Abstract
Breast cancer is the most prevalent malignancy with the second highest cancer mortality rate among American women (1). Despite intensive research efforts and improved screening methods for early detection and treatment, breast cancer mortality has remained persistently constant for more than half a century. Novel preventive approaches are needed that deter or arrest mammary carcinogenesis (2,3). A promising new lead for the control of this malignancy comes from recent epidemiological and experimental studies, which suggest that regular intake of nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of many cancers, including breast cancer (4–11).
Keywords
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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Singletary ES, Bever T, Dempsy P, Farrar WB, Garber J, Harris RE, et al. Screening for and evaluation of suspicious breast lesions. Oncology 1999; 12: 89–138.
Kelloff W, Boone CW, Crowell JA, Steele VE, Lubet RA, Doody LA, et al. New agents for cancer chemoprevention. J Cell Biochem 1996; 26 (Suppl): 1–28.
Weinstein B. The origin of human cancer: molecular mechanisms of carcinogenesis and their implication for cancer prevention and treatment. Cancer Res 1988; 48: 4135–4143.
Rosenberg L. Nonsteroidal anti-inflammatory drugs and cancer. Prey Med 1995; 24: 107–109.
Alshafie GA, Harris RE, Robertson FM, Parrett ML, Rose M, Abou-Issa H. Comparative chemopreventive activity of ibuprofen and N-(4-hydroxyphenyl) retinamide against the development and growth of rat mammary adenocarcinomas. Anticancer Res 1999; 19: 3031–3036.
Thun MJ, Namboodiri MM, Heath CW. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 1991; 325: 1593–1596.
Gridley G, McLaughlin JK, Ekbom A, Klareskog L, Adami HO, Hacker DG, et al. Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst 1993; 85: 307–311.
Harris RE, Namboodiri KK, Farrar WB. Nonsteroidal anti-inflammatory drugs and breast cancer. Epidemiology 1996; 7: 203–205.
Schreinemachers DM, Everson RB. Aspirin use and lung, colon and breast cancer incidence in a prospective study. Epidemiology 1994; 5: 138–146.
Giovannucci E, Egan KM, Hunter DJ, Stampfer MJ, Golditz GA, Willett WC, Speizer FE. Aspirin and the risk of colorectal cancer in women. N Engl J Med 1995; 333: 609–614.
Reddy RB, Rao CV, Rivenson A, Kelloff GJ. Inhibitory effect of aspirin on azoxymethane-induced colon carcinogenesis in F344 rats. Carcinogenesis 1993; 14: 1493–1497.
Ip MM, Mazzer C, Watson D, Carter C, Ip C. The effect of eicosanoid synthesis inhibitors on DMBAinduced rat mammary carcinogenesis. Proc Amer Assoc Cancer Res 1989; 30: 721.
Carter CA, Milholand RJ, Shea W, Ip MM. Effect of PG synthetase inhibitor, indomethacin on 7,12dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats fed different levels of fat. Cancer Res 1983; 43: 3559–3562.
Duperrone C, Castonguay A. Chemopreventive efficacies of aspirin and sulindac against lung tumori-genesis in A/J mice. Carcinogenesis 1997; 18: 1001–1006.
McCormick DL, Moon RC. Inhibition of mammary carcinogenesis by flurbiprofen, a non-steroidal anti-inflammatory agent. Br J Cancer 1983; 48: 859–861.
Perrira MA, Barnes LH, Steele VE, Kelloff GJ, Lubet RA. Peroxicam-induced regression of azoxymethane-induced aberrant crypt foci and prevention of colon cancer in rats. Carcinogenesis 1996; 17: 373–376.
Grubbs CJ, Lubet RA, Koki AT, Leahy KM, Masferrer JL, Steele VE, et al. Celecoxib inhibits N-ButylN-(4-hydroxybutyl)nitrosamine-induced urinary bladder cancer in male B6D2F1 mice and female Fisher-344 rats. Cancer Res 2000; 60: 5599–5602.
Castello JE, Yuan JM, Dominguez GM, Yu MC, Ross RK. Nonsteroidal anti-inflammatory drugs and bladder cancer prevention. Br J Cancer 2000; 82: 1364–1369.
Joarder FS, Abou-Issa H, Robertson FM, Parrett ML, Alshafie GA, Harris RE. Growth arrest of DMBAinduced mammary carcinogenesis with ibuprofen treatment in Sprague-Dawley rats. Oncol Rep 1997; 4: 1271–1273.
DuBois RN, Girdiello FM, Smalley WE. Nonsteroidal anti-inflammatory drugs, eicosanoids, and colorectal cancer prevention. Gastroenterol Clin N Am 1996; 25: 773–791.
Spaguesi MT, Tonelli F, Dolara P, Caderni G, Anastasi A, Bianchini F. Rectal proliferation and polyp occurrence in patients with familial adenomatous polyposis after sulindac treatment. Gastroenterol 1994; 106: 362–366.
Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, et al. Suppression of intestinal polyposis in Apcd716 knockout mice by inhibition of cyclooxygenase-2 (COX-2). Cell 1996; 87: 803–809.
Paganini-Hill A, Chao A, Ross RK, Henderson BE. Aspirin use and chronic disease: a cohort study of the elderly. Br Med J 1989; 229: 1247–1250.
Egan KM, Stampfer MJ, Giovannucci E, Rosner BA, Colditz GA. Prospective study of regular aspirin use and the risk of breast cancer. J Nall Cancer Inst 1996; 88: 988–993.
Harris RE, Namboodiri KK, Farrar WB. Epidemiological study of nonsteroidal anti-inflammatory drugs and breast cancer. Oncol Rep 1995; 2: 591–592.
Harris RE, Namboodiri KK, Stellman SD, Wynder EL. Breast cancer and NSAID use: heterogeneity of effect in a case-control study. Prey Med 1995; 24: 119–120.
Lee PP, Ip MM. Regulation of proliferation of rat mammary tumor cells by inhibitors of cyclooxygenase and Lipooxygenase. Prost Leuk Essen Fatty Acids 1992; 54: 21–31.
McCormick DL, Madigan MJ, Moon RC. Modulation of rat mammary carcinogenesis by indomethacin. Cancer Res 1985; 45: 1803–1808.
Harris RE, Alshafie GA, Abou-Issa H, Seibert K. Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase-2 inhibitor. Cancer Res 2000; 60: 2101–2103.
Thompson HJ, Jiang C, Lu XJ, Mehta RG, Piazza GA, Paranka NS, et al. Sulfone metabolite of sulindac inhibits mammary carcinogenesis. Cancer Res 1997; 57: 267–271.
Robertson FM, Parrett ML, Joarder FS, Ross M, Abou-Issa H, Alshafie GA, Harris RE. Ibuprofen-induced inhibition of cyclooxygenase isoform gene expression and regression of rat mammary carcinomas. Cancer Lett 1998; 122: 165–175.
Mitchell JA, Akarasereenont P, Thiemermann C, Flower Rh, Vane JR. Selectivity of nonsteroidal anti-inflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci USA 1994; 90:11, 693–11, 697.
Kujubu DA, Reddy ST, Fletcher BS, Herschman HR. Expression of the protein product of the prostaglandin synthase-2/TIS 10 gene in mitogen-stimulated Swiss 3T3 cells. JBiol Chem 1993; 268: 5425–5430.
Herschman HR. Regulation of prostaglandin synthase-1 and prostaglandin synthase-2. Cancer Metastasis Rev 1994; 13: 241–256.
DuBois RN, Awad J, Morrow J, Roberts LJ, Bishop P. Regulation of eicosanoid production and mito-genesis by transforming growth factor a and phorbol ester. J Clin Invest 1994; 93: 493–498.
O’Neill GP, Ford-Hutchinson AW. Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett 1993; 330: 156–160.
Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (Part-II). JNatl Cancerinst 1998; 90: 1606 1620.
Eberhart CE, Coffey RI, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN. Up-regulation of cyclooxygenase-2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994; 107: 1183–1188.
Subbaramaiah K, Telang N, Araki R, DeVito B, Weksler B, Dannenberg A. Transcription of cyclooxygenase-2 is enhanced in transformed mammary epithelial cells. Cancer Res 1996; 56: 4424–4429.
Parrett ML, Harris RE, Joarder FS, Clausen KP, Robertson FM. Cyclooxygenase-2 gene expression in human breast cancer. Intl J Oncol 1997; 10: 503–508.
Bennett A. The production of prostanoids in human cancers and their implications for tumor progression. Prog Lipid Res 1986; 25: 539–542.
Lupulescu A. Prostaglandins, their inhibitors and cancer. Prost Leuk Essen Fatty Acids 1996; 54: 83–94.
Bennett A, Charlier EM, McDonald AM, Simpson JS, Stamford IF, Zebro T. Prostaglandins and breast cancer. Lancet 1977; 2: 624–626.
Rigas B, Goldman IS, Levine L. Altered eicosanoid levels in human colon cancer. J Lab Clin Med 1993; 122: 518–523.
Honn KV, Bockman RS, Marnett LJ. Prostaglandins and cancer, a review of tumor initiation through tumor metastasis. Prostaglandins 1981; 21: 833–864.
Benett A, Berstock DA, Carroll MA, Stamford IF, Wilson AJ. Breast cancer, its recurrence and patient survival in relation to tumor prostaglandins. In: Samuelson B, Paolett R, Ramwell P, eds. Advances in Prostaglandin, Thromboxane, and Leukotrine Research, vol. 12. Raven Press, New York, 1983, pp. 299–302.
Parrett ML, Abou-Issa H, Alshafie GA, Ross M, Harris RE, Robertson FM. Comparative ability of ibuprofen and N-(4-hydroxyphenyl) retinamide to inhibit development of rat mammary adenocarcinomas associated with differential inhibition of gene expression of cyclooxygenase isoforms. Anticancer Res 1999; 19: 5079–5086.
Fulton AM, Heppner GH. Relationships of prostaglandin E and natural killer sensitivity to metastatic potential in murine mammary adenocarcinomas. Cancer Res 1985; 45: 4779–4784.
Kundu N, Yang Q, Dorsey R, Fulton AM. Increased cyclooxygenase-2 expression and activity in a murine model of metastatic breast cancer. Intl J Cancer 2001; 93: 681–686.
Rose DP, Hatala AM, Connolly JM, Rayburn J. Effect of diets containing different levels of linoleic acid on human breast cancer growth and lung metastasis in mice. Cancer Res 1993; 53: 4686–4690.
Rose DP, Connolly JM, Liu XH. Effect of linoleic acid on the growth and metastasis of two human breast cancer cell lines in nude mice and the invasive capacity of these cell lines in vitro. Cancer Res 1994; 54: 6557–6562.
Fulton AM. In vivo effects of indomethacin on the growth of murine mammary tumors. Cancer Res 1984; 44: 2416–2420.
Plesia OJ, Smith AH, Grinwich K. Suppression of immune system by tumor cells and role of prostaglandins. Proc Natl Acad Sci USA 1975; 72: 1848–1851.
Fulton AM, Levy JG. The possible role of prostaglandins in mediating immune suppression by specific T suppressor cells. Cell Immunol 1980; 52: 29–37.
Saez E, Tontonoz MC, Nelson JG, Alvarez UT, Ming SM, Baird VA, et al. Activators of the nuclear receptor PPAR-gamma enhance colon polyp formation. Nature Med 1998; 4: 1058–1061.
Lefebvre A-M, Chen I, Desreumaux P, Najib J, Fruchart J-C, Geboes K, et al. Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6JAPCM’“/+ mice. Nature Med 1998; 4: 1053–1057.
Funk CR, Funk LB, Kennedy ME, Pong AS, Fitzgerald GA. Human platelet/ erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression and gene chromosomal assignment. FASEB J 1991; 5: 2304–2315.
Kosaka T, Miata A, Ihara H, Hara S, Sugimoto J, Takeda O, et al. Characterization of the human gene (PTGS2) encoding prostaglandin synthase-2. Eur J Biochem 1994; 221: 889–897.
Picot D, Loll PJ, Garavito RM. The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature 1994; 367: 243–249.
Luong C, Miller A, Barnett J, Chow J, Ramesha C, Browner MF. Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2. Nature Structural Biology 1996; 3: 972–933.
Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells over-expressing prostaglandin endoperoxide synthase-2. Cell 1995; 83: 493–501.
Han JW, Sadowski H, Young DA, Macara IG. Persistent induction of cyclooxygenase in p60 v-src transformed 3T3 fibroblasts. Proc Nall Acad Sci USA 1990; 87: 3373–3377.
Smith WL, DeWitt DL. Prostaglandin endoperoxide H synthases-1 and-2: the mechanisms by which extracellular stimuli activate phospholipases are unresolved. Adv Immunol 1996; 62: 167–215.
Subbaramaiah K, Zahn D, Weksler B, Dannenberg A. Inhibition of cyclooxygenase: a novel approach to cancer prevention. Exp Biol Med 1997; 216: 201–210.
Morita I, Schindler M, Regier MK, Otto JC, Hori T, DeWitt DL, Smith WL. Different intracellular locations for prostaglandin endoperoxide H synthase-1 and -2. JBiol Chem 1995; 270:10, 902–10, 908.
Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: structure, cellular and molecular biology. Ann Rev Biochem 2000; 69: 145–182.
Chulada PC, Loftin CD, Winn VD, Young DA, Tiano HF, Eling TE, Langenbach R. Relative activities of retrovirally expressed murine prostaglandin synthase-1 and -2 depend on source of arachidonic acid. Arch Biochem Biophys 1996; 330: 301–313.
Kargman SL, O’Neill GP, Vickers PJ, Evans JF, Mancini JA, Jothy S. Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. Cancer Res 1995; 55: 2556–2559.
Kutchera W, Jones DA, Matsunami N, Gordon J, McIntyre TM, Zimmerman GA, et al. Prostaglandin H synthase-1 and -2 is expressed abnormally in human colon cancer. Evidence for a transcriptional effect. Proc Natl Acad Sci USA 1996; 93: 4816–4820.
Sano H, Kawahito Y, Wilder R, Hashiramoto A, Mukai S, Asai K, et al. Expression of cyclooxygenase1 and -2 in human colorectal cancer. Cancer Res 1995; 55: 3785–3789.
Blanco A, Habib A, levy-Toledanos S. Maclouf J. Involvement of tyrosine kinases in the induction of cyclooxygenase-2 in human epithelial cells. Biochem J 1995; 312: 419–423.
Narko K, Ristimaki A, MacPhee M, Smith E, Haudenschild CC, Hla T. Tumorigenic transformation of immortalized ECV endothelial cells by cyclooxygenase-1 overexpression. J Biol Chem 1997; 272: 21, 455–21, 460.
Ristimaki A, Honkanen N, Jankala H, Sipponen P, Harkonen M. Expression of cyclooxygenase-2 in human gastric carcinoma. Cancer Res 1997; 57: 1276–1280.
Zimmermann KC, Sarbia M, Weber AA, Borchard F, Gabbert HE, Schror K. Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer Res 1999; 59: 198–204.
Cornwall H, Odukoya 0, Shldar G. Oral mucosal tumor inhibition by ibuprofen. J Oral Maxill Surg 1983; 41: 795–800.
Hida T, Yatabe Y, Achiwa H, Mukamatsu H, Kosaki K, Nakamura S, et al. Increased expression of cyclooxygenase-2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res 1998; 58: 3761–3764.
Hwang D, Scollard D, Byrne J, Levine E. Expression of cyclooxygenase-1 and -2 in human breast cancer. J Natl Cancer Inst 1998; 90: 455–460.
Singh J, Hamid R, Reddy BS. Dietary fat and colon cancer: modulation of cyclooxygenase-2 by type and amounts of dietary fat during the post-initiation phase of colon carcinogenesis. Cancer Res 1997; 57: 3465–3470.
Williams CS, Luongo C, Radhika A, Zhang T, Lamps LW, Nanney LB, et al. Elevated cyclooxygenase-2 levels in Min mouse adenomas. Gastroenterology 1996; 111: 1134–1140.
Liu XH, Rose DP. Differential expression and regulation of cyclooxygenase-1 and -2 in two human breast cancer cell lines. Cancer Res 1996; 56: 5125–5127.
Brown LF, Detmas M, Claffey K, Nagy JA, Feng D, Dvorak AM, Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenic cytokine. EXS 1997; 79: 233–269.
Ziche M, Jones J, Guillino PM. Role of prostaglandin E1 and copper in angiogenesis. J Natl Cancer Inst 1982; 6: 475–482.
Harris RE, Kasbari S, Farrar WB. Prospective study of nonsteroidal drugs and breast cancer. Oncol Rep 1999; 6: 71–73.
Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase-2 in inflammation and pain. Proc Natl Acad Sci USA 1994; 91: 12, 013–12, 017.
Nonsteroidal anti-inflammatory agents: Celecoxib. In: McEvoy GK, ed. The American Hospital Formulary Service Drug Information. American Society of Hospital Pharmacists. Bethesda, MD, 2000, pp. 1872–1879.
Stolfi RL, Stolfi LM, Sawyer RC, Martin DS. Chemotherapeutic evaluation using clinical criteria in spontaneous autochthonous murine breast tumors. J Nail Cancer Inst 1988; 8: 52–55.
Shou M, Korzekwa KR, Krause KW, Buters JT, Grogan J, Gold I, et al. Specificity of cDNA-expressed human and rodent cytochrome P450s in the oxidative metabolism of the potent carcinogen 7, 12-dimethylbenz(a) anthracene. Mol Carcinog 1996; 17: 241–249.
Rioux N, Castonguay A. Prevention of NNK-induced lung tumorigenesis in A/J mice by acetylsalicylic acid and NS-398. Cancer Res 1998; 58: 5354–5360.
Kelly DJ, Mestre JR, Subbaramaiah K, Sacks PG, Schantz SP, Tanabe T, et al. Benzo(a)pyrene up-regulates cyclooxygenase-2 gene expression in oral epithelial cells. Carcinogenesis 1997; 18: 795–799.
Hu Z, Wells PG. In vitro and in vivo biotransformation and covalent binding of benzo(a)pyrene in Gunn and RHA rats with genetic deficiency in bilirubin uridine diphosphate-glucuronosyl transferase. J Pharmacol Exp Ther 1992; 263: 334–342.
Rose DP, Connolly JM. Stimulation of growth of human breast cancer cell lines in culture by linoleic acid. Biochem Biophys Res Commun 1989; 164: 277–283.
Wolff H, Saukkonen K, Antilla S, Karajalainen A, Vainio H, Ristimaki A. Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res 1998; 58: 4997–5001.
Zhao Y, Agarwal VR, Mendelson CR, Simpson ER. Estrogen biosynthesis proximal to a breast tumor is stimulated by PGE2 via cyclic AMP, leading to activation of promotor II of the CYP 19 (aromatase) gene. Endocrinology 1996; 137: 5739–5742.
Brueggemeier RW, Quinn AL, Parrett ML, Joarder FS, Harris RE, Robertson FM. Correlation of aromatase and cyclooxygenase gene expression in human breast cancer specimens. Cancer Lett 1999; 40: 27–35.
Masferrer JL, Leahy KM, Koki AT, Zweifel T, Settle BS, Woerner SL, et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000; 60: 1153–1173.
Tsujii M, Kawano S, Tsujii S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998; 93: 705–716.
Folkman J. Angiogenesis and breast cancer. J Clin Oncol 1994; 12: 441–443.
Folkman J Tumor angiogenesis. In: Mendelsohn J, Howley PM, Israel MA, Liotta LA, eds. The Molecular Basis of Cancer. WB Saunders, Philadelphia, PA, 1995, pp. 206–232.
Abou-Issa H, Alshafie GA, Seibert K, Koki AT, Harris RE, Masferrer JL. Dose-response effects of the COX-2 inhibitor, celecoxib, on the chemoprevention of mammary carcinogenesis. Anticancer Res2001; in press.
Parrett ML, Tober KL, Abou-Issa HM, Alshafie GA, Ross MS, Harris RE, Robertson FM. Ibuprofen inhibition of rat mammary adenocarcinomas growth is associated with diminished expression of specific transcripts of VGEF. Proc Amer Assoc Cancer Res 1999; 40: 2011.
Xin-Hua L, Shen Y, Kirschenbaum A, Levine AC. NS-398, a selective cyclooxygenase-2 inhibitor induces apoptosis and down-regulate bcl-2 expression by LNCaP Cells. Cancer Res 1998; 58: 42454249.
Shiff SJ, Qiao L, Tsai LL, Rigas B. Sulindac sulfide, an aspirin like compound, inhibits proliferation, causes cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells. J Clin Invest 1995; 96: 491–503.
Hanif R, Pittas A, Feng Y, Koutsos ML, Qiao L, Staiano-Coico L, et al. Effects of NSAIDs on proliferation and induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem Pharmcol 1996; 52: 237–245.
Piazza GA, Rahm AL, Krutsch M, Paranka NS, Gross PH, Brendel K, et al. Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res 1995; 55: 3110–3116.
Duggan DE, Hare LE, Ditzler CA, Lei BW, Kwan KC. The disposition of sulindac. Clin Pharmacol Ther 1977; 21: 326–335.
Alshafie GA, Abou-Issa H, Seibert K, Harris RE. Chemotherapeutic evaluation of Celecoxib, a cyclooxygenase-2 inhibitor in a rat mammary tumor model. Oncol Reports 2000; 7: 1377–1381.
Shiff SJ, Rigas B. The role of cyclooxygenase inhibition in the antineoplastic effects of nonsteroidal anti-inflammatory drugs (NSAIDs). J Exp Med 1999; 190: 445–450.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2003 Springer Science+Business Media New York
About this chapter
Cite this chapter
Abou-Issa, H.M., Alshafie, G.A., Harris, R.E. (2003). Chemoprevention of Breast Cancer by Nonsteroidal Anti-Inflammatory Drugs and Selective COX-2 Blockade in Animals. In: Harris, R.E. (eds) COX-2 Blockade in Cancer Prevention and Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-302-6_6
Download citation
DOI: https://doi.org/10.1007/978-1-59259-302-6_6
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-61737-304-6
Online ISBN: 978-1-59259-302-6
eBook Packages: Springer Book Archive