that this could be due at least partly to an
immunological reaction (91,92). Renal adenocarcinoma is one
of the cancer types in which such spontaneous regressions
have been described most frequently (88,90).
Urinary extracts from patients with aplastic anemia (93) and
idiopathic thrombocytopenic purpura (94) are capable of
stimulating megakaryocyte colony growth in culture, and when
injected into rats could also induce thrombocytosis in
peripheral blood and megakaryocytosis in the spleens of
these animals. Stanley et al. (95) demonstrated that rabbits
immunized with human urine concentrates from leukemic
patients developed antibody which neutralized the mouse bone
marrow colony stimulating factor in human urine and human
serum.
Preconclusion
Henry Sigerist said, more than 50 years ago:"I personally
have the feeling that the problem of cancer is not merely a
biological and laboratory problem, but it belongs to a
certain extent to the realm of philosophy... All experiments
require certain philosophical preparation. And I have the
feeling that in the case of cancer many experiments were
undertaken without the necessary philosophical background,
and therefore proved useless" (96).
Conclusion
Urotherapy is suggested as a new kind of immunotherapy for
cancer patients. Unlike the clonal immunotherapy the urine
of the cancer patients contain the many tumor antigens which
constitute the tumor. Oral auto-urotherapy will provide the
intestinal lymphatic system the tumor antigens against which
they may produce antibodies due to non-self recognition.
These antibodies may be transpierced through the blood
stream and attack the tumor and its cells.
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