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Laetrile/Amygdalin (PDQ®)

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Laboratory/Animal/Preclinical Studies

On the basis of standard laboratory tests and animal models used to screen anticancer drugs, there is little evidence to support a specific cancer -killing ability for laetrile. These investigations used numerous cultured cell lines and tumor models, and they explored the following issues: (1) whether laetrile, given alone or in combination with other substances, exhibits anticancer activity of any kind; (2) the toxic effects associated with laetrile treatment; (3) the location of laetrile breakdown in the body and how this breakdown occurs; and (4) the route(s) of excretion for laetrile and its breakdown products.

Animal studies of laetrile have used rodents,[1-12] dogs,[13-15] rabbits,[15] and a cat.[13] Early work led to the hypothesis that enzymes were necessary to release cyanide from amygdalin. When high levels of these enzymes were present, symptoms of cyanide poisoning were more pronounced.[1,15] In two studies sponsored by the National Cancer Institute and published in 1975, various rodent cancers (osteogenic sarcoma, melanoma, carcinosarcoma, lung carcinoma, and leukemia) were transplanted into rats and mice.[2,3] In both studies, the animals were treated with intraperitoneal injections of amygdalin, with or without the enzyme beta-glucosidase. None of the solid tumors or leukemias that were investigated responded to amygdalin at any dose that was tested. No statistically significant increase in animal survival was observed in any of the treatment groups. Similar results were obtained in another study using human breast and colon cancer cells implanted into mice (xenograft models).[12] Amygdalin at every dose level tested produced no response either as a single agent or in combination with beta-glucosidase. It was discovered that animals experienced more side effects when beta-glucosidase was given concurrently (at the same time) with amygdalin, compared with amygdalin alone.[2,3]

Additional cell culture and animal studies involving more than a dozen other tumor models have been published.[1,4,5,7,8,10,11,16-20] In one study, preliminary findings by one of the principal investigators that amygdalin inhibited the growth of primary tumors and the incidence of lung metastases in mice bearing spontaneous (not treatment-induced) mammary adenocarcinomas could not be confirmed.[4] However, positive results were obtained in four studies.[11,17,18,20]

In the first of these studies, amygdalin enhanced the antitumor activity of a combination of enzymes and vitamin A in mice with spontaneous mammary adenocarcinomas.[11] The amygdalin was given by intramuscular injection, the vitamin A was administered orally through a feeding tube, and the enzymes were injected into and around tumor masses. No anticancer activity was observed when amygdalin was given alone.

In the second study, white blood cells and prostate cancer specimens were used to investigate the potential of amygdalin to stimulate the immune system.[18] The researchers found that amygdalin caused a statistically significant increase in the ability of a patient’s white blood cells to adhere to his own prostate cancer cells, suggesting some immune system–boosting potential for amygdalin.

The third study investigated the ability of amygdalin and beta-glucosidase to indirectly sensitize the hypoxic (oxygen-starved) cells at the center of a tumor to the lethal effects of gamma irradiation.[17] Cells at the periphery (outer edge) of a tumor are more sensitive to gamma irradiation because they are not oxygen-deprived. Radiation kills cells, in part, by splitting molecules, including oxygen molecules, to form free radicals, which are highly reactive chemicals that can damage DNA and other important cellular components. It has been proposed that, by inhibiting oxygen uptake by peripheral tumor cells, more oxygen will diffuse to the hypoxic cells, thereby increasing their sensitivity to radiation. In this study, beta-glucosidase was used to break down amygdalin to release cyanide, with the cyanide inhibiting oxygen uptake by peripheral tumor cells. Presumably, cyanide uptake by interior tumor cells is less than that of cells located at a tumor’s periphery. Spheres of tumor cells created in the laboratory and tumor slices were used in the study. The investigators found that amygdalin and beta-glucosidase could act as indirect radiation sensitizers of hypoxic tumor cells. It should be noted, however, that independent confirmation of this positive finding has not been published in a peer-reviewed scientific journal. A major hurdle in the application of this technique to animals and humans is the development of a method for delivering a sufficient amount of cyanide to tumors without causing substantial systemic or regional toxicity.

In the fourth study, cultured human bladder cancer cells were treated with amygdalin alone or a combination of amygdalin and an antibody that was coupled (chemically) to beta-glucosidase.[20] The target for this antibody was the glycoprotein (a protein with sugar molecules attached) MUC1. Aberrant forms of MUC1 are produced and displayed at high levels on the outside of several types of cancer cells, including bladder cancer cells. In this study, amygdalin alone was not very effective in killing the bladder cancer cells, but its cell-killing ability was 36 times greater in the presence of the antibody-enzyme complex. There are two possible explanations for this increase in cell-killing ability. The first is that antibody-enzyme complexes bound via MUC1 produce high rates of amygdalin breakdown at the cell surface. This breakdown leads to high local production of cyanide, which is quickly taken up by the cells and kills them. The second explanation is that antibody-enzyme complexes bound to the cells are internalized, thereby increasing the intracellular concentration of beta-glucosidase. Increased beta-glucosidase activity inside a cell may result in increased breakdown of amygdalin taken up by the cell, and increased cyanide production and cell death. These two potential mechanisms are not mutually exclusive. In another experiment, the researchers cultured bladder cancer cells in the presence of human brain tumor cells that do not express MUC1. When this coculture was treated with amygdalin and the antibody-enzyme complex, the bladder cancer cells were killed selectively. In view of the mechanisms proposed above, this result is not surprising because the bladder cancer cells and the brain tumor cells in this coculture formed homogeneous colonies (colonies that contained exclusively bladder cancer cells or brain tumor cells). Conceivably, selective killing of some types of human cancer cells might be achievable through application of this method; however, these positive results must be confirmed independently, and the effectiveness of this approach in animal models must be demonstrated before its use in humans can be considered.

The toxicity of laetrile appears to be dependent on the route of administration. Oral administration is associated with much greater toxicity than intravenous, intraperitoneal, or intramuscular injection.[1,6,9,10,14,21-23] As noted previously (refer to the History section of this summary for more information), most mammalian cells contain only trace amounts of the enzyme beta-glucosidase;[24] however, this enzyme is present in gastrointestinal tract bacteria and in many food plants.[6,9,15,25-27] Two studies have specifically examined the role of intestinal bacteria in the breakdown of orally administered amygdalin.[9,28] In one study, rats bred and raised under germ-free conditions and rats bred and raised under normal conditions were given oral amygdalin. The germ-free rats exhibited no side effects from the compound, and their blood concentrations of cyanide were indistinguishable from those of untreated rats. Many of the rats with normal quantities of intestinal bacteria showed signs of cyanide poisoning (e.g., lethargy and convulsions), and they had high levels of cyanide in their blood. In the second study, rats were either treated or not treated with the antibiotic neomycin before being given oral amygdalin.[6] In this study, urinary excretion of detoxified cyanide (i.e., thiocyanate) was measured. The amount of urinary thiocyanate was 40 times higher in rats that had not been given the antibiotic, indicating that more amygdalin had been broken down in animals with normal amounts of intestinal bacteria. In humans, as in rats, substantial breakdown of amygdalin occurs in the intestines; however, little breakdown of either intravenously or intramuscularly delivered amygdalin occurs in humans, with most of the intact compound eventually excreted in urine.[26,29]

References

  1. Gostomski FE: The effects of amygdalin on the Krebs-2 carcinoma and adult and fetal DUB(ICR) mice. [Abstract] Diss Abstr Int B 39 (5): 2075-B, 1978.
  2. Wodinsky I, Swiniarski JK: Antitumor activity of amygdalin MF (NSC-15780) as a single agent and with beta-glucosidase (NSC-128056) on a spectrum of transplantable rodent tumors. Cancer Chemother Rep 59 (5): 939-50, 1975 Sep-Oct. [PUBMED Abstract]
  3. Laster WR Jr, Schabel FM Jr: Experimental studies of the antitumor activity of amygdalin MF (NSC-15780) alone and in combination with beta-glucosidase (NSC-128056). Cancer Chemother Rep 59 (5): 951-65, 1975 Sep-Oct. [PUBMED Abstract]
  4. Stock CC, Tarnowski GS, Schmid FA, et al.: Antitumor tests of amygdalin in transplantable animal tumor systems. J Surg Oncol 10 (2): 81-8, 1978. [PUBMED Abstract]
  5. Menon MM, Bhide SV: Perinatal carcinogenicity of isoniazid (INH) in Swiss mice. J Cancer Res Clin Oncol 105 (3): 258-61, 1983. [PUBMED Abstract]
  6. Newton GW, Schmidt ES, Lewis JP, et al.: Amygdalin toxicity studies in rats predict chronic cyanide poisoning in humans. West J Med 134 (2): 97-103, 1981. [PUBMED Abstract]
  7. Hill GJ 2nd, Shine TE, Hill HZ, et al.: Failure of amygdalin to arrest B16 melanoma and BW5147 AKR leukemia. Cancer Res 36 (6): 2102-7, 1976. [PUBMED Abstract]
  8. Lea MA, Koch MR: Effects of cyanate, thiocyanate, and amygdalin on metabolite uptake in normal and neoplastic tissues of the rat. J Natl Cancer Inst 63 (5): 1279-83, 1979. [PUBMED Abstract]
  9. Carter JH, McLafferty MA, Goldman P: Role of the gastrointestinal microflora in amygdalin (laetrile)-induced cyanide toxicity. Biochem Pharmacol 29 (3): 301-4, 1980. [PUBMED Abstract]
  10. Khandekar JD, Edelman H: Studies of amygdalin (laetrile) toxicity in rodents. JAMA 242 (2): 169-71, 1979. [PUBMED Abstract]
  11. Manner HW, DiSanti SJ, Maggio MI, et al.: Amygdalin, vitamin A and enzyme induced regression of murine mammary adenocarcinomas. J Manipulative Physiol Ther 1 (4): 246-8, 1978.
  12. Ovejera AA, Houchens DP, Barker AD, et al.: Inactivity of DL-amygdalin against human breast and colon tumor xenografts in athymic (nude) mice. Cancer Treat Rep 62 (4): 576-8, 1978. [PUBMED Abstract]
  13. Lewis JP: Laetrile. West J Med 127 (1): 55-62, 1977. [PUBMED Abstract]
  14. Schmidt ES, Newton GW, Sanders SM, et al.: Laetrile toxicity studies in dogs. JAMA 239 (10): 943-7, 1978. [PUBMED Abstract]
  15. Dorr RT, Paxinos J: The current status of laetrile. Ann Intern Med 89 (3): 389-97, 1978. [PUBMED Abstract]
  16. Levi L, French WN, Bickis IJ, et al.: Laetrile: a study of its physicochemical and biochemical properties. Can Med Assoc J 92 (20): 1057-61, 1965.
  17. Biaglow JE, Durand RE: The enhanced radiation response of an in vitro tumour model by cyanide released from hydrolysed amygdalin. Int J Radiat Biol Relat Stud Phys Chem Med 33 (4): 397-401, 1978. [PUBMED Abstract]
  18. Bhatti RA, Ablin RJ, Guinan PD: Tumour-associated directed immunity in prostatic cancer: effect of amygdalin. IRCS Med Sci Biochem 9 (1): 19, 1981.
  19. Koeffler HP, Lowe L, Golde DW: Amygdalin (Laetrile): effect on clonogenic cells from human myeloid leukemia cell lines and normal human marrow. Cancer Treat Rep 64 (1): 105-9, 1980. [PUBMED Abstract]
  20. Syrigos KN, Rowlinson-Busza G, Epenetos AA: In vitro cytotoxicity following specific activation of amygdalin by beta-glucosidase conjugated to a bladder cancer-associated monoclonal antibody. Int J Cancer 78 (6): 712-9, 1998. [PUBMED Abstract]
  21. Moertel CG, Ames MM, Kovach JS, et al.: A pharmacologic and toxicological study of amygdalin. JAMA 245 (6): 591-4, 1981. [PUBMED Abstract]
  22. Newmark J, Brady RO, Grimley PM, et al.: Amygdalin (Laetrile) and prunasin beta-glucosidases: distribution in germ-free rat and in human tumor tissue. Proc Natl Acad Sci U S A 78 (10): 6513-6, 1981. [PUBMED Abstract]
  23. Navarro MD: Five years experience with laetrile therapy in advanced cancer. Acta Unio Int Contr Cancrum 15(suppl 1): 209-21, 1959.
  24. Conchie J, Findlay J, Levvy GA: Mammalian glycosidases: distribution in the body. Biochem J 71 (2): 318-25, 1959.
  25. Herbert V: Laetrile: the cult of cyanide. Promoting poison for profit. Am J Clin Nutr 32 (5): 1121-58, 1979. [PUBMED Abstract]
  26. Ames MM, Moyer TP, Kovach JS, et al.: Pharmacology of amygdalin (laetrile) in cancer patients. Cancer Chemother Pharmacol 6 (1): 51-7, 1981. [PUBMED Abstract]
  27. Unproven methods of cancer management. Laetrile. CA Cancer J Clin 22 (4): 245-50, 1972 Jul-Aug. [PUBMED Abstract]
  28. Shils ME, Hermann MG: Unproved dietary claims in the treatment of patients with cancer. Bull N Y Acad Med 58 (3): 323-40, 1982. [PUBMED Abstract]
  29. Ames MM, Kovach JS, Flora KP: Initial pharmacologic studies of amygdalin (laetrile) in man. Res Commun Chem Pathol Pharmacol 22 (1): 175-85, 1978. [PUBMED Abstract]
  • Updated: February 5, 2014