Abstract
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.
Keywords
- 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.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Balmain, A., 1985, Transforming ras oncogenes and multistage carcinogenesis, Br. J. Cancer 51:1–7.
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.
Becker, F. F., 1981, Inhibition of spontaneous hepatocarcinogenesis in C3H/Hen mice by Edi Pro A, an isolated soy protein, Carcinogenesis 2:1213–1214.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Fabre, F., and Roman, H., 1977, Genetic evidence for inducibility of recombination competence in yeast, Proc. Natl. Acad. Sci. USA 74:1667–1671.
Fahmy, M. J., and Fahmy, O. G., 1980, Intervening DNA insertions and the alteration of gene expression by carcinogens, Cancer Res. 40:3374–3382.
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.
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.
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.
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.
Hunter, T., 1981, Oncogenes and proto-oncogenes: How do they differ? J. Natl. Cancer Inst. 73:773–786.
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.
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.
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.
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.
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.
Kennedy, A. R., 1985b, Effects of antioxidants on the induction of malignant transformation in vitro, in: Vitamins and Cancer—Human Cancer Prevention by Vitamins and Micronutrients (F. L. Meyskens and K. N. Prasad, eds.), Humana Press, Clifton, N.J., pp. 51–64.
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.
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.
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.
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.
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.
Kennedy, A. R., 1990b, Is there a critical target gene for the first step in carcinogenesis? Environ. Health Perspect. 93:199–203.
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.
Kennedy, A. R., and Little, J. B., 1978, Protease inhibitors suppress radiation induced malignant transformation in vitro, Nature 276:825–826.
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.
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.
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.
Kennedy, A. R., and Little, J. B., 1981b, Effects of protease inhibitors on radiation transformation in vitro, Cancer Res. 41:2103–2108.
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.
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.
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.
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.
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.
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.
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.
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.
Kuroki, T., and Drevon, C., 1979, Inhibition of chemical transformation in C3H10T1/2 cells by protease inhibitors, Cancer Res. 39:2755–2761.
Land, H., Parada, L. F., and Weinberg, R. A., 1983a, Cellular oncogenes and multistep carcinogenesis, Science 222:771–778.
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.
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.
Lavi, S., 1986, Carcinogen-mediated amplification of specific DNA sequences, J. Cell Biochem. 18:149–156.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Rosen, A., and Klein, G., 1983, UV light-induced immunoglobulin heavy-chain class switch in a human lymphoblastoid cell line, Nature 306:189–190.
Rossman, T. G., and Klein, C. B., 1985, Mammalian SOS system: A case of misplaced analogies, Cancer Invest. 3(2): 175–187.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Troll, W., Frenkel, K., and Wiesner, R., 1984, Protease inhibitors as anticarcinogens, J. Natl. Cancer Inst. 73:1245–1250.
Troll, W., Wiesner, R., and Frenkel, K., 1987, Anticarcinogenic action of protease inhibitors, Adv. Cancer Res. 49:265–283.
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.
Witkin, E. M., 1976, Ultraviolet mutagenesis and inducible DNA repair in Escherichia coli, Bacteriol. Rev. 40:869–907.
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.
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.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1993 Springer Science+Business Media New York
About this chapter
Cite this chapter
Kennedy, A.R. (1993). In Vitro Studies of Anticarcinogenic Protease Inhibitors. In: Troll, W., Kennedy, A.R. (eds) Protease Inhibitors as Cancer Chemopreventive Agents. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2882-1_3
Download citation
DOI: https://doi.org/10.1007/978-1-4615-2882-1_3
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-6249-4
Online ISBN: 978-1-4615-2882-1
eBook Packages: Springer Book Archive