From: rcrs@europa.com (Robert Cathey Research Source) Subject: RCRS update 14 December Representatives of the standard doctrine in cancer therapy have long contended Laetrile is a fraud. In their critiques, they've often contended that there was no mechanism for the activation of the cytotoxic components of the molecule at the cancer lesion. Then on the other hand they've contended that it is a toxic compound. Both statements are incorrect, and reveal either an ignorance of basic physiological chemistry, or willful falsehoods. Even in the various areas where the precise mechanisms for the activation of the various products of Laetrile metabolization are not understood, the inferential data cannot be ignored without departing from scientific honesty. Even amongst those with a friendlier view of the possible utility of the synthetic Laetrile, a beta-glucuronoside, many have accepted the false assertions regarding the non-utilizability in the cancer environment of the dietary beta-glucosides found in nature. This argument says that ordinary amygdalin is not active at the cancer site, but that probably synthetic amygdalin, specifically Kreb's patented Laetrile, a beta-glucuronoside, would be. This contention was based on the inaccurate assumption that beta-glucosidase does not occur in the body, or at the cancer site, but only glucuronidase exists, either in the liver, kidneys, intestines or the cancer site. In fact there is evidence that both beta-glucosidase and beta glucuronidase are produced, or that oxidation accounts for conversion of the dietary nitrilosidic beta-glucoside into the beta-glucuronoside. Furthermore, dietary intake of beta-glucosidase may account for the presence of some of it in the region of the cancer lesion by means similar to those that account for the selective collection of the endogenous beta-glucuronidase at the lesion. In any event, we may infer that the nitriloside molecule is activated at the lesion when it is seen that the lesion is altered by the application of dietary nitrilosides alone (in the presence of active pancreatic enzymes.) This paper will review some of the fundamental aspects of physiological chemistry with respect to the nitrilosides. The fundamental rationale for the use of vitamin B-17 or Laetrile or any nitriloside derives from the contention that cancer is an anomolous spatial and temporal expression of ordinary pregnancy trophoblast. Most recently, a complete biochemical, antigenic and genetic confirmation of the trophoblastic basis of cancer was supplied by Acevedo, et al. in their 1995 report on the hCG-beta subunit expression by both trophoblast and cancer.(1) This has elicited a flurry of research on possible immunological antibody adaptations of hCG-beta,(2) without any regard to the metabolic relevance of these findings in terms of pancreatic enzymes or nitrilosides. But it's still early. Regelson(3)made reference to Beard and Gurchot, and so only indirectly to the late Dr. Ernst T. Krebs, Jr., whose work above all others brought these facts before the modern world. It is a well known fact that both beta-glucosidase and beta-glucuronidase are found in the chorionic or placental environment, as secreted either from the fetus or the maternal universe; and that the general deficiency of either of these is in fact an indication of disease. For example note this on Gaucher's disease from Wiggleworth's Perinatal Pathology: "Gaucher's disease results from deficiency of Beta-glucosidase with consequent accumulation of glucocerebrosides in reticuloendothelial cells. An acute variant of the disease may be fatal in infancy, and some infants at birth had the clinical picture of hydrops fetalis. The typical Gaucher cells may be seen in the liver of affected newborn infants." Now in a coherent progression that may only be coincidental, but one which would follow the evolution of complexity in this enzyme, the same text goes on to describe another complication specifically related to the glucuronidase: "Mucopolysaccharidoses "Mucopolysaccharidosis type VII (Beta-glucuronidase deficiency) is the only member of this group of disorders [liver and biliary system disorders] that may be present in the perinatal period...."(4) Beta-glucuronidase deficiency may also present as fetal hydrops.(5) Naturally these are all commonplaces to those knowledgeable of pregnancy or embryological enzymology or pathology. And it is of course not a question of whether the cancer cell itself produces such an enzyme, which it does not, but the enzyme, where ever it may originate...from the liver, kidneys, intestinal microflora or contiguous somatic cells in the lesion...collects at the cancer lesion by mechanisms not very different than the mechanisms that cause the collection of steroids to an injury site, to say nothing of such steroids secreted from the cancer itself. In fact the beta-glycosidases are typically viewed as a defensive tactic or reaction to these steroids by the soma. From Krebs (Nitrilosides--Laetriles, 1962):(6) "...Fishman(7) in 1947 reported the presence of Beta-glucuronidase in malignant tissue. This enzyme, which hydrolyzes Beta-glucuronoside after the latter has been produced by oxidation of Beta-glucoside, was first reported to exist in animal tissue by Sera(8) in 1914. Fishman and Anlyan(9,10,11) have described levels of Beta-glucuronidase in surgically removed specimens of cancers of the breast, uterus, stomach and mesentery, abdominal wall, and esophagus 100 to 3600 times as high as levels of this enzyme in corresponding uninvolved tissue. While they have empirically interpreted this as "a metabolic response of the tissue to estrogen or a related substance", Beardianism(12,13) maintains that this is directly related to the fact that the syncytial trophoblast produces abundant quantities of estrogenic and related steroids. These steroids elicit from the hostal tissue the production of B-glucuronidase necessary for their detoxification as the corresponding beta-steroid glucuronosides, which are ultimately excreted in the urine as physiologically inert." Beta-glucuronidase catalyzes the hydrolysis of Beta-glucosiduronic acids and the transfer of glucuronyl.(14) That it acts to detoxify the steroids is also born out by empirical evidence such as the elevations of beta-glucuronidase in oestrogen treated postmenopausal women.(15) One problem to be noted in the use of nitrilosides in cancer is that since their optimum action is dependent upon beta-glucuronidase in the cancer lesion, pancreatic enzyme action is first required. This follows on the grounds of the normal evolution of the steroid-producing syncytiotrophoblast or plasmoditrophoblast as the terminal differentiation of cytotrophoblast. Krebs and Bartlett (1949) showed that the sufficiency of this phase of trophoblast formation was dependent upon the adequate action of pancreatic enzymes, specifically carboxy-peptidase, trypsin, chymotrypsin and amylase.(16) The syncytial trophoblast as the sine qua non of steroids in cancer insures the richest collection of the somatic response of beta-glucuronidase in the lesion. Therefore wherever nitrilosides (Laetrile) are to be used, a prior pancreatic enzyme treatment must be viewed as optimizing their effect locally to the cancer lesion. In any case, prior action by the pancreatic enzymes insures the negative cyanide radical of nitriloside will have access to the cancer cytoplasm. Thus when a dietary nitriloside finds its way either to the cancer site, or to any point where it may be scissioned, its components will be released. If remotely, one of these scission products may travel in the blood before being detoxified: cyanide; while the benzaldehyde will be detoxified almost instantly upon entering the blood by oxidation to form benzoic acid. The HCN will travel further perhaps, depending upon the rhodanese or hydroxycobalamin content in the blood, liver or the intestines, which may result either in the radical forming part of thiocyanate or pro-vitamin B-12 respectively.(17) Beyond the cytotoxic capacity of the hydrogen cyanide radical in nitrilosides on the cancer cell, is the well established capacity the HCN has to accelerate proteolysis by the proteolytic enzymes.(18) HCN will also reactivate deactivated Bromelain and Papain, as do cysteine and glutathione.(19) Thus nitrilosides act as catalysors for the pancreatic enzymes, while the pancreatic enzymes act as potentiators or enablers of the chemotherapeutic effects of nitriloside. It is unlikely that the fact these reactions take place was one of the evolutionary pressures that selected the capacity to detoxify the hydrolyzed cyanide or scission products of mandelonitrile compounds. Rhodanese was already a co-factor in the dietary environment that also produced the nitrilosides either as natural pesticides, or as an adventitious result of processes towards strengthening plant cell walls. Both molecules existed long before the evolutional progress brought forth the extended gestation in mammalian life. Thus gestation must have progressed in spite of these factors, and so the extended internal gestational process selected a hardy trophoblast. Not too hardy. Those which were or are hardier, or more aggressive, automatically drop out of the loop: the fetus will never make it (the obverse could also be said: the baby with the stronger pancreatic function makes it). Man reached the limits of gestational development, and the strain against this evolutionary barrier or gestational envelope are realized in what we are seeing in both the frequent complications of pregnancy as well as the cancer epidemic: The hardy trophoblast. In the case of cancer: evoked asexually, or parthenogenetically. It is a fine puzzle for the natural philosopher to discern the roles imposed by the nutritive environment, the external pressures, and the extended pregnancy of mammalian life, so as to provide these interplays of seemingly mutually antithetical life-cycles: the asexual (trophoblast) and the sexual or germ-bearing individual cell (totipotent cells.) Thus we may dispense with any general obligative genetic hypothesis concerning tumorigenesis, and we must acknowledge that cancer is generally a systemic, epigenetic phenomenon. Specifically, a metabolic deficiency disease.* Footnote:In a separate paper (Cathey et al, 1997) we discuss the wide variety of environmental pathways that lead to a widespread experience in industrial society of pancreatic insufficiency, leading to what we have termed the pancreatic insufficiency syndrome, of which cancer is merely the most severe expression.(20) Furthermore, the dependency of the sexual upon the asexual, and the compounded complexities of stereo-chemistry make this formerly Gordian knot of the cancer problem much easier to unravel. The fact that substrates and enzymes almost always are found together proves that the trick of stereochemical isolates which man only clumsily mimics, may have to do with converting the mirror image into something else. Thus in seeds we find both glucosidases and glucosides. The active enzyme, beta-glucosidase is stereochemically of the opposite rotation from the sugar or glucoside. Recent work on this problem of isolated isomer formation illuminates these mechanisms, but does not necessarily disprove this possibility.(21) Naturally the activity of the pancreatic enzymes, the proteolytic and amylolytic enzymes are a required precursor for successful activity of the nitrilosides, since the same defensive mechanisms (pericellular sialomucin, hCG) which the trophoblast uses to avoid the white blood cells will repulse the negative ionic scission products of the nitriloside. No one questions that cancers are rich steroid pools, with mixed phenotypes, showing endothelial, transporting epithelium and endocrinal characteristics(22), just as trophoblast does(23,24). And the mechanisms of the body detoxification of these hormones is also well known. Admitting these two general facts compels an accession to the factual metabolic relevance of cyanophoric glycosides, since the detoxification mechanisms used by the body: viz. the glycosidases, will release the anti-neoplastic components of the beta-glycosides in the cancer(trophoblast) environs. Therefore it is not the relevantly informed experts that criticize the relevance of dietary or synthetic cyanophoric glycosides, but the ignorant who do so. References (1) Acevedo, HF. Tong JY. Hartsock RJ. Human chorionic gonadotropin-beta subunit gene expression in cultured human fetal and cancer cells of different types and origins, Cancer 76(8):1467-75, Oct 15 1995; See also:Metastatic Phenotype Correlates with High Expression of Mem- brane-Associated Complete Beta-Human Chorionic Gonadotropin In Vivo, Acevedo, H., and Harstock, R.J., Cancer 78(11):2388-99, Dec 1 1996. (2) Life supporting hormone may advance growth of cancer, Cancer Bio- technology Weekly, Oct 30, 1995 p10(2). (3) Regelson, W. Have we found the "Definitive Cancer Biomarker"?, Cancer 76(8):1299-1301, Oct 15 1995. (4) Perinatal Pathology, J.S. Wigglesworth, Volume 15 in the Series Major Problems in Pathology, 2nd Edition, Saunders, 1996. p. 280. (5) Op. cit. 68. (6) Nitrilosides (Laetriles), Krebs, E.T., and Bouziane, N.R., 1962. The following references were derived from this monograph. The monograph is available from the RCRS along with a collection on other monographs, including the Unitarian or Trophoblastic Thesis of Cancer, and clinical evaluation reports on Laetrile. ----References in quote from Krebs and Bouziane--------- (7) Fishman, W.H., "B-Glucuronidase Activity of Blood and Tissue of Obstetrical and Surgical Patients," Science, 105:646 (1947) (8) Sera, Y., "Aur Kenntnis der Gepaarten Glukuronsaure, III Ueber die Spaltung der Orcin -und Chloroglucinglukuronsaure durch Organsafte," Z.Physiol.Chem., 92:261-275 (1914). (9) Fishman, W.H., and A.J. Anlyan, "A Comparison of the B-Glucuronidase Activity of Normal, Tumor, and Lymph Node Tissues of Surgical Patients," Science, 106:66-67 (1947). (10)Fishman, W.H., and A.J. Anlyan, "The Presence of High B-Glucuronidase Activity in Cancer Tissue," J.Biol.Chem., 169:449-450 (1947). (11)Fishman, W.H., and A.J. Anlyan, "B-Glucuronidase Activity in Human Tissues. Some Correlations with the Processes of Malignant Growth and the Physiology of Reproduction," Fourth Int.Cancer Research Congress, 6:1034-1041 (1950). (12)Beard, J., "The Embryology of Tumors," Anat. Anz., 23:486-494 (1903):Centrbl.L.allg.Path.Anat., 14:513-520, (1903). (13)Beard, J., "The Interlude of Cancer," Med.Record, 69:1020 (1903). ----End references for quote from Krebs and Bouziane--------- (14) The Plasma Proteins, Ed. F.W.Putnam, Vol.II, p 69.; and refs: Fishman, W.H., J.Biol.Chem. 131, 225 (1939); Fishman,W.H., in: "The Enzymes", Sumner, J., and Myrback, K., eds., Vol.1, part 1, p.635, Acad.Press, 1950; Masamune, H., J.Biochem.(Tokyo) 19, 353(1934). (15)Op. cit.; and refs: Fishman, W.H., Kasdon, S.C.,Bonner, C.D., Fishman, L.W. and Homburger, F., J.Clin.Endocrinol. 11, 1425, (1951). (16)Krebs, E.T., and Bartlett, C.L., The Pregnancy Toxemias - The Role of The Trophoblast and The Pancreas, Medical Record 162(10):1-12, October, 1949. (http://www.europa.com/~rsc/krebs49b.htm) (17)Krebs, E.T., Nitrilosides (Vitamin B-17)--Their Nature, Occurance and Metabolic Significance (Antineoplastic Vitamin B-17), Summary of remarks before Congress of the International Medical Society for Blood and Tumor Disease, Nov. 7, 1970, Baden-Baden, West Germany. Reprinted in: Journal of Applied Nutrition, Volume 22, Numbers 3 and 4, 1970.(http://www.europa.com/~rsc/krebs3.htm) (18)Mendel, L.B. and Blood, A.F., Some Peculiarities of the Proteo- lytic Activity of Papain: The Acceleration of Proteolysis by HCN, J.Biol.Chem, Vol. 8:177-213, 1910. (19)Sumner, J.B., and Somers, G.F., Chemistry and Methods of Enzymes, Academic Press, NY, 1943, pg.160. (20)Cathey, R.S., Blood, A. 1997(In MS) (21)Davin, L.B., Wang, H-B., et al. Stereoselective Bimolecular Phen- oxy Radical Coupling by an Auxilary (Dirigent) Protein Without an Active Center, Science, 275:362-66, 17 Jan 1997. (22)Dermer, G.B., The Immortal Cell, Why Cancer Research Fails, Avery Publishing Group, 1994; and for only one recent example: Wada C, Shionoya S, Fujino Y, Tokuhiro H, Akahoshi T, Uchida T, Ohtani H, Genomic instability of microsatellite repeats and its association with the evolution of chronic myelogenous leukemia, Blood 83: 3449-3456 (1994); Dermer's book points out the unreliability of cell-line research against often opposite characteristics as found in vivo. (23)Strauss, J.F.,III, MaCalman,C.D., and Samuel Perry, Differentiation- Dependent Changes in Trophoblast Cell Membrane Function, Presented before International Workshop for the Maternal-Placental-Fetal Dialogue, February 1-3, 1996, Maui Marriott, Hawaii, USA. (24)Bellet, D.,Biology of the trophoblastic tissue and placental tumors, Rev Prat 1992 Apr 1;42(7):811-6. English Abstract: "The trophoblast of early placenta has many attributes of malignant tissue: it displays highly proliferative and invasive properties and expresses hormones, growth factors, growth factor receptors and oncogene products. Moreover, this tissue may have an autocrine control of growth. Collectively, these properties are similar to those of malignant tissues and the normal trophoblast is then considered as a "pseudomalignant" tissue. Moreover, either benign (hydatidiform mole) or malignant (choriocarcinoma) trophoblastic disease may be developed from the trophoblastic cells. In this article, the biological features of both the normal and the tumoral trophoblast will be presented. Finally, the trophoblast is a model and a source of molecules of biological interest." Service d'immunologie moleculaire, Institut Gustave-Roussy, Villejuif. Rev Prat 1992 Apr 1;42(7):811-6 -------------------------------------------------------------------------- To Receive the RCRS Email Updates, send an email to rcrs@europa.com and write "Subscribe" in the subject line. ============================= ROBERT CATHEY RESEARCH SOURCE 113 S.E. 61ST AVENUE PORTLAND, OREGON 97215-1234 (503)234-7878 (503)238-0469 FAX Internet: rcrs@europa.com URL:http://www.europa.com/~rsc =========================================+ The RCRS web-site is maintained entirely + through donations. Please contribute to + keep this resource on the Web. + Send your mailing address for a free + sample of SOURCES, the RCRS Newsletter. + =========================================+