UROTHERAPY FOR PATIENTS WITH CANCER Joseph Eldor, MD Theoretical Medicine Institute P.O.Box 12142, Jerusalem, 91120,Israel E-mail: a1b2c3d4@netvision.net.il Subcutaneous urine injections was practiced in 1912 by Duncan (1) from New York under the name of auto-pyotherapy for urinary infections, and in 1919 by Wildbolz (1) from Bern for diagnostic purposes. Cimino (2) from Palermo reported in 1927 on the use of auto uro-therapy for urinary infections. Rabinowitch (3) in 1931 described this auto-urine therapy for gonarthritis. Jausion et al. (4) 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 (5)in 1936 treated patients with acute and subacute glomerulonephritis by injection of an autogenous urinary extract. Sandweiss, Saltzstein and Farbman (6) 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 (7). In 1926 Seiffert first described the construction of ileal loop conduits for urinary diversion (8). 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 (9). 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 (10). Peyer`s patches are immunocompetent lymphoid organs which participate in intestinal immune responses (11). 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 (12). Stem cells in the mucosa of the small bowel can divide every 8 to 12 hours (13). Tapper and Folkman (14) 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 (15). The continued presence of urine bathing the intestinal mucosa appears to locally inhibit regeneration of the Peyer`s patches. Starkey et al. (16) 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 (17,18). 2. The mechanical effect of the fecal stream on the stoma (19). 3. The age of the anastomosis (20). 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 (17,21-23). It is common knowledge that malignant tumors may disappear spontaneously although very infrequently (24-26). Usually it is accepted that this could be due at least partly to an immunological reaction (27,28). Renal adenocarcinoma is one of the cancer types in which such spontaneous regressions have been described most frequently (24,26). Urinary extracts from patients with aplastic anemia (29) and idiopathic thrombocytopenic purpura (30) 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. (31) 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. 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. References: 1. Jausion H. Sur l'auto-ouro-therapie. Journal D'Urologie 1935;39:58-59 2. Cimino T. Premiers essais de vaccine-proteine-therapie des infections non gonococciques ni tuberculeuses des voies urinaires a l'aide des injections sous-cutanees de l'urine purulente du sujet, sterilisee par l'ebullition (ouro-therapie). Rivista Sanitaria 1927;186 3. Rabinowitch IM. Auto-urine-therapy in gonarthritis. Vratchebnaia gazeta 1931;35:677-8 4. Jausion H, Giard R, Martinaud G. L'auto-ouro-therapie. La Presse Medicale 1933;76:1467-1470 5. Day HB. Treatment of glomerulonephritis by antigen. Lancet 1936;1456-9 6. Sandweiss DJ, Saltzstein HC, Farbman AA. The prevention or healing of experimental ulcer in Mann-Williamson dogs with the Anterior-Pituitary-Like hormone (Antuitrin-S). Am J Dig Dis 1938;5:24-30 7. Sandweiss DJ, Saltzstein HC, Farbman AA. The relation of sex hormones to peptic ulcer. Am J Dig Dis 1939;6:6-12 8. Seiffert L. Die "Darn-Siphonblase". Arch fur Klin Chir 1935;183:569 9. Bricker EM. Bladder substitution after pelvic evisceration. Surg Clin North Am 1950;30:1511 10. Hammer E. Cancer du colon sigmoide dix ans apres implantation des ureteres d'une vessie exstrophiee. J Urol Nephrol 1929;28:260 11. Miller-Schoop JW, Good RA. Functional studies of Peyer`s patches: Evidence for their participation in intestinal immune responses. J Immunol 1975;144:1757 12. Barclay THC, Schapira DV. Malignant tumors of the small bowel. Cancer 1983;51:878-881 13. Loeffler M, Stein R, Wichmann HE, Potten CS, Kaur P, Chwalinski S. Intestinal cell proliferation. I. A comprehensive model of steady-state proliferation in the crypt. Cell Tissue Kinet 1986;19:627-645 14. Tapper D, Folkman J. Lymphoid depletion in ileal loops: Mechanism and clinical implications. J Pediatr Surg 1976;11:871-880 15. Wilson WEC, Kirkpatrick CH, Talmage DW. Suppression of immunologic responsiveness in uremia. Ann Intern Med 1965;62:1 16. Starkey RH, Cohen S, Orth DN. Epidural growth factor: Identification of a new hormone in human urine. Science 1975;189:800-802 17. Urdaneta LF, Duffell D, Creevy CD, Aust JB. Late development of primary carcinoma of the colon following ureterosigmoidostomy: report of three cases and literature review. Ann Surg 1966;164:503-13 18. Harguindey SS, Colbeck RC, Bransome ED JR. Ureterosigmoidostomy and cancer: new observations (letter). Ann Intern Med 1975;83:833 19. Rivard JY, Bedard A, Dionne L. Colonic neoplasms following ureterosigmoidostomy. J Urol 1975;113:781-6 20. Carswell JJ III, Skeel DA, Witherington R, Otken LB Jr. Neoplasia at the site of ureterosigmoidostomy. J Urol 1976;115:750-2 21. Lasser A, Acosta AE. Colonic neoplasms complicating ureterosigmoidostomy. Cancer 1975;35:1218-22 22. Sooriyaarachchi GS, Johnson RO, Carbone PP. Neoplasms of the large bowel following ureterosigmoidostomy. Arch Surg 1977;112:1174-7 23. Eraklis AJ, Folkman MJ. Adenocarcinoma at the site of ureterosigmoidostomies for exstrophy of the bladder. J Pediatr Surg 1978;13:730-4 24. Everson T. Spontaneous regression of cancer. Ann NY Acad Sci 1964;114:721-35 25. Stephenson H, Delmez J, Renden D, Kimpton R, Todd P, Charron T, Lindberg D. Host immunity and spontaneous regression of cancer evaluated by computerized data reduction study. Surg Gynecol Obstet 1971;133:649-55 26. Cole W. Spontaneous regression of cancer: The metabolic triumph of the host? Ann NY Acad Sci 1974;230:111-41 27. Burnet F. Immunological aspects of malignant disease. Lancet 1967;II:1171-4 28. Droller M. Immunotherapy and genitourinary neoplasia. Urol Clin N Am 1980;7:831-46 29. Enomoto K, Kawakita M, Kishimoto S, Katayama N, Miyake T. Thrombopoiesis and megakaryocyte colony stimulating factor in the urine of patients with aplastic anemia. Br J Haematol 1980;45:551-556 30. Kawakita M, Enomoto K, Katayama N, Kishimoto S, Miyake T. Thrombopoiesis and megakaryocyte colony stimulating factors in the urine of patients with idiopathic thrombocytopenic purpura. Br J Haematol 1981;48:609-615 31. Stanley ER, McNeill TA, Chan SH. Antibody production to the factor in human urine stimulating colony formation in vitro by bone marrow cells. Br J Haematol 1970;18:585-590