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--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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