Anticarcinogenic Activity of Protease Inhibitors Overview

  • Ann R. Kennedy


Cancer is one of the leading causes of death in the United States. There is known to be a great variation in cancer incidence with diet, as has been recently reviewed (Grobstein et al., 1982). Epidemiological data suggest that environmental, specifically nutritional, factors play a major role in the etiology of cancer at many different sites (Grobstein et al., 1982; Doll and Peto, 1981; Correa, 1981; Phillips, 1975). There are now many different epidemiological studies which suggest that components of vegetables, particularly legumes (Correa, 1981), might play a beneficial role in lowering the incidence of cancer (some examples of such studies are given in the references cited above). Legumes are known to contain high levels of protease inhibitors (Birk, 1974). Rice, maize, and beans, all of which are known to contain high levels of protease inhibitors (Birk, 1974, 1975), in the diet are associated with a reduced incidence of colon, breast, and prostate cancers (Correa, 1981). The intake of breads and cereals, food sources which are also known to contain high levels of protease inhibitors, has been associated with a lowered incidence of oral and pharyngeal cancers (Winn et al., 1984). Other studies with high levels of protease inhibitors in the diet have also suggested a reduced risk of developing colorectal and breast cancers (Blondell, 1988). The role of vegetable-derived protease inhibitors as active cancer chemopreventive agents is discussed in several other chapters in this volume (e.g., Chapter 1).


Protease Inhibitor Trypsin Inhibitor Soybean Trypsin Inhibitor Protease Inhibitor Activity Pancreatic Carcinogenesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adler, G., Mullenhoff, A., Bozkurt, T., Koop, I., Goke, B., Beglinger, C., and Arnold, R., 1986, Pancreatic function and plasma CCK in humans after ingestion of a proteinase inhibitor (FOY-305), Dig. Dis. Sci. 31:1123.CrossRefGoogle Scholar
  2. Adler, G., Mullenhoff, A., Bozkurt, T., Goke, B., Koop, I., and Arnold, R., 1988, Comparison of the effect of single and repeated administrations of a protease inhibitor (camostate) on pancreatic secretion in man, Scand. J. Gastroenterol. 23:158–162.PubMedCrossRefGoogle Scholar
  3. Andrén-Sandberg, A., and Ihse, I., 1983, Regulatory effects on the pancreas of intraduodenal pancreatic juice and trypsin in the Syrian golden hamster, Scand. J. Gastroenterol. 18:697–706.PubMedCrossRefGoogle Scholar
  4. Armstrong, B., and Doll, R., 1975, Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary factors, Int. J. Cancer 15:617–631.PubMedCrossRefGoogle Scholar
  5. Ashendel, C. L., 1985, The phorbol ester receptor: A phospholipid-regulated protein kinase, Biochim. Biophys. Acta 822:219–242.PubMedCrossRefGoogle Scholar
  6. Ausman, L. M., Harwood, J. P., King, N. W., Sehgal, P. K., Nicolosi, R. J., Hegsted, M. D., Liener, I. E., Donatucci, D., and Tarcza, J., 1985, The effects of long-term soy protein and milk protein feeding on the pancreas of Cebus albifrons monkeys, J. Nutr. 115:1691–1701.PubMedGoogle Scholar
  7. Baturay, N. Z., and Kennedy, A. R., 1986, Pyrene acts as a cocarcinogen with the carcinogens, benzo(a)pyrene, β-propiolactone and radiation in the induction of malignant transformation of cultured mouse fibroblasts; soybean extract containing the Bowman-Birk inhibitor acts as an anticarcinogen, Cell Biol. Toxicol. 2:21–32.PubMedCrossRefGoogle Scholar
  8. Bauer, E. A., Uitto, J., Walters, R. C., and Eisen, A. Z., 1979, Enhanced collagenase production by fibroblasts derived from human basal cell carcinomas, Cancer Res. 39:4594–4599.PubMedGoogle Scholar
  9. Becker, F. F., 1981, Inhibition of spontaneous hepatocarcinogenesis in C3H/Hen mice by Edi Pro A, an isolated soy protein, Carcinogenesis 2:1213–1214.PubMedCrossRefGoogle Scholar
  10. BEIR V Report, 1990, Health effects of exposure to low levels of ionizing radiation: BEIR V, A. C. Upton (Chairman) et al., Committee on the Biological Effects of Ionizing Radiations; Board of Radiation Effects Research Commission on Life Sciences, National Research Council, National Academy Press, Washington, D.C., pp. 1–400.Google Scholar
  11. Berenblum, I., Burger, M., and Knyszynski, A., 1974, Inhibition of radiation-induced lymphatic leukemia in C57BL mice by 195 alpha-2-globulin (α2-MG) from human blood serum, Radiat. Res. 60:501–505.PubMedCrossRefGoogle Scholar
  12. Bernacka, K., Kuryliszyn-Moskal, A., and Sierakowski, S., 1988, The levels of alpha-antitrypsin and alpha-antichymotrypsin in the sera of patients with gastrointestinal cancers during diagnosis, Cancer 62:1188–1193.PubMedCrossRefGoogle Scholar
  13. Billings, P. C., Morrow, A. R., Ryan, C. A., and Kennedy, A. R., 1989, Inhibition of radiation-induced transformation of C3H/10T1/2 cells by carboxypeptidase inhibitor I and inhibitor II from potatoes, Carcinogenesis 10:687–691.PubMedCrossRefGoogle Scholar
  14. Billings, P. C., Longnecker, M. P., Keary, M, and Taylor, P. R., 1990a, Protease inhibitor content of human dietary samples, Nutr. Cancer 14:81–93.CrossRefGoogle Scholar
  15. Billings, P. C., Newberne, P., and Kennedy, A. R., 1990b, Protease inhibitor suppression of colon and anal gland carcinogenesis induced by dimethylhydrazine, Carcinogenesis 11:1083–1086.PubMedCrossRefGoogle Scholar
  16. Birk, Y., 1961, Purification and some properties of a highly active inhibitor of trypsin and α-chymotrypsin from soybeans, Biochim. Biophys. Acta 54:378–381.PubMedCrossRefGoogle Scholar
  17. Birk, Y., 1974, Structure-activity relationship of several trypsin and chymotrypsin inhibitors from legume seeds, in: Proteinase Inhibitors (N. Fritz, H. Tschesche, L. J. Green, and E. Truscheit, eds.), Springer-Verlag, Berlin, pp. 355–361.CrossRefGoogle Scholar
  18. Birk, Y., 1975, Proteinase inhibitors from plant sources, Methods Enzymol. 45:695–751.CrossRefGoogle Scholar
  19. Birk, Y., 1985, The Bowman-Birk inhibitor, Int. J. Peptide Protein Res. 25:113–131.CrossRefGoogle Scholar
  20. Blondell, J. M., 1988, Urban-rural factors affecting cancer mortality in Kentucky, 1950-1969, Cancer Detect, and Prevent. 11:209–223.Google Scholar
  21. Bodwell, C. E., and Hopkins, D. T., 1985, Nutritional characteristics of oilseed proteins, in: New Protein Foods, Volume 5 (A. A. Altschul and H. L. Wilcke, eds.), Academic Press, New York, pp. 221–257.Google Scholar
  22. Bodwell, C. E., Adkins, J. S., and Hopkins, D. T. 1981, Protein Quality in Humans: Assessment and in Vitro Estimation, AVI Publishing, Westport, Conn., pp. 278–301.Google Scholar
  23. Bowman, D. E., 1946, Differentiation of soybean antitryptic factors, Proc. Soc. Exp. Biol. Med. 63:547–550.PubMedGoogle Scholar
  24. Bozzini, A., and Silano, V., 1978, Control through breeding methods of factors affecting nutritional quality of cereals and grain legumes, in: Nutritional Improvement of Food and Feed Proteins (M. Freidman, ed.), Plenum Press, New York, pp. 249–274.CrossRefGoogle Scholar
  25. Carroll, K. K., and Khor, H. T., 1975, Dietary fat in relation to tumorigenesis, Prog. Biochem. Pharmacol. 10:308–353.PubMedGoogle Scholar
  26. Chapman, H. A., Jr., and Stone, O. L., 1984, Comparison of live human neutrophil and alveolar macrophage elastolytic activity in vitro: Relative resistance of macrophage elastolytic activity to serum and alveolar proteinase inhibitors, J. Clin. Invest. 74:1693–1700.PubMedCrossRefGoogle Scholar
  27. Chawla, R. K., Rausch, D. J., Miller, F. W., Vogler, W. R., and Lawson, D. H., 1984, Abnormal profile of serum proteinase inhibitors in cancer patients, Cancer Res. 44:2718–2723.PubMedGoogle Scholar
  28. Chernick, S. S., Lepkovsky, S., and Chaikoff, I. L., 1948, A dietary factor regulating the enzyme content of the pancreas; changes induced in size and proteolytic activity of the chick pancreas by the ingestion of raw soybean meal, Am. J. Physiol. 155:33–41.PubMedGoogle Scholar
  29. Chiarella, H. R., Yao, B.C., and Thompson, W. A. B., 1976, Soybean trypsin inhibitor activity of soy infant formulas and its nutritional significance for the rat, J. Agric. Food Chem. 24:393–397.CrossRefGoogle Scholar
  30. Coburn, M., Schuel, H., and Troll, W., 1981, A hydrogen peroxide block to polyspermy in the sea urchin, Arbacia punctulata, Dev. Biol. 84:235–238.PubMedCrossRefGoogle Scholar
  31. Corasanti, J. G., Hobika, G. H., and Markus, G., 1982, Interference with dimethylhydrazine induction of colon tumors in mice by ε-aminocaproic acid, Science 216:1020–1021.PubMedCrossRefGoogle Scholar
  32. Correa, P., 1981, Epidemiologic correlations between diet and cancer frequency, Cancer Res. 41:3685–3690.PubMedGoogle Scholar
  33. Corwin, L. M., and Gordon, R. K., 1982, Vitamin E and immune regulation, in: Vitamin E: Biochemical, Hematological, and Clinical Aspects (B. Lubin and L. J. Machlin, eds.), N.Y. Acad. Sci., New York, pp. 437–451.Google Scholar
  34. Crass, R. A., and Morgan, R. G. H., 1982, The effect of long-term feeding of soya bean flour diets on pancreatic growth in the rat, Br. J. Nutr. 47:119–129.PubMedCrossRefGoogle Scholar
  35. Diaz, G. R., Devaux, M. A., Johnson, C. D., Adrich, Z., and Sarles, H., 1982, Physiological conditions for the study of basal and meal-stimulated exocrine pancreatic secretion in the dog. Absence of feedback inhibition of basal secretion, Can. J. Physiol. Pharmacol. 60:1287–1295.CrossRefGoogle Scholar
  36. Doell, B. H., Ebden, C. J., and Smith, C.A., 1981, Trypsin inhibitor activity of conventional foods which are part of the British diet and some soya products, Qual. Plant. Plant Foods Hum. Nutr. 31:139–150.CrossRefGoogle Scholar
  37. Doll, R., and Peto, R., 1981, The causes of cancer: Quantitative estimates of avoidable risks of cancer in the United States today, J. Natl. Cancer Inst. 66:1193–1308.Google Scholar
  38. Douglas, B. R., Woutersen, R. A., Jansen, J. B. M. J., de Jong, A. J. L., Rovati, L. C., and Lamers, C. B. H. W., 1989, Modulation by CR-1409 (lorglumide), a cholecystokinin receptor antagonist, of trypsin inhibitor-enhanced growth of azaserine-induced putative preneoplastic lesions in rat pancreas, Cancer Res. 49:2438–2441.PubMedGoogle Scholar
  39. Dresden, M. H., Heilman, S. A., and Schmidt, J. D., 1972, Collagenolytic enzymes in human neoplasms; Cancer Res. 32:993–996.PubMedGoogle Scholar
  40. Durbec, J. P., Chevilotte, G., Bidart, J. M., Berthezene, P., and Sarles, H., 1983, Diet, alcohol, tobacco and risk of cancer of the pancreas—A case control study, Br. J. Cancer 47:463–470.PubMedCrossRefGoogle Scholar
  41. Flavin, D. F., 1982, The effect of soybean trypsin inhibitors on the pancreas of animals and man, Vet. Hum. Toxicol. 24:25–28.PubMedGoogle Scholar
  42. Folsch, U. R., Winckler, K., and Wormsley, K. G., 1974, Effect of a soybean diet on enzyme content and ultrastructure of the rat exocrine pancreas, Digestion 11:161–171.PubMedCrossRefGoogle Scholar
  43. Frenkel, K., Chrzan, K., Ryan, C., Wiesner, R., and Troll, W., 1987, Chymotrypsin-specific protease inhibitors decrease H2O2 formation by activated human polymorphonuclear leukocytes, Carcinogenesis 8:1207–1212.PubMedCrossRefGoogle Scholar
  44. Fukui, Y, Takamura, C., Yamamura, M., and Yamamoto, M., 1975, Effect of leupeptin on carcinogenesis of rat mammary tumor induced by 7, 12-dimethylbenz(a)-anthracene, Proc. Japan Cancer Assoc, 34th Annual Meeting, p. 20.Google Scholar
  45. Fushiki, T., and Iwai, K., 1989, Two hypotheses on the feedback regulation of pancreatic enzyme secretion, FASEB J. 3:121–126.PubMedGoogle Scholar
  46. Gallaher, D., and Schneeman, B. O., 1986, Nutritional and metabolic response to plant inhibitors of digestive enzymes, Adv. Exp. Med. Biol. 199:167–184.PubMedCrossRefGoogle Scholar
  47. Gertler, A., and Nitsan, Z., 1970, The effect of trypsin inhibitors on pancreotopeptidase E, trypsin, chymotrypsin, and amylase in the pancreas and intestinal tract of chicks receiving raw and heated soya bean diets, Br. J. Nutr. 24:803–804.CrossRefGoogle Scholar
  48. Gold, E. B., Gordis, L., Diener, M. D., Seltser, R., Boitnott, J. K., Bynum, T. E., and Hutcheon, D. F., 1985, Diet and other risk factors for cancer of the pancreas, Cancer 55:460–467.PubMedCrossRefGoogle Scholar
  49. Goldfarb, R. H., Kitson, R. P., Giffen, C. Z., and Yavelow, J., 1989, Anticarcinogenic and anti-proteolytic Bowman-Birk inhibitor (BBI): Failure to inhibit both LAK cell proteases and LAK cell-mediated killing of tumor cells, Proc. Am. Assoc. Cancer Res. (March, 1989), Volume 30, Abstract No. 711, p. 179.Google Scholar
  50. Goldstein, B. D., Witz, G., Amoruso, M., and Troll, W., 1979, Protease inhibitors antagonize the activation of polymorphonuclear leukocyte oxygen consumption, Biochem. Biophys. Res. Commun. 88:854–860.PubMedCrossRefGoogle Scholar
  51. Gorrill, A. D. L., and Thomas, J. W., 1967, Body weight changes, pancreas size and enzyme activity, and proteolytic enzyme activity and protein digestion in intestinal contents from calves fed soybean and milk protein diets, J. Nutr. 92:215–223.PubMedGoogle Scholar
  52. Grau, C. R., and Carroll, R. W., 1958, Evaluation of protein quality, in: Processed Plant Protein Foodstuffs (A. M. Altschul, ed.), Academic Press, New York, pp. 153–189.Google Scholar
  53. Green, G. M., and Lyman, R. L., 1972, Feedback regulation of pancreatic enzyme secretion as a mechanism for trypsin inhibitor induced hypersecretion in rats, Proc. Soc. Exp. Biol. Med. 140:6–12.PubMedGoogle Scholar
  54. Green, G. M., Olds, B. O., Matthews, G., and Lyman, R. L., 1973, Protein as a regulator of pancreatic enzyme secretion in the rat, Proc. Soc. Exp. Biol. Med. 142:1162–1167.PubMedGoogle Scholar
  55. Grobstein, C., Cairns, J., Berliner, R. et al., 1982, Diet, Nutrition and Cancer, Committee on Diet, Nutrition and Cancer, Assembly of Life Sciences, National Research Council, National Academy of Sciences, Washington, D.C.Google Scholar
  56. Gumbmann, M. R., Spangler, W. L., Dugan, G. M., Rackis, J. J., and Liener, I. E., 1985, The USDA trypsin inhibitor study, IV: The chronic effects of soyflour and soy protein isolate in rats after two years, Qual. Plant. Plant Foods Hum. Nutr. 35:275–314.CrossRefGoogle Scholar
  57. Harlan, J. M., Killen, P. D., Harker, L. A., Striker, G. E., and Wright, D. G., 1981, Neutrophil-mediated endothelial injury in vitro: Mechanisms of cell detachment, J. Clin. Invest. 68:1394–1403.PubMedCrossRefGoogle Scholar
  58. Hasdai, A., and Liener, I. E., 1983, Growth, digestibility, and enzymatic activities in the pancreas and intestines of hamsters fed raw and heated soy flour, J. Nutr. 113:662–668.PubMedGoogle Scholar
  59. Hooks, R. D., Hays, V. W., Speer, V. C., and McCall, J. T., 1965, Effects of raw soybeans on pancreatic enzyme concentrations and performance of pigs, Fed. Proc. Fed. Am. Soc. Exp. Biol. 24:894.Google Scholar
  60. Hozumi, M., Ogawa, M., Sugimura, T., Takeuchi, T., and Umezawa, H., 1972, Inhibition of tumorigenesis in mouse skin by leupeptin, a protease inhibitor from actinomycetes, Cancer Res. 32:1725–1728.PubMedGoogle Scholar
  61. Hwang, D. L. R., Davis-Lin, K. T., Yang, W. K., and Foard, D. T., 1977, Purification, partial characterization and immunological relationships of multiple low molecular weight proteinase inhibitors of soybean, Biochim. Biophys. Acta 495:369–382.PubMedCrossRefGoogle Scholar
  62. Ikenaka, T., Odani, S., and Koide, T., 1974, Proteinase inhibitors, Proc. 2nd Int. Res. Conf. (Baker Symp. V), Grosse Leder, 1973, Springer-Verlag, Berlin, p. 325.Google Scholar
  63. Inoue, M., Kishimoto, A., Takai, Y., and Nishizuka, Y., 1977, Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues, J. Biol. Chem. 252:7610–7616.PubMedGoogle Scholar
  64. Ishiura, S., 1981, Calcium-dependent neutral protease from chicken skeletal muscle. I. Purification and characterization, J. Biochem. 84:225–230.Google Scholar
  65. Jonat, C., Rahmsdorf, H. J., Park, K.-K., Cato, A. C. B., Gebel, S., Ponta, H., and Herrlich, P., 1990, Antitumor promotion and antiinflammation: Down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone, Cell 62:1189–1204.PubMedCrossRefGoogle Scholar
  66. Kakade, M. L., Barton, T. L., Schaible, P. J., and Evan, R. J., 1967, Biochemical changes in the pancreas of chicks fed raw soybeans and soybean meal, Poult. Sci. 46:1578–1585.PubMedCrossRefGoogle Scholar
  67. Kakade, M. L., Hoffa, D. E., and Liener, I. E., 1973, Contribution of trypsin inhibitors to the deleterious effects of unheated soybeans fed to rats, J. Nutr. 103:1772–1778.PubMedGoogle Scholar
  68. Kakade, M. L., Thompson, R. D., Englestad, W. W., Behrens, G. C., Yoder, R. D., and Crave, F. M., 1976, Failure of soybean trypsin inhibitors to exert deleterious effects in calves, J. Dairy Sci. 59:1484–1489.PubMedCrossRefGoogle Scholar
  69. Kaneko, A., Enomoto, K., Oyamada, M., Sawada, N., Dempo, K., and Mori, M., 1986, Induction of a novel Ca2+-dependent chymotrypsin-like serine protease by tumor promoters in rat livers, J. Natl. Cancer Inst. 77:121–125.PubMedGoogle Scholar
  70. Kassell, B., 1970, Trypsin and chymotrypsin inhibitors from soybeans, Methods Enzymol. 19:853–862.CrossRefGoogle Scholar
  71. Kennedy, A. R., 1984, Discussion (pp. 127-136) of “Analysis of phorbol ester receptors: A biochemical approach to understanding the mechanism of action of tumor promoters,” by P. M. Blumberg, B. Konig, N. A. Sharkey, S. Jaken, K. L. Leach, and A. G. Jeng, in: Molecular and Cellular Approaches to Understanding Mechanisms of Toxicity, pp. 108-127, Proceedings of a conference held in Boston on September 1-2, 1983 (A. H. Tashjian, Jr., ed.), published by the President and Fellows of Harvard College.Google Scholar
  72. Kennedy, A. R., 1985, The conditions for the modification of radiation transformation in vitro by a tumor promoter and protease inhibitors, Carcinogenesis 6:1441–1446.PubMedCrossRefGoogle Scholar
  73. Kennedy, A. R., 1986, Role of free radicals in the initiation and promotion of radiation-induced and chemical carcinogen induced cell transformation, in: Oxygen and Sulfur Radicals in Chemistry and Medicine (A. Breccia, M.A. J. Rodgers, and G. Semerano, eds.), Edizioni Scientifiche, “Lo Scarabeo,” Bologna, Italy, pp. 201–209.Google Scholar
  74. Kennedy, A. R., and Billings, P. C., 1987, Anticarcinogenic actions of protease inhibitors, in: Anticarcinogenesis and Radiation Protection (P. A. Cerutti, O. F. Nygaard, and M. G. Simic, eds.), Plenum Press, New York, pp. 285–295.CrossRefGoogle Scholar
  75. Kennedy, A. R., and Little, J. B., 1981, Effects of protease inhibitors on radiation transformation in vitro, Cancer Res. 41:2103–2108.PubMedGoogle Scholar
  76. Kennedy, A. R., and Symons, M. C. R., 1987, “Water structure” vs “radical scavenger” theories as explanations for the suppressive effects of DMSO and related compounds on radiation induced transformation in vitro. Carcinogenesis 8:683–688.PubMedCrossRefGoogle Scholar
  77. Kennedy, A. R., Radner, B., and Nagasawa, H., 1984, Protease inhibitors reduce the frequency of spontaneous chromosome abnormalities in cells from patients with Bloom syndrome, Proc. Natl. Acad. Sci. USA 81:1827–1830.PubMedCrossRefGoogle Scholar
  78. Kennedy, A. R., Billings, P. C., Maki, P. A., and Newberne, P., 1993, Effects of various protease inhibitor preparations on oral carcinogenesis in hamsters induced by 7,12-dimethylbenz(a) anthracene, Nutrition and Cancer 19:191–200.PubMedCrossRefGoogle Scholar
  79. Kunitz, M., 1947, Crystalline soybean trypsin inhibitor, J. Gen. Physiol. 30:291–310.PubMedCrossRefGoogle Scholar
  80. Kuroki, T., and Drevon, C., 1979, Inhibition of chemical transformation in C3H/10T1/2 cells by protease inhibitors, Cancer Res. 39:2755–2761.PubMedGoogle Scholar
  81. Leb, L., Beatson, P., Fortier, N., Newburger, P. E., and Snyder, L. M., 1985, Modulation of mononuclear phagocyte cytotoxicity by alpha-tocopherol (vitamin E), J. Leuk. Biol. 37:449–459.Google Scholar
  82. Liener, I. E., 1979a, Significance for humans of biologically active factors in soybeans and other food legumes, J. Am. Oil Chem. Soc. 56:121–129.PubMedCrossRefGoogle Scholar
  83. Liener, I. E., 1979b, Protease inhibitors and lectins, in: International Review of Biochemistry (A. Veuberger and T. H. Jakes, eds.), University Park Press, Baltimore, pp. 97–122.Google Scholar
  84. Liener, I. E., 1989, Control of anti-nutritional and toxic factors in oilseeds and legumes, in: Food Uses of Whole Oil and Protein Seeds (E. W. Lusas, D. R. Erikson, and W.-K. Nip, eds.), American Oil Chemists Society, Champaign, 111., pp. 344–371.Google Scholar
  85. Liener, I.E., and Hasdai, A., 1986, The effect of long-term feeding of raw soy flour on the pancreas of mouse and hamster, Adv. Exp. Med. Biol. 199:189–197.PubMedCrossRefGoogle Scholar
  86. Liener, I. E., and Kakade, M. L., 1980, Protease inhibitors, in: Toxic Constituents of Plant Foodstuffs (I. E. Liener, ed.), Academic Press, New York, pp. 7–71.Google Scholar
  87. Liener, I. E., Goodale, R. L., Deshmukh, A., Satterberg, T. L., Ward, G., DiPietro, C. M., Bankey, P. E., and Borner, J. W., 1988, Effect of a trypsin inhibitor from soybeans (Bowman-Birk) on the secretory activity of the human pancreas, Gastroenterology 94:419–427.PubMedGoogle Scholar
  88. Lim, T. S., Putt, N., Safranski, D., Chung, C., and Watson, R. R., 1981, Effect of vitamin E on cellmediated immune responses and serum corticosterone in young and maturing mice, Immunology 44:289–295.PubMedGoogle Scholar
  89. Liotta, L. A., Tryggvason, K., Garbisa, S., Hart, I., Foltz, C. M., and Shafie, S., 1980, Metastatic potential correlates with enzymatic degradation of basement membrane collagen, Nature 284:67–68.PubMedCrossRefGoogle Scholar
  90. McGuiness, E. E., Morgan, R. G. H., Levison, D. A., Frape, D. L., Hopwood, D., and Wormsley, K. G., 1980, The effect of long-term feeding of soya flour on the rat pancreas, Scand. J. Gastroenterol. 15:497–502.CrossRefGoogle Scholar
  91. McGuiness, E. E., Morgan, R. G. H., and Wormsley, K. G., 1984, Effects of soybean flour on the pancreas of rats, Environ. Health Perspect. 56:205–212.CrossRefGoogle Scholar
  92. Mack, T. M., 1982, Pancreas, in: Cancer Epidemiology and Prevention (D. Schottenfeld and J. Fraumeni, eds.), Saunders, Philadelphia, pp. 638–667.Google Scholar
  93. Madar, Z., Birk, Y., and Gertler, A., 1974, Native and modified Bowman-Birk trypsin inhibitor— Comparative effect on pancreatic enzymes upon ingestion by quails, Comp. Biochem. Physiol. 48B:251–256.Google Scholar
  94. Mainz, D. L., Black, O., and Webster, P. D., 1973, Hormonal control of pancreatic growth, J. Clin. Invest. 52:2300–2304.PubMedCrossRefGoogle Scholar
  95. Matsushima, T., Kakizoe, T., Kawachi, T., Hara, K., Sugimura, T., Takeuchi, T., and Umezawa, H., 1976, Effects of protease inhibitors of microbial origin on experimental carcinogenesis, in: Fundamentals in Cancer Prevention (P. N. Magee et al., eds.), University of Tokyo Press, Tokyo, University Park Press, Baltimore, pp. 57–69.Google Scholar
  96. Melmed, R. N., El-Aaser, A. A. A., and Holt, S. J., 1976, Hypertrophy and hyperplasia of the neonatal rat exocrine pancreas induced by orally administered soybean trypsin inhibitor, Biochim. Biophys. Acta 421:280–282.PubMedCrossRefGoogle Scholar
  97. Messadi, D. V., Billings, P., Shklar, G., and Kennedy, A. R., 1986, Inhibition of oral carcinogenesis by a protease inhibitor, J. Natl. Cancer Inst. 76:447–452.PubMedGoogle Scholar
  98. Messina, M. J., and Barnes, S., 1991, Workshop report from the Division of Cancer Prevention and Control: The role of soy products in reducing the risk of cancer, J. Natl. Cancer Inst. 83:541–546.PubMedCrossRefGoogle Scholar
  99. Mills, P. K., Beeson, W. L., Abbey, D. E., Fraser, G. E., and Phillips, R. L., 1988, Dietary habits and past medical history as related to fatal pancreas cancer risk among Adventists, Cancer (Philadelphia) 61:2578–2585.CrossRefGoogle Scholar
  100. Miyasaka, K., and Green, G. M., 1984, Effect of partial exclusion of pancreatic juice on rat basal pancreatic secretion, Gastroenterology 86:114–119.PubMedGoogle Scholar
  101. Miyasaka, K., Nakamura, R., Funakoshi, A., and Kitani, K., 1989, Stimulatory effect of monitor peptide and human pancreatic secretory trypsin inhibitor on pancreatic secretion and cholecystokinin release in conscious rats, Pancreas 4:139–144.PubMedCrossRefGoogle Scholar
  102. Morgan, R. G. H., 1987, Raw soy flour and pancreatic cancer in experimental animals, in: Experimental Pancreatic Carcinogenesis (D. G. Scarpelli, J. K. Reddy, and D. S. Longnecker, eds.), CRC Press, Boca Raton, Fla., pp. 159–174.Google Scholar
  103. Nairn, M., Gertler, A., and Birk, Y., 1982, The effect of dietary raw and autoclaved soya-bean protein fractions on growth, pancreatic enlargement and pancreatic enzymes in rats, Br. J. Nutr. 47:281–288.CrossRefGoogle Scholar
  104. Nash, D. R., McLarty, J. W., and Fortson, N. G., 1980, Pretreatment, prediagnosis immunoglobulin, and alpha1-antitrypsin levels in patients with bronchial carcinoma, J. Natl. Cancer Inst. 64:721–724.PubMedGoogle Scholar
  105. Nishizuka, Y., 1984, The role of protein kinase C in cell surface signal transduction and tumor promotion, Nature 308:693–698.PubMedCrossRefGoogle Scholar
  106. Nitsan, Z., and Alumot, E., 1964, Overcoming the inhibition of intestinal proteolytic activity caused by raw soybean in chicks of different ages, J. Nutr. 84:179–184.PubMedGoogle Scholar
  107. Nitsan, Z., and Nir, I., 1977, A comparative study of the nutritional and physiological significance of raw and heated soybeans in chicks and goslings, Br. J. Nutr. 37:81–91.PubMedCrossRefGoogle Scholar
  108. Nomura, T., Hata, S., Enomoto, T., Tanaka, H., and Shibata, K., 1980, Inhibiting effects of antipain on urethane induced lung neoplasia in mice, Br. J. Cancer 42:624–626.PubMedCrossRefGoogle Scholar
  109. Noonan, N. E., and Noonan, K. D., 1977, The effect of TLCK on transcription and its role in modifying cell growth, J. Cell. Physiol. 92:137–144.PubMedCrossRefGoogle Scholar
  110. Norell, S. E., Ahlbom, A., Erwald, R., Jacobson, G., Lindberg-Navier, I., Olin, R., Tornberg, B., and Wiechel, K. L., 1986, Diet and pancreatic cancer: A case-control study, Am. J. Epidemiol. 124:894–902.PubMedGoogle Scholar
  111. Odani, S., and Ikenaka, T. J., 1973, Scission of soybean Bowman-Birk proteinase inhibitor into two small fragments having either trypsin or chymotrypsin inhibitor activity, J. Biochem. 74:857–860.PubMedGoogle Scholar
  112. Ohkoshi, M., and Fujii, S., 1983, Effect of the synthetic protease inhibitor N, N-dimethylcarbamoyl-methyl 4-(4-guanidinobenzoyloxy) phenylacetate methanesulfate on carcinogenesis by 3-meth-ylcholanthrene in mouse skin, J. Natl. Cancer Inst. 71:1053–1057.PubMedGoogle Scholar
  113. Osborne, T. B., and Mendel, L. B., 1917, The use of soybean as food, J. Biol. Chem. 32:369–387.Google Scholar
  114. Palladino, M. A., Galton, J. E., Troll, W., and Thorbecke, G. J., 1982, 7-Irradiation-induced mortality: Protective effect of protease inhibitors in chickens and mice, Int. J. Radiat. Biol. 41:183–191.CrossRefGoogle Scholar
  115. Patten, J. R., Richards, E. A., and Wheeler, J., 1971a, The effect of raw soybean on the pancreas of adult dogs, Proc. Soc. Exp. Biol. Med. 137:58.Google Scholar
  116. Patten, J. R., Richards, E. A., and Wheeler, J., 1971b, The effect of dietary soybean trypsin inhibitor on the histology of dog pancreas, Life Sci. 10(2): 145–150.CrossRefGoogle Scholar
  117. Patten, J. R., Patten, J. A., and Pope, H., 1973, II. Sensitivity of the guinea pig to raw soya bean in the diet, Food Cosmet. Toxicol. 11:577–583.PubMedCrossRefGoogle Scholar
  118. Persiani, S., Yeung, A., Shen, W. C., and Kennedy, A. R., 1992, Polylysine conjugates of Bowman-Birk protease inhibitor as targeted anticarcinogenic agents, Carcinogenesis 12:1149–1152.CrossRefGoogle Scholar
  119. Phillips, R. L., 1975, Role of lifestyle and dietary habits in risk of cancer among Seventh Day Adventists, Cancer Res. 35:3515–3522.Google Scholar
  120. Phillips, R. L., Garfinkel, L., Kuzma, J. W., Beeson, W. L., Lotz, T, and Brin, B., 1980, Mortality among California Seventh-Day Adventists for selected cancer sites, J. Natl. Cancer Inst. 65:1097–1107.PubMedGoogle Scholar
  121. Pineda, O., Torun, B., Viteri, F. E., and Arroyave, G., 1982, Protein quality in relation to estimates of essential amino acid requirements, in: Protein Quality in Humans: Assessment and In Vitro Estimation (C. E. Bodwell, J. S. Adkins, and D. T. Hopkins, eds.), AVI Publishing, Westport, Conn., pp. 29–42.Google Scholar
  122. Quigley, J. P., 1979, Proteolytic enzymes of normal and malignant cells, in: Surfaces of Normal and Malignant Cells (R. O. Hynes, ed.), Wiley, New York, pp. 247–255.Google Scholar
  123. Rackis, J. J., McGhee, J. E., and Booth, A. N., 1975, Biological threshold levels of soybean trypsin inhibitor by rat bioassay, Cereal Chem. 52:85–93.Google Scholar
  124. Rackis, J. J., Wolf, W. J., and Baker, E. C., 1986, Protease inhibitors in plant foods: Content and inactivation, Adv. Exp. Med. Biol. 199:299–347.PubMedCrossRefGoogle Scholar
  125. Richter, B. D,., and Schneeman, B. O., 1987, Pancreatic response to long-term feeding of soy protein isolate, casein or egg white in rats, J. Nutr. 117:247–252.PubMedGoogle Scholar
  126. Robbins, D. J., Liener, I. E., Spangler, W. M., and de Bruyn, D. B., 1988, The effects of a raw soy protein diet on the pancreas of the chacma baboon, Nutr. Rep. Int. 38:9–16.Google Scholar
  127. Roebuck, B. D., Kaplita, P. V., Edwards, B. R., and Praissman, M., 1987, Effects of dietary fats and soybean protein on azaserine-induced pancreatic carcinogenesis and plasma cholecystokinin in the rat, Cancer Res. 47:1333–1338.PubMedGoogle Scholar
  128. Rossman, T. G., and Troll, W., 1980, Protease inhibitors in carcinogenesis: Possible sites of action, in: Carcinogenesis: Modifiers of Chemical Carcinogenesis, Volume 5 (T. J. Slaga, ed.), Raven Press, New York, pp. 127–143.Google Scholar
  129. Rothman, S. S., and Wells, H., 1967, Enhancement of pancreatic enzyme synthesis by pancreozymin, Am. J. Physiol. 213:215–218.PubMedGoogle Scholar
  130. Ryan, C. A., and Kassell, B. 1970, Chymotrypsin inhibitor I from potatoes, Methods Enzymol. 19:883–889.CrossRefGoogle Scholar
  131. Ryser, H. J. P., 1971, Chemical carcinogenesis, N. Engl. J. Med. 285:721–734.PubMedCrossRefGoogle Scholar
  132. St. Clair, W., Billings, P., Carew, J., Keller-McGandy, C., Newberne, P., and Kennedy, A. R., 1990, Suppression of DMH-induced carcinogenesis in mice by dietary addition of the Bowman-Birk protease inhibitor, Cancer Res. 50:580–586.Google Scholar
  133. Sale, J. K., Goldberg, D. M., Fawcett, A. N., and Wormsley, K. G., 1977, Chronic and acute studies indicating absence of exocrine pancreatic feedback inhibition in dogs, Digestion 15:540–555.PubMedCrossRefGoogle Scholar
  134. Schelp, F.-P., and Pongpaew, P., 1988, Protection against cancer through nutritionally-induced increase in endogenous proteinase inhibitors—A hypothesis, Int. J. Epidemiol. 17:287–292.PubMedCrossRefGoogle Scholar
  135. Schingoethe, D. J., Aust, S. D., and Thomas, J. W., 1970, Separation of a mouse growth inhibitor in soybeans from trypsin inhibitors, J. Nutr. 100:739–748.PubMedGoogle Scholar
  136. Scrimshaw, N. S., Wayler, A. H., Murray, E., Steinke, F. H., Rand, W. M., and Young, V. R., 1983, Nitrogen balance response in young men given one or two isolated soy proteins or milk proteins, J. Nutr. 113:2492–2497.PubMedGoogle Scholar
  137. Shasby, D. M., 1985, Antioxidant activity of some antiproteases, Am. Rev. Respir. Dis. 131:293–294.PubMedGoogle Scholar
  138. Sheela, S., and Barrett, J. C., 1982, In vitro degradation of radiolabeled, intact basement membrane mediated by cellular plasminogen activator, Carcinogenesis 3:363–369.PubMedCrossRefGoogle Scholar
  139. Silverman, J., and Adams, J. O., 1983, N-Nitrosamines in laboratory animal feed and bedding, Lab. Anim. Sci. 33:161–164.PubMedGoogle Scholar
  140. Slaga, T. J., Klein-Szanto, A. J. P., Fischer, S. M., Weeks, C. E., Nelson, K., and Major, S., 1980, Studies on the mechanism of action of anti-tumor-promoting agents: Their specificity in twostage promotion. Proc. Natl. Acad. Sci. USA 77:2251–2254.PubMedCrossRefGoogle Scholar
  141. Smirnoff, P., Khalef, S., Birk, Y., and Applebaum, S. W., 1979, Trypsin and chymotrypsin inhibitor from chick peas, Int. J. Peptide Protein Res. 14:186–192.CrossRefGoogle Scholar
  142. Snyder, W. S. (Chairman), Cook, M. J., Karhausen, L. R., Nasset, E. S., Howells, G. P., and Tipton, I.H., 1974, Report of the Task Group on Reference Man, International Commission of Radiological Protection, No. 3, Pergamon Press, Elmsford, N.Y., pp. 348–352.Google Scholar
  143. Solomon, D. H., O’Brian, C. A., and Weinstein, I. B., 1985, N-α-tosyl-L-lysine chloromethyl ketone and N-α-tosyl-L-phenylalanine chloromethyl ketone inhibit protein kinase C., FEBS Lett. 190:342–344.PubMedCrossRefGoogle Scholar
  144. Soy Protein Council, 1987, Soy protein products: Characteristics, nutritional aspects and utilization, pp. 7–13.Google Scholar
  145. Struthers, B. J., MacDonald, J. R., Dahlgren, R. R., and Hopkins, D. T., 1983, Effects on the monkey, pig and rat pancreas of soy products with varying levels of trypsin inhibitor and comparison with the administration of cholecystokinin, J. Nutr. 113:86–97.PubMedGoogle Scholar
  146. Su, L. N., Toscano, W. A., Jr., and Kennedy, A. R., 1991, Suppression of phorbol ester-enhanced radiation-induced malignancy in vitro by protease inhibitors is independent of protein kinase C., Biochem. Biophys. Res. Commun. 176:18–24.PubMedCrossRefGoogle Scholar
  147. Sugita, H., Ishiura, S., Suzuki, K., and Imahori, K., 1980, Inhibition of epoxide derivatives on chicken calcium-activated neutral protease (CANP) in vitroand in vivo}. J. Biochem. 87:339–341.PubMedGoogle Scholar
  148. Takai, Y., Kishimoto, A., Inoue, M., and Nishizuka, Y., 1977, Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues, 1. Purification and characterization of an active enzyme from bovine cerebellum, J. Biol. Chem. 252:7603–7609.PubMedGoogle Scholar
  149. Takai, Y., Kishimoto, A., Iwasa, M., Kawahara, Y., Mori, T., and Nishizuka, Y., 1979, Calcium-dependent activation of a multifunctional protein kinase by membrane phospholipid, J. Biol. Chem. 254:3692–3695.PubMedGoogle Scholar
  150. Taylor, A. C., Levy, B. M., and Simpson, T. W. 1970, Collagenolytic activity of sarcoma tissue in culture, Nature 228:366–367.PubMedCrossRefGoogle Scholar
  151. Torun, B., Pineda, O., Vireti, F. E., and Arrayave, G., 1982, Use of amino acid composition data to predict protein nutritive value for children with specific reference to new estimates for their essential amino acid requirements, in: Protein Quality in Humans: Assessment and In Vitro Evaluation (C. E. Bodwell, J. S. Adkins, and D. T. Hopkins, eds.), AVI Publishing, Westport, Conn., pp. 374–393.Google Scholar
  152. Toskes, P. P., 1986, Negative feedback inhibition of pancreatic exocrine secretion in humans, Adv. Exp. Med. Biol. 199:142–152.Google Scholar
  153. Troll, W., 1976, Blocking tumor promotion by protease inhibitors, in: Fundamentals in Cancer Prevention (P. N. Magee et al., eds.), University Park Press, Maryland, pp. 41–55.Google Scholar
  154. Troll, W., Klassen, A., and Janoff, A., 1970, Tumorigenesis in mouse skin: Inhibition by synthetic inhibitors of proteases, Science 169:1211–1213.PubMedCrossRefGoogle Scholar
  155. Troll, W., Belman, S., Weisner, R., and Shellabarger, C. J., 1979a, Protease action in carcinogenesis, in: Biological Functions of Proteinases (H. Holtzer and H. Tschesche, eds.), Springer-Verlag, Berlin}, pp. 165–170CrossRefGoogle Scholar
  156. Troll, W., Weisner, R., Belman, S., and Shellabarger, C. J., 1979b, Inhibition of carcinogenesis by feeding diets containing soybeans. Proc. Am. Assoc. Cancer Res. 20:265.Google Scholar
  157. Troll, W., Weisner, R., Shellabarger, C. J., Holtzman, S., and Stone, J. P., 1980, Soybean diet lowers breast tumor incidence in irradiated rats, Carcinogenesis 1:469–472.PubMedCrossRefGoogle Scholar
  158. Troll, W., Witz, G., Goldstein, B., Stone, D., and Sugimura, T., 1982, The role of free oxygen radicals in tumor promotion and carcinogenesis, in: Carcinogenesis: A Comprehensive Survey, Volume 7 (E. Hecker, N. E. Fusenig, W. Kunz, F. Marks, and H. W. Theilmann, eds.), Raven Press, New York, pp. 593–597.Google Scholar
  159. Umezawa, K., 1972, Enzyme Inhibitors of Microbial Origin, University of Tokyo Press, Tokyo, pp. 29–32.Google Scholar
  160. Verloes, R., and Kanarek, L., 1976, Proteolytic activity associated with tumor growth and metastasis. Influence of trypsin inhibitor (soya bean) on Ehrlich ascites tumor growth, Arch. Int. Physiol. Biochem. 84:1119–1120.Google Scholar
  161. von Hofe, E., Brent, R., and Kennedy, A. R., 1990, Inhibition of x-ray induced exencephaly by protease inhibitors, Radiat. Res. 123:108–111.CrossRefGoogle Scholar
  162. von Hofe, E., Newberne, P. M., and Kennedy, A. R., 1991, Inhibition of N-nitro-somethylbenzylamine induced esophageal neoplasms by the Bowman-Birk protease inhibitor, Carcinogenesis 12:2147–2150.CrossRefGoogle Scholar
  163. Wang, S. Y., and Gudas, L. J., 1990, A retinoic acid-inducible mRNA from F9 teratocarcinoma cells encodes a novel protease inhibitor homologue, J. Biol. Chem. 265:15818–15822.PubMedGoogle Scholar
  164. Watanabe, S., Shiratori, K., Takeuchi, T., and Chey, W. Y, 1986, Intrajejunal administration of a synthetic trypsin inhibitor (camostate) stimulates the release of endogenous secretin but not cholecystokinin in humans, Gastroenterology 90:1685.Google Scholar
  165. Weed, H., McGandy, R. B., and Kennedy, A. R., 1985, Protection against dimethylhydrazine induced adenomatous tumors of the mouse colon by the dietary addition of an extract of soybeans containing the Bowman-Birk protease inhibitor, Carcinogenesis 6:1239–1241.PubMedCrossRefGoogle Scholar
  166. Weinstein, I. B., 1978, Current concepts on mechanisms of chemical carcinogenesis, Bull. N.Y. Acad. Med. 54:366–383.PubMedGoogle Scholar
  167. Winn, D. M., Ziegler, R. G., Pickle, L. W., Gridley, G., Blot, W. J., and Hoover, R. N., 1984, Diet in the etiology of oral and pharyngeal cancer among women from the southern United States, Cancer Res. 44:1216–1222.PubMedGoogle Scholar
  168. Witschi, H., and Kennedy, A. R., 1989, Modulation of lung tumor development in mice with the soybean-derived Bowman-Birk protease inhibitor, Carcinogenesis 10:2275–2277.PubMedCrossRefGoogle Scholar
  169. Witz, G., Goldstein, B. D., Amoruso, M., Stone, D. S., and Troll, W., 1980, Retinoid inhibition of superoxide anion radical production by human polymorphonuclear leukocytes stimulated with tumor promoters, Biochem. Biophys. Res. Commun. 97:883–888.PubMedCrossRefGoogle Scholar
  170. Wolf, W. J., and Cowan, J. C., 1975, Soybeans as a Food Source, CRC Press, Boca Raton, Fla., pp. 51–53.Google Scholar
  171. Wynder, E. L., 1975, An epidemiological evaluation of the causes of cancer of the pancreas, Cancer Res. 35:2228–2233.PubMedGoogle Scholar
  172. Yamamoto, R. S., Umezawa, H., Takeuchi, T., Matsushima, T., Hara, K., and Sugimura, T., 1974, Effect of leupeptin on colon carcinogenesis in rats with azoxymethane, Proc. Am. Assoc. Cancer Res. 15:38.Google Scholar
  173. Yamamura, M., Nakamura, N., Fukui, Y., Takamura, C., Yamamoto, M., Minato, Y., Tamura, Y., and Fujii, S., 1978, Inhibition of 7, 12 DMBA-induced mammary tumorigenesis by a synthetic protease inhibitor, N, N-dimethylamino (p-p′-guanidino-benzoyloxy) benzilcarbonyloxyglyco-late, Gann 69:749–752.PubMedGoogle Scholar
  174. Yamauchi, Y., Kobayashi, T., and Watanabe, A., 1987, Anticarcinogenic effects of a serine protease inhibitor (FOY-305) through the suppression of neutral serine protease activity during chemical hepatocarcinogenesis in rats, Hiroshima J. Medical Sciences 36:81–87.Google Scholar
  175. Yanatori, Y., and Fujita, T., 1976, Hypertrophy and hyperplasia in the endocrine and exocrine pancreas of rats fed soybean trypsin inhibitor or repeatedly injected with pancreozymin, Arch. Histol. Jpn. 39:67–78.PubMedCrossRefGoogle Scholar
  176. Yavelow, J., Gidlund, M., and Troll, W., 1982, Protease inhibitors from processed legumes effectively inhibit superoxide generation in response to TPA, Carcinogenesis 1:135–138.CrossRefGoogle Scholar
  177. Yavelow, J., Finlay, T. H., Kennedy, A. R., and Troll, W., 1983, Bowman-Birk soybean protease inhibitor as an anticarcinogen, Cancer Res. 43:2454–2459.Google Scholar
  178. Yavelow, J., Collins, M., Birk, Y., Troll, W., and Kennedy, A. R., 1985, Nanomolar concentrations of Bowman-Birk soybean protease inhibitor suppress X-ray induced transformation in vitro, Proc. Natl. Acad. Sci. USA 82:5395–5399.PubMedCrossRefGoogle Scholar
  179. Yen, J. T., Jensen, A. H., and Simon, J., 1977, Effect of dietary raw soybean and soybean trypsin inhibitor on trypsin and chymotrypsin activities in the pancreas and in small intestinal juice of growing swine, J. Nutr. 107:156–165.PubMedGoogle Scholar
  180. Young, V. R., Wayler, A., Garza, C., Steinke, F. H., Murray, E., Rand, W. M., and Scrimshaw, N. S., 1984, A long-term metabolic balance study in young men to assess the nutritional quality of an isolated soy protein and beef proteins, Am. J. Clin. Nutr. 39:8–15.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Ann R. Kennedy
    • 1
  1. 1.Department of Radiation Oncology, School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA

Personalised recommendations