UROTHERAPY FOR PATIENTS WITH CANCER

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 vertebrats

    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 antiges.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 cancershas 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 isdetermined 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 voidedurine 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 gas  tointestinal 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 immu-ne 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)waspurified 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 inthe 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 regressionshave been described most frequently 

(88,90).Urinary extracts from patients with aplastic anemia 

(93) an 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 ofcancer 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.