In Vitro Studies of Anticarcinogenic Protease Inhibitors

  • Ann R. Kennedy


Several different types of agents have been shown to modify the yield of transformed cells in vitro. We have observed that certain protease inhibitors have the ability to suppress radiation- and chemical-induced malignant transformation in vitro in a highly significant fashion (Kennedy and Little, 1978, 1980a, 1981b; Littler al., 1979; Kennedy and Weichselbaum, 1981; Kennedy, 1982, 1984a, b, 1985a, 1988, 1990a; Yavelow etal., 1983, 1985; Baturay and Kennedy, 1986; Billings et al., 1987a, 1989). Several other investigators have also observed that some protease inhibitors can effectively suppress transformation in vitro (Kuroki and Drevon, 1979; Borek et al., 1979; DiPaolo et al., 1980; Popescu et al., 1980; Sun et al. 1988). The studies showing that protease inhibitors suppress transformation in vitro have utilized several different model systems, several different carcinogens (including x-radiation, UV light, chemical carcinogens, and steroid hormones as the inducing agents) and several different agents as promoters (or cocarcinogens) (reviewed in Kennedy, 1984a), as shown in Tables I and II (culture dishes containing transformed foci/cells are shown in Fig. 1). These results suggest that protease inhibitors are capable of suppressing similar processes induced by different carcinogens (with or without promotion or cocar-cinogenesis) in several different cell systems. Protease inhibitors have an unusual ability to suppress information in vitro in a highly significant manner, as opposed to the marginal effects observed for many other classes of possible human cancer chemopreventive agents which we have studied (Kennedy, 1984a,b, 1985b, 1986; Kennedy et al., 1984b). Not only are many other potential chemopreventive agents marginal in their effectiveness, but most of them need to be added to cultures at toxic or nearly toxic levels to observe any effect [e.g., see the effective levels of vitamin E (Radner and Kennedy, 1986)]. By comparison, protease inhibitors are effective at very low concentrations.


Protease Inhibitor Fluocinolone Acetonide Chymotrypsin Inhibitor Cancer Chemopreventive Agent Hamster Embryo Cell 
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. Balmain, A., 1985, Transforming ras oncogenes and multistage carcinogenesis, Br. J. Cancer 51:1–7.PubMedCrossRefGoogle Scholar
  2. 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
  3. 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
  4. Billings, P. C., St. Clair, W., Ryan, C. A., and Kennedy, A. R., 1987a, Inhibition of radiation-induced transformation of C3H/10T1/2 cells by chymotrypsin inhibitor 1 from potatoes, Carcinogenesis 8:809–812.PubMedCrossRefGoogle Scholar
  5. Billings, P. C., Carew, J. A., Keller-McGandy, C. E., Goldberg, A., and Kennedy, A. R., 1987b, A serine protease activity in C3H/10T1/2 cells that is inhibited by anticarcinogenic protease inhibitors, Proc. Natl. Acad. Sci. USA 84:4801–4805.PubMedCrossRefGoogle Scholar
  6. Billings, P. C., St. Clair, W., Owen, A. J., and Kennedy, A. R., 1988, Potential intracellular target proteins of the anticarcinogenic Bowman-Birk protease inhibitor identified by affinity chromatography, Cancer Res. 48:1798–1802.PubMedGoogle Scholar
  7. 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
  8. Billings, P. C., Habres, J. M., and Kennedy, A. R., 1990, Inhibition of radiation-induced transformation of C3H10T1/2 cells by specific protease substrates, Carcinogenesis 11:329–332.PubMedCrossRefGoogle Scholar
  9. Borek, C., and Cleaver, J. E., 1981, Protease inhibitors neither damage DNA nor interfere with DNA repair or replication in human cells, Mutat. Res. 82:373–380.PubMedCrossRefGoogle Scholar
  10. Borek, C., Miller, C., Pain, C., and Troll, W., 1979, Conditions for inhibiting and enhancing effects of the protease inhibitor antipain on x-ray-induced neoplastic transformation in hamster and mouse cells, Proc. Natl. Acad. Sci. USA 76:1800–1803; corrections etc. in Proc. Natl. Acad. Sci. USA 76:6699.PubMedCrossRefGoogle Scholar
  11. Bos, J. L., Fearon, E. R., Hamilton, S. R., Verlaan-de Vries, M., van Boom, J. H., van der Eb, A. J., and Vogelstein, B., 1987, Prevalence of ras gene mutations in human colorectal cancers, Nature 327:293–297.PubMedCrossRefGoogle Scholar
  12. Brown, K., Quintanilla, M., Ramsden, M., Kerr, I. B., Young, S., and Balmain, A., 1986, V-ras genes from Harvey and BALB murine sarcoma viruses can act as initiators of two-stage mouse skin carcinogenesis, Cell 46:447–456.PubMedCrossRefGoogle Scholar
  13. Caggana, M., and Kennedy, A. R., 1989, C-fos mRNA levels are reduced in the presence of antipain and the Bowman-Birk inhibitor, Carcinogenesis 10:2145–2148.PubMedCrossRefGoogle Scholar
  14. Campisi, J., Gray, H. E., Pardee, A. B., Dean, M., and Sonenshein, G. E., 1984, Cell cycle control of c-myc but not c-ras expression is lost following chemical transformation, Cell 36:241–247.PubMedCrossRefGoogle Scholar
  15. Capon, D. J., Seeburg, P. H., McGrath, J. P., Hayflick, J. S., Edman, U., Levinson, A. D., and Goeddel, D. V., 1983, Activation of Ki-ras 2 gene in human colon and lung carcinomas by two different point mutations, Nature 304:507–513.PubMedCrossRefGoogle Scholar
  16. Carew, J. A., and Kennedy, A. R., 1990, Identification of a proteolytic activity which responds to anticarcinogenic protease inhibitors in C3H10T1/2 cells, Cancer Lett. 49:153–163.PubMedCrossRefGoogle Scholar
  17. Chang, J. D., and Kennedy, A. R., 1988, Cell cycle progression of C3H10T1/2 and 3T3 cells in the absence of a transient increase in c-myc RNA levels, Carcinogenesis 9:17–20.PubMedCrossRefGoogle Scholar
  18. Chang, J. D., Billings, P., and Kennedy, A. R., 1985, C-myc expression is reduced in antipain-treated proliferating C3H10T1/2 cells, Biochem. Biophys. Res. Comm. 133:830–835.PubMedCrossRefGoogle Scholar
  19. Chang, J. D., Li, J.-H., Billings, P. C., and Kennedy, A. R., 1990, Effects of protease inhibitors on c-myc expression in normal and transformed C3H10T1/2 cells, Molec. Carc. 3:226–232.CrossRefGoogle Scholar
  20. Chen, A. C., and Herschman, H. R., 1989, Tumorigenic methylcholanthrene transformants of C3H/10T1/2 cells have a common nucleotide alteration in the c-ki-ras gene, Proc. Natl. Acad. Sci. USA 86:1608–1611.PubMedCrossRefGoogle Scholar
  21. Connan, G., Rassoulzadegan, M., and Cuzin, F., 1985, Focus formation in rat fibroblasts exposed to a tumour promoter after transfer of polyoma pit and myc oncogenes, Nature 314:277–279.PubMedCrossRefGoogle Scholar
  22. 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
  23. Der, C. J., and Cooper, G. M., 1983, Altered gene products are associated with activation of cellular rask genes in human lung and colon carcinomas, Cell 32:201–208.PubMedCrossRefGoogle Scholar
  24. DiPaolo, J. A., Amsbaugh, S. C., and Popescu, N. C., 1980, Antipain inhibits N-methyl-N′-nitro-N-nitrosoguanidine-induced transformation and increases chromosomal aberrations, Proc. Natl. Acad. Sci. USA 77:6649–6653.PubMedCrossRefGoogle Scholar
  25. Dotto, G. P., Parada, L. F., and Weinberg, R. A., 1985, Specific growth response of ras-transformed embryo fibroblasts to tumor promoters, Nature 318:472–475.PubMedCrossRefGoogle Scholar
  26. Fabre, F., and Roman, H., 1977, Genetic evidence for inducibility of recombination competence in yeast, Proc. Natl. Acad. Sci. USA 74:1667–1671.PubMedCrossRefGoogle Scholar
  27. Fahmy, M. J., and Fahmy, O. G., 1980, Intervening DNA insertions and the alteration of gene expression by carcinogens, Cancer Res. 40:3374–3382.PubMedGoogle Scholar
  28. Flick, M. B., and Kennedy, A. R., 1991, Effect of protease inhibitors on DNA amplification in SV40-transformed Chinese hamster embryo cells, Cancer Lett. 56:102–108.CrossRefGoogle Scholar
  29. Garte, S. J., Currie, D. C., and Troll, W., 1987, Inhibition of H-ras oncogene transformation of NIH3T3 cells by protease inhibitors, Cancer Res. 47:3159–3162.PubMedGoogle Scholar
  30. German, J., 1983, Bloom’s syndrome. X. The cancer proneness points to chromosome mutation as a crucial event in human neoplasia, in: Chromosome Mutation and Neoplasia (J. German, ed.), Liss, New York, pp. 347–357.Google Scholar
  31. Gottesman, S., 1987, Regulation by proteolysis, in: Eschericia coli and Salmonella typhimurium (F. Neidhardt, ed.), American Society for Microbiology, Washington, D.C., pp. 1308–1312.Google Scholar
  32. Hunter, T., 1981, Oncogenes and proto-oncogenes: How do they differ? J. Natl. Cancer Inst. 73:773–786.Google Scholar
  33. Kelly, K., Cochran, B. H., Stiles, C. D., and Leder, P., 1983, Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor, Cell 35:603–610.PubMedCrossRefGoogle Scholar
  34. Kennedy, A. R., 1982, Antipain, but not cycloheximide, suppresses radiation transformation when present for only one day at five days post-irradiation, Carcinogenesis 3:1093–1095.PubMedCrossRefGoogle Scholar
  35. Kennedy, A. R., 1984a, Promotion and other interactions between agents in the induction of transformation in vitro in fibroblasts, in: Mechanisms of Tumor Promotion, Volume III (T. J. Slaga, ed.), CRC Press, Boca Raton, Fla., pp. 13–55.Google Scholar
  36. Kennedy, A. R., 1984b, Prevention of radiation-induced transformation in vitro, in: Vitamins, Nutrition and Cancer (K. N. Prasad, ed.), Karger, Basel, pp. 166–179.Google Scholar
  37. Kennedy, A. R., 1985a, The conditions for the modification of radiation transformation in vitro by a tumor promoter and protease inhibitors, Carcinogenesis 6:1441–1446.PubMedCrossRefGoogle Scholar
  38. Kennedy, A. R., 1985b, Effects of antioxidants on the induction of malignant transformation in vitro, in: Vitamins and CancerHuman Cancer Prevention by Vitamins and Micronutrients (F. L. Meyskens and K. N. Prasad, eds.), Humana Press, Clifton, N.J., pp. 51–64.Google Scholar
  39. Kennedy, A. R., 1985c, Evidence that the first step leading to carcinogen-induced malignant transformation is a high frequency, common event, in: Carcinogenesis: A Comprehensive Survey, Volume 9 (J. C. Barrett and R. W. Tennant, eds.), Raven Press, New York, pp. 355–364.Google Scholar
  40. 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
  41. Kennedy, A. R., 1988, Implications for mechanisms of tumor promotion and its inhibition by various agents from studies of in vitro transformation, in: Tumor Promoters, Biological Approaches for Mechanistic Studies and Assay Systems (R. Langenbach, J. C. Barrett, and E. Elmore, eds.), Raven Press, New York, pp. 201–212.Google Scholar
  42. Kennedy, A. R., 1989, Initiation and promotion of radiation induced transformation in vitro: Relevance of in vitro studies to radiation induced cancer in human populations, in: Cell Transformation and Radiation-Induced Cancer (K. H. Chadwick, C. Seymour and B. Barnhart, eds.), IOP Publishing, Adam Hilger, Bristol and New York, pp. 263–270.Google Scholar
  43. Kennedy, A. R., 1990a, Effects of protease inhibitors and vitamin E in the prevention of cancer, in: Nutrients and Cancer Prevention (K. N. Prasad and F. L. Meyskens, Jr., eds.), Humana Press, Clifton, N.J., pp. 79–98.CrossRefGoogle Scholar
  44. Kennedy, A. R., 1990b, Is there a critical target gene for the first step in carcinogenesis? Environ. Health Perspect. 93:199–203.CrossRefGoogle Scholar
  45. 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
  46. Kennedy, A. R., and Little, J. B., 1978, Protease inhibitors suppress radiation induced malignant transformation in vitro, Nature 276:825–826.PubMedCrossRefGoogle Scholar
  47. Kennedy, A. R., and Little, J. B., 1980a, Radiation transformation in vitro: Modification by exposure to tumor promoters and protease inhibitors, in: Radiation Biology in Cancer Research (R. E. Meyn and H. R. Withers, eds.), Raven Press, New York, pp. 295–307.Google Scholar
  48. Kennedy, A. R., and Little, J. B., 1980b, An investigation of the mechanism for the enhancement of radiation transformation in vitro by TPA, Carcinogenesis 1:1039–1047.PubMedCrossRefGoogle Scholar
  49. Kennedy, A. R., and Little, J. B., 1981a, High efficiency, kinetics and numerology of transformation by radiation in vitro, in: Cancer: Achievements, Challenges and Prospects for the 1980’s, Volume 1 (J. H. Burchenal and J. F. Oettgen, eds.), Grune & Stratton, New York, pp. 491–500.Google Scholar
  50. Kennedy, A. R., and Little, J. B., 1981b, Effects of protease inhibitors on radiation transformation in vitro, Cancer Res. 41:2103–2108.PubMedGoogle Scholar
  51. Kennedy, A. R., and Little, J. B., 1984, Evidence that a second event in x-ray induced oncogenic transformation in vitro occurs during cellular proliferation, Radiat. Res. 99:228–248.PubMedCrossRefGoogle Scholar
  52. 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
  53. Kennedy, A. R., and Weichselbaum, R. R., 1981, Effects of 17-β-estradiol on radiation transformation in vitro; inhibition of effects by protease inhibitors, Carcinogenesis 2:67–69.PubMedCrossRefGoogle Scholar
  54. Kennedy, A. R., Radner, B. and Nagasawa, H., 1984a, 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
  55. Kennedy, A. R., Troll, W., and Little, J. B., 1984b, Role of free radicals in the initiation and promotion of radiation transformation in vitro, Carcinogenesis 5:1213–1218.PubMedCrossRefGoogle Scholar
  56. Kennedy, A. R., Cairns, J., and Little, J. B., 1984c, The timing of the steps in transformation of C3H10T1/2 cells by X-irradiation, Nature 307:85–86.PubMedCrossRefGoogle Scholar
  57. Kennedy, A. R., Fox, M., Murphy, G., and Little, J. B., 1980, Relationship between x-ray exposure and malignant transformation in C3H10T1/2 cells, Proc. Natl. Acad. Sci. USA 77:7262–7266.PubMedCrossRefGoogle Scholar
  58. Korbelik, M., Osmak, M., Suhar, A., Škrk, J., Turk, V., and Petrovic, D., 1988, Modification of potentially lethal damage repair by some intrinsic intra-and extracellular agents: I. Proteinases and proteinase inhibitors, Int. J. Radiat. Biol. 54:461–474.PubMedCrossRefGoogle Scholar
  59. Kuroki, T., and Drevon, C., 1979, Inhibition of chemical transformation in C3H10T1/2 cells by protease inhibitors, Cancer Res. 39:2755–2761.PubMedGoogle Scholar
  60. Land, H., Parada, L. F., and Weinberg, R. A., 1983a, Cellular oncogenes and multistep carcinogenesis, Science 222:771–778.PubMedCrossRefGoogle Scholar
  61. Land, H., Parada, L. F., and Weinberg, R. A., 1983b, Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes, Nature 304:596–602.PubMedCrossRefGoogle Scholar
  62. Lavi, S., 1981, Carcinogen-mediated amplification of viral DNA sequences in simian virus 40-transformed Chinese hamster embryo cells, Proc. Natl. Acad. Sci. USA 78:6144–6148.PubMedCrossRefGoogle Scholar
  63. Lavi, S., 1986, Carcinogen-mediated amplification of specific DNA sequences, J. Cell Biochem. 18:149–156.CrossRefGoogle Scholar
  64. Leder, P., Battey, J., Lenoir, G., Moulding, C., Murphy, W., Potter, H., Stewart, T., and Taub, R., 1983, Translocations among antibody genes in human cancer, Science 222:765–771.PubMedCrossRefGoogle Scholar
  65. Li, J.-H., Billings, P. C., and Kennedy, A. R., 1992, Induction of oncogene expression by sodium arsenite in C3H/10T1/2 cells; inhibition of c-myc expression by protease inhibitors, Cancer J. 5:354–358.Google Scholar
  66. Little, J. B., and Kennedy, A. R., 1982, Promotion of X-ray transformation in vitro, in: Carcinogenesis: Cocarcinogenesis and Biological Effects of Tumor Promoters, Vol. 7 (E. Hecker, N. E. Fusenig, W. Kunz, F. Marks, and H. W. Theilmann, eds.), Raven Press, New York, pp. 243–257.Google Scholar
  67. Little, J. B., Nagasawa, H., and Kennedy, A. R., 1979, DNA repair and malignant transformation: Effect of X-irradiation, TPA and protease inhibitors on transformation and sister chromatid exchanges in mouse 10T1/2 cells, Radiat. Res. 79:241–255.PubMedCrossRefGoogle Scholar
  68. Little, J. W., Edmiston, S. H., Pacelli, L. Z., and Mount, D. W., 1980, Cleavage of the Escherichia coli lex A protein by the rec A protease, Proc. Natl. Acad. Sci. USA 77:3225–3229.PubMedCrossRefGoogle Scholar
  69. Messadi, P. 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
  70. Meyn, M. S., Rossman, T., and Troll, W., 1977, A protease inhibitor blocks SOS functions in Escherichia coli; antipain prevents X repressor inactivation, ultraviolet mutagenesis and filamentous growth, Proc. Natl. Acad. Sci. USA 74:1152–1156.PubMedCrossRefGoogle Scholar
  71. Miller, R. C., Geard, C. R., Osmak, R. S., Rutlege-Freeman, M., Ong, A., Mason, H., Napholz, A., Perez, N., Harisiadis, L., and Borek, C., 1981, Modification of sister chromatid exchanges and radiation-induced transformation in rodent cells by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and two retinoids, Cancer Res. 41:655–659.PubMedGoogle Scholar
  72. Mondai, S., and Heidelberger, C., 1980, Inhibition of induced differentiation of C3H/10T1/2clone 8 mouse embryo cells by tumor promoters, Cancer Res. 40:334–338.Google Scholar
  73. Mordan, L. J., Bergin, L. M., Budnick, J. E., Meegan, R. R., and Bertran, J. S., 1982, Isolation of methylcholanthrene-“initiated” C3H/10T1/2 cells by inhibiting neoplastic progression with retinyl acetate, Carcinogenesis 3:279–285.PubMedCrossRefGoogle Scholar
  74. Newbold, R. F., and Overell, R. W., 1983, Fibroblast immortality is a prerequisite for transformation by EJ c-Ha-ras oncogene, Nature 304:648–651.PubMedCrossRefGoogle Scholar
  75. Ohkoshi, M., and Fujii, S., 1983, Effect of the synthetic protease inhibitor [N, N-dimethylcarb-amoylmethyl 4-(4-guanidinobenzoyloxy)-phenyl acetate] methanesulfate on carcinogenesis by 3-methylcholanthrene in mouse skin, J. Natl. Cancer Inst. 71:1053–1057.PubMedGoogle Scholar
  76. Parada, L. F., and Weinberg, R. A., 1983, Presence of a Kirsten murine sarcoma virus ras oncogene in cells transformed by 3-methylcholanthrene, Mol. Cell Biol. 3:2298–2301.PubMedGoogle Scholar
  77. Persiani, S., Yeung, A., Shen, W.-C., and Kennedy, A. R., 1991, Polylysine conjugates of Bowman-Birk protease inhibitor as targeted anticarcinogenic agents, Carcinogenesis 12:1149–1152.PubMedCrossRefGoogle Scholar
  78. Popescu, N. C., Amsbaugh, S. C., and DiPaolo, J. A., 1980, Enhancement of N-methyl-N-nitro-N-nitrosoguanidine transformation of Syrian hamster embryo cells by a phorbol diester is independent of sister chromatid exchanges and chromosome aberrations, Proc. Natl. Acad. Sci. USA 77:7282–7286.PubMedCrossRefGoogle Scholar
  79. Radner, B. S., and Kennedy, A. R., 1986, Suppression of x-ray induced transformation by vitamin E in mouse C3H/10T1/2 cells, Cancer Lett. 32:25–32.PubMedCrossRefGoogle Scholar
  80. Rosen, A., and Klein, G., 1983, UV light-induced immunoglobulin heavy-chain class switch in a human lymphoblastoid cell line, Nature 306:189–190.PubMedCrossRefGoogle Scholar
  81. Rossman, T. G., and Klein, C. B., 1985, Mammalian SOS system: A case of misplaced analogies, Cancer Invest. 3(2): 175–187.PubMedCrossRefGoogle Scholar
  82. St. Clair, W. H., Billings, P. C., and Kennedy, A. R., 1990, The effects of the Bowman-Birk protease inhibitor on c-myc expression and cell proliferation in the unirradiated and irradiated mouse colon, Cancer Lett. 52:145–152.PubMedCrossRefGoogle Scholar
  83. Sawey, M. J., Hood, A. T., Burns, F. J., and Garte, S. J., 1987, Activation of myc and ras oncogenes in primary rat tumors induced by ionizing radiation, Mol. Cell Biol. 7:932–935.PubMedGoogle Scholar
  84. Scott, R. E., and Maercklein, P. B., 1985, An initiator of carcinogenesis selectively and stably inhibits stem cell differentiation: A concept that initiation of carcinogenesis involves multiple phases, Proc. Natl. Acad. Sci. USA 82:2995–2999.PubMedCrossRefGoogle Scholar
  85. Smirnoff, P., Khalef, S., Birk, Y., and Applebaum, S.W., 1979, Trypsin and chymotrypsin inhibitor from chickpeas, Int. J. Peptide Protein Res. 14:186–192.CrossRefGoogle Scholar
  86. Smith, G. J., and Grisham, J. W., 1987, Activation of the Ha-ras gene in C3H/10T1/2 cells transformed by exposure to N-methyl-N′-nitro-N-nitrosoguanidine, Biochem. Biophys. Res. Commun. 147:1194–1199.PubMedCrossRefGoogle Scholar
  87. Spandidos, D. A., and Wilkie, N. M., 1984, Malignant transformation of early passage rodent cells by a single mutated human oncogene, Nature 310:469–475.PubMedCrossRefGoogle Scholar
  88. Stewart, T. A., Pattengale, P. K., and Leder, P., 1984, Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes, Cell 38:627–637.PubMedCrossRefGoogle Scholar
  89. Sukumar, S., Pulciani, S., Doniger, J., DiPaolo, J. A., Evans, C. H., Zarbl, B., and Barbacid, M., 1985, A transforming ras gene in tumorigenic guinea pig cell lines initiated by diverse chemical carcinogens, Science 223:1197–1199.CrossRefGoogle Scholar
  90. Sun, C., Colman, M., and Redpath, J. L., 1988, Suppression of the radiation-induced expression of a tumor-associated antigen in human cell hybrids by the protease inhibitor antipain, Carcinogenesis 9:2333–2335.PubMedCrossRefGoogle Scholar
  91. Tlsty, T. O., Brown, P. C., and Schimke, R. T., 1984, Ultraviolet radiation facilitates methotrexate resistance and amplification of the dihydrofolate reductase gene in cultured 3T6 mouse cells, Mol. Cell Biol. 4:1050–1056.PubMedGoogle Scholar
  92. Troll, W., Frenkel, K., and Wiesner, R., 1984, Protease inhibitors as anticarcinogens, J. Natl. Cancer Inst. 73:1245–1250.PubMedGoogle Scholar
  93. Troll, W., Wiesner, R., and Frenkel, K., 1987, Anticarcinogenic action of protease inhibitors, Adv. Cancer Res. 49:265–283.PubMedCrossRefGoogle Scholar
  94. Wintersberger, U., 1984, The selective advantage of cancer cells: A consequence of genome mobilization in the course of the induction of DNA repair processes? (model studies of yeast) Adv. Enzyme Regul. 22:311–323.PubMedCrossRefGoogle Scholar
  95. Witkin, E. M., 1976, Ultraviolet mutagenesis and inducible DNA repair in Escherichia coli, Bacteriol. Rev. 40:869–907.PubMedGoogle Scholar
  96. 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
  97. 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

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