Presented by THE ROBERT CATHEY RESEARCH SOURCE http://www.europa.com/~rsc --------------------------------------------------------------------------- NITRILOSIDES (LAETRILES) Their Rationale and Clinical Utilization in Human Cancer Ernst T. Krebs, Jr. and N.R. Bouziane, M.D., Ph.D. INTRODUCTION Some twenty years of research by Ernst T. Krebs, Jr., and associates of the John Beard Memorial Foundation in California have confirmed the suggestion of John Beard of Edinburgh University sixty years ago that the primitive trophoblast cell is the con stant malignant component of all exhibitions of cancer. At least one chemical produced by this cell, human chorionic gonadotrophic hormone (HCGH), permits detection of cancer at a very early stage. We have been using non-toxic nitrilosides (Laetrile), to which the trophoblast is susceptible, on terminal cancer cases for more than three years in Canada under the sponsorship of The McNaughton Foundation. Obviously, the nitrilosides (Laetriles) wouid be better used prophylactically or therapeutically at a much earlier stage in the disease. The results of this clinical evaluation will be presented following an outline of the scientific basis of this approach SCIENTIFIC BASIS OF THIS THERAPY Effective, rational chemotherapy in human cancer depends ultimately upon whether this is biologically and biochemically a single disease or a multiplicity of diseases. As proponents of the Unitarian or Trophoblastic Thesis of Cancer[l] we believe that all established evidence supports the former. We maintam that the trophoblast cell is the constant malignant component not only of the malignant exhibition of cancer, chorionepithelioma, but also of all other exhibitions of cancer however morphologically it is masked; and that it is in every way identical with normal pregnancy trophoblast. It is another tenet of Beardianism that, just as the trophoblast of pregnancy is held in check first by the normally functioning maternal pancreas alone, and later by the fetal pancreas as well, the malignant induction of ectopic trophoblast likewise is prevented by the enzymatic processes of an intact pancreas. Should there be a deficiency, however, of pancreatic enzymes (be it of genetic, infectious, degenerative, etc., origin ) the uninhibited overgrowth of the placental of ectopic trophoblast results in a hydatidiform mole or a chorionepithelioma, or in an exhibition of malignancy at the ectopic site as the case may be. From theoretical consideration, then, the use of modified, more sensitive, micro-Aschheim Zondek tests[2,3] should demonstrate the presence of chorionic gonadotrophin[4,5] in the blood and urine of patients with chorionepitheliomas and much lower concentrat ions of this same cytotrophoblastic hormone in all other exhibitions of cancer--the concentration being proportional to the biological level of malignancy.[6] These micro-Aschheim Zondek tests can also be used to evaluate the response of all types of cancer to chemotherapeutic agents. Roffo's laboratory, Howard Beard, and Navarro and his colleagues at the University of Santo Tomas and the municipal hospitals of Manila have all reported 95-100% positive and negative accuracy in large series of cancer and non cancer patients respectively. They have all reported instances of subclinical detection of cancer or its recurrence prior to biopsy, cytology study, or Roentragram. Clinical investigators with Laetrile have reported cases in which consistently positive HCGH tests have become negative after parenteral administration. The amelioration of non-specific signs and symptoms associated with positive reactors has accolnpanied many such instances. BETA-GLUCURONIDASE Independent of the foregoing considerations, Fishman[7] in 1947 reported the presence of Beta-glucuronidase in malignant tissue. This enzyme, which hydrolyzes B-glucuronoside after the latter has been produced by oxidation of B-glucoside, was first reported to exist in animal tissue by Sera[8] in 1914. Fishman and Anlyan,[9,10,11] have described levels of B-glucuronidase in surgically removed specimens of cancers of the breast, uterus, stomach and mesentary, 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[l2,13] 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 B-steroid glucuronosides, which are ultimately excreted in the urine as physiologically inert. RHODANESE In addition to their high levels of B-glucuronidase, malignant lesions are characterized by a generally profound deficiency of most other enzymes and a specific deficiency in rhodanese, as was reported by Homburger,(l4) and Mendel, Rodney and Bowman.[l5] Rosenthal reported an 80% decrease in rhodanese in hepatomatous liver tissue, and a similar decrease was found in the leukemic invasion of tissues.[l6] Lang,[l7] who discovered this enzyme in 1933, found that it converts hydrocyanic acid to rhodanate (thiocyanate or sulfocyanate) in the presence of thiosulfate or colloid sulfur thusly: HCN + Na2S203-----------Na SCN + NaHSO3 Sumner and Somers[18] point out that rhodanese undoubtedly prevents the accumulation of excessively toxic exhibitions of HCN arising from the scission of dietary B-glucuronosides and B-glucosides by paralleling them both in sites of occurence and in concentration. It exceeds the concentration of B-glucuronidase and B-glucosidase in all but malignant tissues. Whether or not human chorionic gonadotrophin produced by exhibitions of lesser malignancy accounts for the absence of rhodanese in the definitely malignant (trophoblast) cells, the fact that it does account for such rhodanese deficiency in the immediately contiguous somatic cells was demonstrated by Sanchez and Bertran.[l9] They reported that five international units of an aqueous solution of chorionic gonadotrophin 24 hours after injection decreased rhodanese activity in the tissue of rats 90% or more. CYANOPHORIC GLUCOSIDES AND CYANOPHORIC GLUCURONOSIDES Aware of the high concentration of B-glucuronidase in malignant tissue, Danielli[20] in 1950, and Conchie, Hay, and Levy[21] and Williams [22] in 1961, suggested the use of glucuronides as tumor inhibiting agents. Working within the context of the unitarian or trophoblastic thesis of cancer, Krebs and others[23] as early as 1925 observed in crude vegetable extracts definitive palliative and therapeutic properties with respect to human cancer. In the 1940's he identified this property with such constitutents of B-cyanogenetic glucosides as prunasin (l-mandelo- nitrile-B-glucoside) and amygdalin (d,l-gentio-bioside). These materials were isolated in crystalline form and demonstrated to be non-toxic. Subsequent synthesis of specific glucuronosides such as 1-mandelonitrile-B-glucuronoside has provided preparations with therapeutic properties substantially superior to the previously demonstrated activity of the glucosidic nitrilosides.[24] A large homologous series of nitrilosides with widely varying aglycones and sugars, is now under study. PHARMACOLOGY AND TOXICOLOGY When the Laetriles are incubated in vitro with a B-glucosidase, there is a quantitative and dramatic release of HCN, nascent above its boiling point of 26°C. McIlroy[25] and Edmunds and Gunn[26] have demonstrated a clear counterpart to this reaction in both plants and animals. The Laetriles are hydrolyzed in vivo to free nascent HCN, benzaldehyde, and a sugar or its acid. As previously explained the HCN is detoxified in somatic tissue by rhodanese to thiocyanate, which is then eliminated in the saliva, sweat, bile, and urine. The benzaldehyde is immediately oxidized to benzoic acid and detoxified through the liver by glycine conjugation as hippuric acid and/or glucuronic acid conjugation as benzoyl glucuronoside. Since these nitrilosides are reasonably homologous with natural compounds found in many edible plants, and since all detoxification products are normal constituents of human blood and urine, they are expectedly free of toxicity. The intact Laetrile molecule is devoid of pharmacological or toxicological properties, these being present only after hydrolysis. Although free HCN is very volatile and may be lethal on inhalation, the cyanogenetic glucuronosides are non-toxic when administered parenterally. One gram of d,l-mandelonitrile-B-glucuronoside contains 30 mg of incipient HCN, and doses of over 5 grams have been administered intravenously without toxic effects. In normal tissues the excess of rhodanese, as compared with B-glucosidase and B-glucuronidase, results in the detoxification of scission products; but as the result of the lack of rhodanese in malignant cells, the HCN released by B-glucuronidase is not detoxified and remains free to exert its lethal effects against such cells and the contiguous somatic in which rhodanese is inhibited by chorionic gonadotrophin. Stern and Willheim[27] in their "Biochemistry of Malignant Tumors" have summarized evidence for the selective sensitivity of cancer cells to cyanides. The present Laetriles depend for their cancericidal action almost exclusively upon potential HCN, although Waterman[28] has reported that benzaldehyde impedes the growth of inoculated tumors when brought into direct contact with the inoculum. Utilization of cancericidal aglycones and sugar derivatives will, of course, augment the present cancericidal action. While benzaldehyde and benzoic acid are, for example, antiseptic as well as analgesic, the substitution of an hydroxyl radical in the benzaldehyde ring would of course yield a more active analgesic upon hydrolysis--salicylic acid. CLINICAL EVALUATION OF LAETRILE Every chemical, reaction, product of reaction, source of reactant, and means of detoxification described above has been independently established and generally accepted. However, although the high concentration of B-glucuronidase, the apparent presence of a source of estrogen, and the deficiency of rhodanese have been empirically established in all exhibitions of cancer, acceptance of the above explanation of these phenomena in malignancies other than chorionepitheliomas is limited to adherents of the unitarian or trophoblastic thesis of cancer. We therefore feel that the Laetriles should be treated empirically as isolates in terms of ordinary clinical practicability until proof of their utility and acceptance of that proof permits their return to this unified context of Beardianism. The purpose of this clinical investigation was to determine whether there could be obtained at the malignant focus, a release of HCN of a magnitude sufficient to yield a substantial cytotoxic effect without exposing the host to undue toxicity. With the assistance of several medical associates a wide variety of terminal cancer cases, on whom all conventional methods of treatment had previously proved unsuccessful or inadvisable, were selected. ADMINISTRATION Laetrile is soluble in distilled water or normal salt solution and is administered parenterally. While some clinical investigators have given it intramuscularly, intrapleurally, intraperitoneally, locally, by means of arterial perfusion, and by iontophoresis, we have thus far confined our work to the intravenous and intramuscular, as well as administration by high retention enema and injection directly into certain lesions. Primary and secondary carcinomas of the lung have proved to be the most amenable to this route of therapy, because it avoids the rich reservoirs of B-glucuronidase in the liver, spleen, and kidneys. The most desirable route in malignancies beyond these organs can only be determined by an intelligent consideration of such factors as the underlying anatomy and physiopathology, the extent of the metastases, and the concentration of B-glucuronidase in the cells. There has been considerable variation in the dosage of Laetrile administered. In the early 1950's Navarro[29] and others used 50-100 mg doses and in 1957 these were increased to 250-500 mg. The total dosage a patient received seldom exceeded 2 grams. We feel now that each patient should receive a minimum of 30 grams. In some cancers, such as carcinoma of the breast, and in instances when only a brief stay in hospital was possible, Laetrile was given in doses of 3 gms per day for 10 successive days. Other doctors have preferred to give 1 gm per day for 30 days. It is our conclusion that, where time permits, it is most desirable to give the patient 1 gm of Laetrile every second day for the first 1-2 weeks. When it becomes evident that the drug is effective and that the patient is able to tolerate the breakdown of malignant tissue, this should be increased to 1 gm per day until the minimum dosage of 30 grams is attained. Such a routine produces results which are equally as good as those obtained with larger doses and seems to offer the advantage of taxing the regenerative processes of the body less severely. In a few of the most terminal and hopeless cases death ensued before adequate treatment could be given. But many of the patients, having received the basic 30 grams of Laetrile and having then continued on a maintenance dosage of 1-2 grams per week, became ambulatory and gradually resumed their normal activities. SUPPLEMENTARY THERAPY It has been our experience that, while Laetrile alone has proved to be effective, even better results can be obtained with some supplementary therapy as well. Pangamic acid is a methylating agent which appears to improve liver function with respect to its capacity to detoxify elements released from the malignant lesion following Laetrile therapy. Our patients received 100-200 mg of pangamic acid intramuscularly daily during their stay in hospital. There-after, a similar dosage was given with each maintenance dose of Laetrile. This substance may also be given orally should the patient so request it; but it appears to be more effective when given intramuscularly. CRITERIA FOR EVALUATION The progress of our patients was measured by a consideration of the clinical signs and symptoms, and by pathological, cytological, and radiological reports. Samples of the blood and urine were analyzed at intervals to detect any alterations in hematopoietic processes or in renal function during treatment. RESULTS Of the cases treated the results appearing in table 1 have been outlined because of the completeness of the data and because they serve to illustrate the wide range of malignancies which respond to Laetrile therapy. It is hoped that the following more detailed descriptions of some of the cases, might further illustrate our conclusions. CASE # 1: Mr. A.G., 44 year old radio announcer, was perfectly well until May, 1960. When examined on June 7th he complained of dysphagia and otalgia of one month duration. Examination revealed a left anterior tonsillar pillar which was indurated, leukoplasic, and thickened at its inferior insertion. There was no evidence of adenopathy. A diagnosis of epidermoid carcinoma (Grade 1) was made on the basis of histopathological report following biopsy. Because of the radio-resistance of such lesions, the radiotherapy which had been initiated was discontinued and the patient was submitted to cobalt therapy during June, July and August. The lesion continued to progress and his general condition worsened; but, because of his occupation, he refused surgery. By March 20, 1961, cervical brachial, and coronary adenopathy had developed to the extent that surgery was impossible. He had been able to swallow only liquids for six months. On March 23, 1961, Laetrile therapy (1 gm per day I. V.) plus B15 (100 mg per day I.M.) was begun. After the first 6 grams of Laetrile progression of the lesion was halted and by April 4th he was released from hospital in a much improved condition. Dosage was reduced to 1 gm of Laetrile and 100 mg of B15 twice per week. By June 27, 1961, the dysphagia, adenopathy, and otalgia had disappeared, the primary lesion was considerably reduced in size, and the patient had gained 11 pounds. During the last year, on a regimen of 1 gm. Laetrile and 100 mg of B15 one to two times per week, his condition has continued to improve and there is no longer any evidence of the primary lesion. With cessation of treatment with Laetrile for more than 6 weeks the dysphagia and otalgia return but there has been no recurrence of the primary lesion or of the cervical adenopathy. The patient should therefore continue on maintenance dosage indefinitely. CASE # 2: Mrs. G.S., 63 year old housewife, was first diagnosed as having a glandular epithelioma of the left breast with metastases in Nov. 1959. A radical mastectomy was performed at that time, and from Jan. 22 to April 4, 1960, she received radiotherapy (13,230 r to the left axillary and supraclavicular regions, left chest, and mediastinum) on May 5, 1961, she was admitted to hospital completely incapacitated by pain and by intense dyspnea and severe coughing at the least effort. Physical and radiological examination revealed metastases to the right and left supraclavicular nodes and to both lungs--probably due to radiotherapy. Cytology reports on a left pleural effusion were negative. During her stay in hospital she received 200 mg of B15 intramuscularly each day and 1 gm of Laetrile intravenously every second day from May 24th until July 2lst. From July 2lst to July 28th she received 3 gms of Laetrile per day. Within a month after Laetrile therapy was begun her dyspnea and cough had disappeared and she had become ambulatory. When released from hospital on July 28, 1961, the patient appeared clinically to be greatly improved, although X-ray studies of the lungs showed no change with the exception of the absence of any pleural effusion. Since that time she continued to receive 1 gram of Laetrile I.V. and 200 mg of B15 I.M. twice weekly. Her pain almost completely disappeared, she is no longer troubled by dyspnea or coughing, and she gradually resumed her normal activities. It can be seen from the table (see: http://www.europa.com/~rsc/cancer/images/krb5tab1.gif) that her blood picture improved and there has been no evidence of any toxicity. CASE # 3 : Mrs. L.N., 52 year old housewife, was admitted to hospital March 6, 1962, with complaints of metrorrhagia of three months duration (menopause 6 years ago) and of right upper quadrant pain and dyspepsia of fifteen days duration. On the basis of clinical evidence and the cytological report following curettage a diagnosis of adenocarcinoma of the uterus ( class V ) vas made. The patient was started on Laetrile on March 21, 1962, receiving intravenously I gm per day for three day's and then 500 mg every second day, until her release from hospital on May 22nd. She was also given 100 mg of B 15 every other day during hospitalization. A second cytological report on April 26th revealed no evidence of adenocarcinoma but only of endocervical hyperplasia. Her abdominal pain and metrorrhagia had ceased by this time and she had begun to gain weight. Since her release from hospital we have continued to give her 1 gm of Laetrile I.V. and 100 mg of B15 I.M. twice weekly. She has had no recurrence of symptoms, has regained her appetite and strength, is sleeping better, and does her house-work without effort. Her urine, which originally contained traces of albumin and bacteria, mucus, hyalin casts and calcium oxylate crystals, is now normal. Her blood picture has not changed significantly, although Vita-Iron has been used to maintain her hemoglobin levels. No toxicity has been noted. CASE # 4: This 55 year old patient, Mr. G.G., was admitted to hospital June 2, 1962. A barium series and cinefturography at another hospital on May 7, 1962, had revealed an apithelioma of the esophagus. There was evidence of mucosal ulceration and of severe narrowing of the lumen for a length of 10 cm at the junction of the middle and lower thirds of the esophagus. At the time of admission to this hospital he was near death--unable to take any solid food and, in fact, even regurgitating liquids. He complained of pain in the right upper quadrant. X-rays of the lungs on June 4th revealed an ill-defined opacity in the right middle lobe suggestive of pneumonia (he had been treated with tetracycline 2 weeks before for pneumonia), and pleural thickening and effusion on the left side. It was uncertain whether left pulmonary metastases were present. The patient was treated with Fortemycin and with 1 gram of Laetrile I.V. and 100 mg of B15 I.M. daily. He required Phenergan and Demerol in order to sleep at night. His pain fever had disappeared within 6 days, and after two weeks in hospital he was able to eat solid foods, had gained twelve pounds, and was ambulatory. X-rays of the lungs on June l6th were normal with exception of some pleural thickening in the left axillary line. On June 24, 1962, the patient was released from hospital. Treatment was reduced to 1 gram of Laetrile I.V. and 100 mg of B 15 I.M. every second day. X-ray studies of the lungs on July 27th were normal. A barium meal at this time revealed that the mucosa of an 8 cm segment of the distal third of the esophagus was irregular and that the lumen was somewhat reduced in calibre, but that the barium passed through without obstruction. The patient at present feels well and has returned to work. He no longer requires analgesics to sleep. His urine has been normal throughout the course of treatment; but his hematocrit and hemoglobin, which were 31 % and 10.2 gm% respectively on June 4th had increased to 37 % and 11.8 gm% respectively by July 7th. There has been no evidence of toxicity. CASE # 5 : Mrs. G.M., 53 years old, was first discovered to have a glandular epithelioma of the ascend ing colon on August 20, 1961, at which time a resection and anastamosis was done. On Feb. 15, 1962, she presented with symptoms of obstruction. This was confirmed by barium er.ema and a second operation was performed on Feb. 20th. A recurrence of the glandular epithelioma was found at the site of anastomosis; this had spread to involve the posterior abdominal wall, a number of mesenteric lymph nodes, and the greater omentum. It was impossible to excise the entire mass, but a side to side anastomosis of the terminal part of the ileum and the transverse colon was performed to relieve the obstruction. She was then started on Laetrile, receiving 500 mg I.V. every second day for six days, then 1 gm per day for another six days. She has received 1 gm of Laetrile every second day since that time, and has also been given 200 1~ mg of B 15 I.M. with each injection of Laetrile. At present she is feeling very well and is able to perform her household duties without difficulty. Her pain and colic is greatly diminished, her appetite has improved, her bowels are functioning normally, and she has no difficulty sleeping. There has been a noticeable reduction in the size of her abdominal mass. Urinalyses have remained normal and her hemoglobin, which had dropped to 10.6 gm% following her operation in February has increased to 11.7 gm%. There has been no indication of any toxicity. CONCLUSION To maintain that any of these patients has been cured---"cure" being defined as a five year period free of tumor recurrence---is not our purpose. In accordance with the concepts of Beardianism, cancer, like pallegra or scurvy, is a deficiency disease which must be controlled either permanently or until the enzymatic deficiency of the pancreas is rectified. It appears to us that the effectiveness of the Laetrile as much a palliative has been clearly demonstrated in a wide variety of malignant exhibitions, particularly in primary and secondary neoplasms of the lung. It is also very evident that Laetrile possesses strong analgesic properties; and, although none of the patients mentioned in the abvve reports were troubled with fetor, in other cases treated this symptom was also relieved when present. Furthermore, there has been no indication ot any toxicity in any of our cases in spite of the large amounts of Laetrile administered. In view of these facts it would seem only reasonable to suggest that this drug be more properly evaluated prior to the use of other palliatives, immediately following the detection of cancer. It should be remembered, too, that to date the successful resolution of the anemias, vitamin deficiencies, and all other chronic diseases has only been accomplished by non-toxic physiologic means of prophylactic significance. Whether the systemically non-toxic and apparently cancericidal Laetriles are also of preventative as well as palliative import is cetainly worthy of additional scrutiny. SUMMARY 1) Malignant tumors are focally characterized by a high concentration of B-glucuronidase and a deficiency of rhodanese. 2) Specific nitrilosides (Laetriles), which upon hydrolysis yield hydrogen cyanide, an agly- cone (benzyaldehyde) and a sugar moiety, have been prepared to exploit this I3-glucu- ronidase-rhodanese pattern. 3) Following parenteral administration there appears to be released in a wide variety of selectively sensitive malignant tissues such an excess of nascent HCN as to produce effects of definite palliative, and possible prophylactic, consequences in human cancer. 4) Laetrile also possesses strong analgesic pro- perties and shows no evidence of any toxicity. 5) On the basis of the results reported in this paper and those obtained by other clinical investigators using Laetrile, it is suggested that this drug might be more properly eva- Iuated in less terminal cases untreated by other palliatives. BIBLIOGRAPHY l. Krebs, E.T., Jr., E.T. Krebs, Sr., and H.H. 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J., The Plant Glycosides, London, Edward Arnold and Co., 1951, pp. 9-10. 26.Edmunds, C. W., and J. A. Gunn, Cush- nys Pharmacology and Therapeutics (ed. 12), Philadelphia, Lea and Febiger, 1940, pp. 682-685. 27.Stern,K., and R. Wilheim, The Bioche- mistry of Malignant Tumors, Brooklyn, New York, Reference Press, 1943. 28.Waterman, N., "Der Heutige Stand Der Chemotherapeutischen Carcinoforschung," Ergebn. der inn. med u Kinderk. 30:304- 376. ( 1946). 29.Navarro Manuel D., "Laetrile Therapy in Cancer," read at Eighth International Cancer Congress, Moscow, Russia, July 22-28, 1962. Reprinted in The Philippine Journal of Cancer, July-Sept., 1962. --------------------------------------------------------------------------- The ROBERT CATHEY RESEARCH SOURCE. All pages Copyright © 1996 R.S.Cathey, except where specified otherwise.