Molecular biology of P-glycoprotein

  • Marilyn M. Cornwell
Part of the Cancer Treatment and Research book series (CTAR, volume 57)


Since the advent of chemotherapy it has been observed that certain types of cancer are rarely sensitive to treatment with chemotherapy. Other cancers that are initially responsive to treatment eventually become resistant to the treatment regimen being used and to some other drugs as well. Resistance to chemotherapy remains one of the fundamental barriers to curative treatment. The mechanisms by which tumor cells become drug resistant have been under intensive study. It is clear from the accumulated data that drug resistance is a complex phenomenon, including more than one mechanism. Resistance may be caused by a change in one, more than one, facet of drug interaction with a cell, from drug influx/efflux and drug metabolism to drug-target site interactions.


Multidrug Resistance Chinese Hamster Ovary Cell Line Confer Drug Resistance Rodent Gene Human Multidrug Resistance 
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  1. 1.
    Biedler, J.L. and Riehm, H. Cellular resistance to actinomycin D in Chinese hamster ovary cell in vitro: cross resistance, radiographie and cytogenetic studies. Cancer Res. 30:1174–1184, 1970.PubMedGoogle Scholar
  2. 2.
    Akiyama, S.-I., Fojo, A, Hanover, J.A., Pastan, I., and Gottesman, M.M Isolation and genetic characterization of human KB cell lines resistant to multiple drugs. Somat. Cell Mol. Genet. 11:117–126, 1985.CrossRefGoogle Scholar
  3. 3.
    Howell, N., Belli, T.A, Zaczkiewics, L.T., and Belli, J.A. High level, unstable adriamycin resistance in a Chinese hamster mutant cell line with double minute chromosomes. Cancer Res. 44:4023–4030, 1984.PubMedGoogle Scholar
  4. 4.
    Croop, J.M., Gros, P., and Housman, D.E. Genetics of multidrug resistance. J. Clin. Invest. 81:1303–1309, 1988.PubMedCrossRefGoogle Scholar
  5. 5.
    Gottesman, M.M. and Pastan, I. The multidrug transporter: a bouble edged sword. J. Biol. Chem. 263:12163–12166, 1988.PubMedGoogle Scholar
  6. 6.
    Endicott, J. and Ling, V. The biochemistry of P-glycoprotein-mediated multidrug resistance. An. Rev. Biochem. 58:137–171, 1989.CrossRefGoogle Scholar
  7. 7.
    Roninson, I.B., Chen, J.E., Choi, K., Gros, P., Housman, D., Fojo, A., Shen, D., Gottesman, M.M., and Pastan, I. Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinama cells. Proc. Natl. Acad. Sci. USA 83:4538–4542, 1986.PubMedCrossRefGoogle Scholar
  8. 8.
    van der Bliek, A.M., Baas, F., de Lange, T., Kooiman, P.M., van der Veld-Koerts, T., and Borst, P. The human mdr3 gene encodes a novel P-glycoprotein homologue and gives rise to alternatively spliced mRNAs in liver. EMBO J. 6:3325–3331, 1987.PubMedGoogle Scholar
  9. 9.
    Callen, D.F., Baker, E., Simmers, R.N., Seshardri, R., and Roninson, I.B. Localization of the human multiple drug resistance gene, MDR1, to 7q21.1._Hum. Genet. 77:142–144, 1987.Google Scholar
  10. 10.
    Trent, J.M. and Witkowski, CM. Clarification of the chromosomal assignment of the human P-glycoprotein/mdrl gene: possible coincidence with the cystic fibrosis and c-met oncogene. Cancer Genet. Cytogenet 26:187–190, 1987.PubMedCrossRefGoogle Scholar
  11. 11.
    Ueda, K., Cardarelli, C, Gottesman, M.M., and Pastan, I. Expression of a full-length cDNA for the human mdrl gene confers resistance to colchicine, doxorubicin and vin-blastine. Proc. Natl. Acad. Sci. USA 85:1595–1599, 1987.Google Scholar
  12. 12.
    van der Bliek, A.M., Baas, F., van der Veld-Koerts, T., Biedler, J.L., Meyers, M.B., Ozols, R.F., Hamilton, T.C., Joenje, H., and Borst, P. Genes amplified and overexpressed in human multidrug-resistant cell lines. Cancer Res. 48:5927–5932, 1988.PubMedGoogle Scholar
  13. 13.
    Chen, C, Clark, D., Ueda, K., Pastan, I., Gottesman, M.M., and Roninson, I.B. Genomic organization of the human multidrug resistance (MDR1) gene and origin of P-glycoproteins. J. Biol. Chem. 265:506–514, 1990.PubMedGoogle Scholar
  14. 14.
    Kane, S.E., Pastan, I., and Gottesman, M.M. Genetic basis of multidrug resistance of tumor cells. J. Bioenerg. Biomembr., 1990, in press.Google Scholar
  15. 15.
    Chen, C, Chin, J.E., Ueda, K., Clark, D.P., Pastan, I., Gottesman, M.M., and Roninson, I.B. Internal duplication and homology with bacterial transport proteins in the mdrl (P-glycoprotein) gene from multidrug-resistant human cells. Cell 47:381–389, 1987.CrossRefGoogle Scholar
  16. 16.
    Juliano, R.L. and Ling, V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta 455:152–162, 1976.PubMedCrossRefGoogle Scholar
  17. 17.
    Riordan, J.R., Deuchars, K., Kartner, N., Alon, N., Trent, J., and Ling, V. Amplification of P-glycoprotein genes in multidrug-resistant mammalian cell lines. Nature 316:817–819, 1985.PubMedCrossRefGoogle Scholar
  18. 18.
    Meyers, M.B., Spengler, B.A., Chang, T.D., Melera, P.W., and Biedler, J.L. Gene amplification-associated cytogenetic aberrations and protein changes in vincristine-resistant Chinese hamster, mouse, and human cells. J. Cell Biol. 100:588–596, 1985.PubMedCrossRefGoogle Scholar
  19. 19.
    Shen, D., Fojo, A., Chin, J.E., Roninson, I.B., Richert, N., Pastan, I., and Gottesman, M.M. Human multidrug resistant cell lines: increased mdrl expression can precede gene amplification. Science 232:643–645, 1986.PubMedCrossRefGoogle Scholar
  20. 20.
    Cornwell, M.M., Safa, A.R., Felsted, R.L., Gottesman, M.M., and Pastan, I. Membrane vesicles from multidrug-resistant human cancer cells contain a specific 150-170 kDa protein detected by photaffinity labeling. Proc. Natl. Acad. Sci. USA 83:3847–3850, 1986.PubMedCrossRefGoogle Scholar
  21. 21.
    Cornwell, M.M., Tsuruo, T., Gottesman, M.M., and Pastan, I. ATP-binding properties of P-glycoprotein from multidrug resistant KB cells FASEB J. 1:51–54, 1987.Google Scholar
  22. 22.
    Safa, A.R., Glover, G.J., Meyers, M.B., Biedler, J.L., and Felsted, R.L. Vinblastine photoaffinity labeling of high molecular weight surface membrane glycoprotein specific for multidrug resistant cells. J. Biol. Chem. 261:6137–6140, 1986.PubMedGoogle Scholar
  23. 23.
    Horio, M., Gottesman, M.M., and Pastan, I. ATP-dependent transport of vinblastine in vesicles from human multidrug-resistant cells. Proc. Natl. Acad. Sci. USA 85:3580–3584, 1988.PubMedCrossRefGoogle Scholar
  24. 24.
    Thiebaut, F., Tsuruo, T., Hamada, H., Gottesman, M.M., Pastan, I., and Willingham, M.C. Cellular localization of the multridrug-resistant gene product P-glycoprotein in normal human tissues. Proc. Natl. Acad. Sei. USA 84:7735–7738, 1987.CrossRefGoogle Scholar
  25. 25.
    van der Bliek, A.M., Kooiman, P.M., Schneider, C, and Borst, P. Sequence of mdr3 encoding a human P-glycoprotein. Gene 71:401–411, 1988.PubMedCrossRefGoogle Scholar
  26. 26.
    Gros, P., Croop, J., and Housman, D. Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell 47:409–411, 1986.CrossRefGoogle Scholar
  27. 27.
    Hsu, S.I-H., Lothstein, L. and Horwitz, S.B. Differential overexpression of three mdr gene family members in multidrug-resistant J774.2 mouse cells. J. Biol. Chem. 264:12053–12062, 1989.PubMedGoogle Scholar
  28. 28.
    Endicott, J.A., Juranka, P.F., Sarangi, F., Gerlach, J.H., Deuchars, L.L., and Ling, V. Simultaneous expression of two P-glycoprotein genes in drug-sensitive Chinese hamster ovary cells. Mol. Cell. Biol. 7:4075–4081, 1987.PubMedGoogle Scholar
  29. 29.
    Ng, W.F., Sarangi, F., Zastawny, R.L., Veinot-Drebot, L., and Ling, V. Identification of members of the P-glycoprotein multigene family. Mol. Cell. Biol. 9:1224–1232, 1989.PubMedGoogle Scholar
  30. 30.
    Jongsma, A.P.M. Spengler, B.A., van der Bliek, A.M., Borst, P., and Biedler, J.L. Chromosomal localization of three genes coamplified in the multidrug-resistant CHRC5 Chinese hamster ovary cell line. Cancer Res. 47:2875–2878, 1987.PubMedGoogle Scholar
  31. 31.
    Martinsson, T. and Levan, G. Localization of the multidrug resistance-associated 170 kDa P-glycoprotein by in situ hybridization. Cytogenet. Cell Genet. 45:99–101, 1987.CrossRefGoogle Scholar
  32. 32.
    van der Bliek, A.M., van der Velde-Koerts, T., Ling, V., and Borst, P. Overexpression and amplification of five genes in a multidrug resistant Chinese hamster ovary cell line. Mol. Cell. Biol. 6:1671–1678, 1986.PubMedGoogle Scholar
  33. 33.
    Raymond, M. and Gros, P. Mammalian multidrug-resistance gene: correlation of exon organization with structural domains and duplication of an ancestral gene. Proc. Natl. Acad. Sci. USA 86:6488–6492, 1989.PubMedCrossRefGoogle Scholar
  34. 34.
    Gros, P., Raymond, M., Bell, J., and Housman, D. Cloning and characterization of a second member of the mouse mdr gene family. Mol. Cell. Biol. 8:2770–2778, 1988.PubMedGoogle Scholar
  35. 35.
    Gros, P., BenNeriah, Y., Groop, J.M., and Housman, D.E. Isolation and expression of a cDNA (mdrl) that confers multidrug resistance. Nature 323:728–731, 1986.PubMedCrossRefGoogle Scholar
  36. 36.
    Higgins, CF., Hues, I.D., Salmond, G.P.C., Gill, D.R., Downie, J.A., Evans, I.J., Holland, I.B., Gray, L., Buckel, S.D., Bell, A.W., and Hermodson, M.A. A family of related ATP-binding subunits coupled to many distinct biological processes in bacteria. Nature 323:448–450, 1986.PubMedCrossRefGoogle Scholar
  37. 37.
    Felmlee, T., Pellett, S., and Welch, R.A. Nucleotide sequence of an Escherichia coli chromosomal hemolysin. J. Bact. 163:94–105, 1985.PubMedGoogle Scholar
  38. 38.
    Stanfield, S.W., Ielpi, L., O’Brchta, D., Helinski, D.R., and Ditta, G.S. The ndv gene product of Rhizobium meliloti is required for-(1 2) glucan production and has homology to the ATP-binding export protein HylB. J. Bacteriol. 170:3523–3530, 1988.PubMedGoogle Scholar
  39. 39.
    Strathdee, C.A. and Lo, R.Y.C. Cloning, nucleotide sequence, and characterization of genes encoding the secretion function of the Pasteurella haemolytica leukotoxin determinant. J. Bact. 171:916–928, 1989.PubMedGoogle Scholar
  40. 40.
    Glaser, P., Sakamoto, H., Bellalou, J., Ulimann, L, and Danchin, A. Secretion of cyclolysin, the calmodulin sensitive adenylate cyclase-haemolysin bifunctional protein of Bordetella pertussis. EMBO J. 7:3997–4004, 1988.PubMedGoogle Scholar
  41. 41.
    Gill, D.R., Hatfull, G.F., and Salmond, G.P.C. A new cell division operon in Escherichia coli. Mol. Gen. Genet. 205:134–145, 1986.CrossRefGoogle Scholar
  42. 42.
    Evans, I.J. and Downie, J.A. The nodi gene product of Rhizobium leguminosarum is closely related to ATP-binding bacterial transport proteins: nucleotide sequence analysis of the nodi and nod j genes. Gene 43:95–101, 1986.PubMedCrossRefGoogle Scholar
  43. 43.
    Ames, G. Bacterial periplasmic transport systems: structure, mechanism, and evolution. Ann. Rev. Biochem. 55:397–425, 1986.PubMedCrossRefGoogle Scholar
  44. 44.
    Wilson, CM., Serrano, A.E., Wasley, A., Bogenschutz, M.P., Shankar, A.H., and Wirth, D.F. Amplification of a gene related to mammalian mdr genes in a drug-resistant Plas-modium falciparum. Science 244:1184–1186, 19CrossRefGoogle Scholar
  45. 45.
    Foote, S.J., Thompson, J.K., Cowman, A.F., and Kemp. D.J. Amplification of the multidrug resistance gene in some chloroquine-resistant isolates of P. falciparum. Cell 57:921–930, 19PubMedCrossRefGoogle Scholar
  46. 46.
    McGrath, J.P. and Varshvsky, A. The yeast STE6 gene encodes a homologue of the mammalian multidrug resistance P-glycoprotein. Nature 340:400–404, 1989.PubMedCrossRefGoogle Scholar
  47. 47.
    Kuchler, K., Sterne, R.E., and Thorner, J. EMBO J., in press, 1989.Google Scholar
  48. 48.
    Sullivan, D.T. and Sullivan, M.C. Transport defects as the physiological basis for eye color mutants of Drosophila melanogaster. Biochem. Genet. 13:603–613, 1975.Google Scholar
  49. 49.
    Sullivan, D.T., Bell, L.A., Paton, D.R, and Sullivan, M.C. Purine transport by malpighian tubules of pteridine-deficient eye color mutants of Drosophila melanogaster. Biochem. Genet. 17:565–573, 1979.Google Scholar
  50. 50.
    Dreesen, T.D., Johnson, D.H., and Henikoff, S. The brown protein of Drosophila melanogaster is similar to the white protein and to components of active transport complexes. Mol. Cell. Biol. 8:5206–5215, 1988.PubMedGoogle Scholar
  51. 51.
    O′Hare, K., Murphy, C, Levis, R., and Rubin, G.M. DNA sequence of the white locus of Drosophila melanogaster. J. Mol. Biol. 180:437–455, 1984.CrossRefGoogle Scholar
  52. 52.
    Mount, S.M. Sequence similarity. Nature 325:48751, 1987.CrossRefGoogle Scholar
  53. 53.
    Shen, D., Cardarelli, C, Hwang, J., Cornwell, M., Richert, N., Ishii, S., Pastan, I., and Gottesman, M.M. Multiple drug resistant human KB carcinoma cells independently selected for high-level resistance to colchicine, adriamycin, or vinblastine show changes in expression of specific proteins. J. Biol. Chem. 261:7762–7770, 1986.PubMedGoogle Scholar
  54. 54.
    Bradley, G., Juranka, P.F., and Ling, V. Mechanism of multidrug resistance. Biochim. Biophys. Acta 948:87–128, 1988.PubMedGoogle Scholar
  55. 55.
    Fojo, A.T., Whang-Peng, J., Gottesman, MN.M, and Pastan, I. Amplification of DNA sequences in human multidrug-resistant KB carcinoma cells. Proc. Natl. Acad. Sci. USA 82:7661–7664, 1985.PubMedCrossRefGoogle Scholar
  56. 56.
    de Bruijn, M.H.L., van der Bliek, A.M., Biedler, J.L., and Borst, P. Differential amplification and disproportionate expression of five genes in three multidrug-resistant Chinese hamster lung cell lines. Mol. Cell. Biol. 6:4717–4722, 1986.PubMedGoogle Scholar
  57. 57.
    Stahl, F., Martinsson, T., Dahllof, B., and Levan, G. Amplification and overexpression of genes in SEWA murine multidrug-resistant cells and mapping of the P-glycoprotein genes to chromosome 5 in mouse. Hereditas 108:251–258, 1988.PubMedCrossRefGoogle Scholar
  58. 58.
    Fojo, A.T., Shen, D., Mickley, L.A., Pastan, I., and Gottesman, M.M. Intrinsic drug resistance in human kidney cancer is associated with expression of a human multidrug resistance gene. J. Clin. Oncol. 5:1922–1927, 1987.PubMedGoogle Scholar
  59. 59.
    Fojo, A.T., Ueda, K., Slamon, D.J., Poplack, D.G., Gottesman, M.M., and Pastan I. Expression of a multidrug-resistance gene in human tumors and tissues. Proc. Natl. Acad. Sei. USA 84:265–269, 1987.CrossRefGoogle Scholar
  60. 60.
    Sugawara, I., Kataoka, I., Morishita, Y., Hamada, H., Tsuruo, T., Itayama, S., and Mori, S. Tissue distriction of P-glycoprotein encoded by a multidrug resistant gene as revealed by a monoclonal antibody, MRK16._Cancer Res. 48:4611–4614, 1988.PubMedGoogle Scholar
  61. 61.
    Kakehi, Y., Kanamuaru, H., Yoshida, O., Ohkubo, H., Nakanishi, S., Gottesman, M.M., and Pastan, I. Measurement of multidrug resistance messenger RNA in urogenital cancers: elevated expression in renal cell carcinoma is associated with intrinsic drug resistance. J. Urol. 139:862–865, 1988.PubMedGoogle Scholar
  62. 62.
    Chin, J.E., Soffir, R., Noonan, K.E., Choi, K., and Roninson, I.B. Structure and expression of the human MDR (P-glycoprotein) gene family. Mol. Cell. Biol. 9:3808–3820, 1989.PubMedGoogle Scholar
  63. 63.
    Baas, F. and Borst, P. The tissue dependent expression of hamster P-glycoprotein genes. FEBS Lett. 229:329–332, 1988.PubMedCrossRefGoogle Scholar
  64. 64.
    Mukhopadhyay, T., Batsakis, J.G., and Kuo, M.T. Expression of the mdr (P-glycoprotein) gene in Chinese hamster digestive tracts. J. Natl. Cancer Inst. 80:269–275, 1988.PubMedCrossRefGoogle Scholar
  65. 65.
    Croop, J.M., Raymond, M., Haber, D., Devault, A., Arceci, R.J., Gros, P., and Housman, D.E. The three mouse multidrug resistance genes are expressed in a tissue-specific manner in normal mouse tissues. Mol. Cell. Biol. 9:1346–1350, 1989.PubMedGoogle Scholar
  66. 66.
    Arceci, R.J., Croop, J.M., Horwitz, S.B., and Housman, D. The gene encoding multidrug resistance is induced and expressed at high levels during pregnancy in the secretory epithelium of the uterus. Proc. Natl. Acad. Sci. USA 85:4350–4354, 1988.PubMedCrossRefGoogle Scholar
  67. 67.
    Gottesman, M.M. Multidrug resistance during chemical carcinogenesis: a mechanism revealed? J. Natl. Cancer Inst. 80:1352–1353, 1989.CrossRefGoogle Scholar
  68. 68.
    Kamimoto, Y., Gatmaitan, Z., Hsu, J., and Arias, I.M. The function of Gpl70, the multidrug resistance gene product, in rat liver canalicular membrane vesicles. J. Biol. Chem. 264:11693–11698, 1989.PubMedGoogle Scholar
  69. 69.
    Yang, C.-P.H., DePinho, S.G., Greenberger, L.M., Arceci, R.J., and Horwitz, S.B. Progesterone interacts with P-glycoprotein in multidrug-resistant cells and in the endo-metrium of gravid uterus. J. Biol Chem. 264:782–788, 1989.PubMedGoogle Scholar
  70. 70.
    Benard, J., Da Silva, J., Teyssier, J.-R., and Riou, G. Over-expression of mdrl gene with no DNA amplification in a multiple-drug-resistant human ovarian carcinoma cell line. Int. J. Cancer 43:471–477, 1989.PubMedCrossRefGoogle Scholar
  71. 71.
    Chin, K.-V., Tanaka, S., Darlington, G., Pastan, I., and Gottesman, M.M. Heat shock and arsenite increase expression of the multidrug resistance (MDR1) gene in human renal carcinoma cells. J. Biol. Chem. 265:221–226, 1989.Google Scholar
  72. 72.
    Bates, S.E., Mickley, L.A., Chen, Y.-N., Richert, N., Rudick, J., Biedler, J.L., and Fojo, A.T. Expression of a drug resistance gene in human neuroblastoma cell lines: modulation by retinoic acid-induced differentiation. Mol Cell. Biol. 9:4337–4344, 1989.PubMedGoogle Scholar
  73. 73.
    Thorgiersson, S.S., Huber, B.E., Sorrell, S., Fojo, A., Pastan, I., and Gottesman, M.M. Expression of the multidrug resistance gene in hepatocarcinogenesis and regenerating rat liver. Science 236:1120–1122, 1987.CrossRefGoogle Scholar
  74. 74.
    Burt, and Thorgierrson, S.S. Coinduction of MDR1 multidrug-resistance and cytochrome P-450 genes in rat liver by xenobiotics. J. Natl. Cancer. Inst. •, 1988Google Scholar
  75. 75.
    Marino, P.A., Gottesman, M.M., and Pastan, I. Cell Growth Differen., in press, 1990.Google Scholar
  76. 76.
    Ueda, K., Cardarelli, C, Gottesman, M.M., and Pastan I. The human multidrug resistance (mdrl) gene: cDNA cloning and transcription initiation. J. Biol Chem. 262:505–508, 1987.PubMedGoogle Scholar
  77. 77.
    Ueda, K., Pastan, I., and Gottesman, M.M. Isolation and sequence of the promoter region of the human multidrug resistance (P-glycoprotein) gene. J. Biol. Chem. 262:17432–17436, 1987.PubMedGoogle Scholar
  78. 78.
    Rothenberg, M., Mickely, L.A., Cole, D.E., Balis, R.M., Tsuruo, T., Poplack, D.G., and Fojo, A.T. Expression of the mdrl/P-170 gene in patients with acute lymphoblastic leukemia. Blood 74:1388–1395, 1989.PubMedGoogle Scholar
  79. 79.
    Currier, S.J., Ueda, K., Willingham, M.C., Pastan, I., and Gottesman, M.M. Deletion and insertion mutants of the multidrug transporter. J. Biol. Chem. 264:14376–14381, 1989.PubMedGoogle Scholar
  80. 80.
    Azzaria, M., Schurr, E., and Gros, P. Discrete mutations introduced in the predicted nucleotide-binding sites of the mdrl gene abolish its ability to confer multidrug resistance. Mol. Cell. Biol. 9:5289–5297, 1989.PubMedGoogle Scholar
  81. 81.
    Bruggemann, E.P., Germann, U.A., Gottesman, M.M., and Pastan, I. Two different regions of phosphoglycoprotein are photoaffinity-labeled by azidopine. J. Biol. Chem. 264:15483–15488, 1989.PubMedGoogle Scholar
  82. 82.
    Yoshimura, A., Kuwazuru, Y., Sumizawa, T., Ichikawa, M., Ikeda, S.-I., Uda, T., and Akiyama, S.-I. Cytoplasmic orientation and two-domain structure of the multidrug transporter, P-glycoprotein, demonstrated with sequence-specific antibodies. J. Biol. Chem. 264:16282–16291, 1989.PubMedGoogle Scholar
  83. 83.
    Choi, K., Chen, C, Krigler, M., and Roninson, I.B. An altered pattern of cross-resistance in multidrug resistant human cells results from spontaneous mutations in the mdrl (P-glycoprotein) gene. Cell 53:519–529, 1988.PubMedCrossRefGoogle Scholar
  84. 84.
    Moscow, J.A. and Cowan, K.H. Multidrug resistance. J. Natl. Cancer Inst. 80:14–20, 1988.PubMedCrossRefGoogle Scholar
  85. 85.
    Greenberger, L.M., Williams, S.S., and Horwitz, S.B. Biosynthesis of heterogeneous forms of multidrug resistance-associated glycoproteins. J. Biol. Chem. 262:13685–13689, 1987.PubMedGoogle Scholar

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© Springer Science+Business Media New York 1991

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  • Marilyn M. Cornwell

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