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Applications of Biotechnology in Drug Discovery and Evaluation

  • Chapter
Biotechnology and Pharmacy

Abstract

As should be expected, a large portion of this volume has been dedicated to products that are presently available through various biotechnological processes (e.g., human insulin, tissue plasminogen activator, interferons, and monoclonal antibodies). These substances have either demonstrated or theoretical utility in the treatment of human disease conditions and clearly will have increasing impact on the practice of contemporary pharmacy. From a pragmatic viewpoint, however, widespread clinical use of these products is generally limited by the necessity of parenteral administration. A direct method of circumventing this problem involves the development of novel drug-delivery systems (see Chapter 6, this volume). An alternative approach involves defining the structural and conformational characteristics of the active region of large-molecular-weight drugs and then producing relatively small molecular weight structural analogues that are anticipated to mediate similar biological responses (see Chapter 14, this volume).

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Abbreviations

CAT:

chloramphenicol acetyltransferase

CCK:

cholecystokinin

CPA:

cytopathic effects

DEMO:

difluoromethylornithine

EDTA:

ethylenediaminetetraacetic acid

EGF:

epidermal growth factor

ELISA:

enzyme-linked immunosorbent assay

HIV:

human immunodeficiency virus

HRE:

hormone-responsive element

LTR:

long terminal repeat

MDR1:

the human gene responsible for multiple-drug resistance

MDR:

the nonhuman counterpart of the MDR1 gene (definitions from Gottesman and Pastan86)

ODC:

ornithine decarboxylase

PAGE:

polyacrylamide gel electrophoresis

PDBu:

phorbol dibutyrate

PDGF:

platelet-derived growth factor

PKC:

protein kinase C

RT:

reverse transcriptase

SDS:

sodium dodecyl sulfate

SFU:

syncytium-forming units

SSC:

standard saline citrate

TBP-1:

TAT-binding protein 1

TCDD:

2,3,7,8-tetrachlorodibenzo-p-dioxin

TGF:

transforming growth factor

TPA:

12-O-tetradecanoylphorbol-13-acetate

TPK:

tyrosine-specific protein kinase

XTT:

2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide

References

  1. Farnsworth, N.R. and Pezzuto, J.M. 1983. Practical pharmacologic evaluation of plants. In Pharmacological screening of plants and natural substances, no. 13. Stockholm: International Foundation for Science. Pp. 138–160.

    Google Scholar 

  2. Cordell, G.A., Beecher, C.W.W., and Pezzuto, J.M. 1991. Can ethnopharmacology contribute to the development of new anticancer drugs? J. Ethnopharmacol. 32: 117–133.

    CAS  Google Scholar 

  3. Duh, C.-Y., Pezzuto, J.M., Kinghorn, A.D., Leung, S.L., and Farnsworth, N.R., 1987. Plant anticancer agents. 44. Cytotoxic constituents from Stizophyllum riparium. J. Nat. Prod. 50: 63–74.

    CAS  Google Scholar 

  4. Choi, Y.-H., Kim, J., Pezzuto, J.M., Kinghorn, A.D., Farnsworth, N.R., Lotter, H., and Wagner, H. 1986. Agrostistachin, a novel cytotoxic macrocyclic diterpene from Agrostistachys hookeri. Tetrahedron Lett. 27: 5795–5798.

    CAS  Google Scholar 

  5. Jayasuriya, H., McChesney, J.D., Swanson, S.M., and Pezzuto, J.M. 1989. Antimicrobial and cytotoxic activity of rottlerin-type compounds from Hypericum drummondii. J. Nat. Prod. 52: 325–331.

    CAS  Google Scholar 

  6. Kigodi, P.G.K., Blasko, G., Thebtaranonth, Y., Pezzuto, J.M., and Cordell, G.A. 1989. A new limonoid from Ayadirachta indica. Spectroscopic and biological investigation of nimbolide and 28-deoxynimbolide. J. Nat. Prod. 52: 1118–1127.

    Google Scholar 

  7. Wong, S.-M., Oshima, Y., Pezzuto, J.M., Fong, H.H.S., and Farnsworth, N.R. 1986. Plant anticancer agents. 39. Triterpenes from Iris missouriensis (Iradaceae). J. Pharm. Sci. 75: 317–320.

    CAS  Google Scholar 

  8. Suffness, S.M. and Pezzuto, J.M. 1991. Assays for Cytotoxicity and Antitumor Activity. In Methods of plant biochemistry, vol. 6, chap. 4, K. Hostettmann, ed. London: Academic Press. Pp. 71–133.

    Google Scholar 

  9. Kafatos, F.C., Jones, C.W., Efstratiadis, A. 1979. Determination of nucleic acid sequence homologies and relative concentrations by a dot hybridization procedure. Nucleic Acids Res. 7: 1541–1552.

    CAS  Google Scholar 

  10. Thomas, P.S. 1980. Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc. Natl. Acad. Sci. U.S.A. 77: 5201–5205.

    CAS  Google Scholar 

  11. Ross, J. 1976. A precursor of globin messenger RNA. J. Mol. Biol. 106: 403–420.

    CAS  Google Scholar 

  12. Chirgwin, J., Przybyla, A., MacDonald, R., and Rutter, W.J. 1979. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18: 5294–5299.

    CAS  Google Scholar 

  13. Cheley, S., and Anderson, R. 1984. A reproducible microanalytical method for the detection of specific RNA sequences by dot-blot hybridization. Anal. Biochem. 137: 15–19.

    CAS  Google Scholar 

  14. Pearse, M.J., and Wu, L. 1988. Preparation of both DNA and RNA for hybridization analysis from limiting quantities of lymphoid cells. Immunol. Lett. 18: 219–224.

    CAS  Google Scholar 

  15. White, B.A., and Bancroft, F.C. 1982. Cytoplasmic dot hybridization. J. Biol. Chem. 257: 8569–8572.

    CAS  Google Scholar 

  16. Bayer, E.A., and Wilchek, M. 1978. The avidin-biotin complex as a tool in molecular biology. Trends Biochem. Sci. 3: N257 - N259.

    CAS  Google Scholar 

  17. Goding, J.W. 1986. The avidin-biotin system. In Monoclonal antibodies: Principles and practice. New York: Academic Press. Pp. 262–266.

    Google Scholar 

  18. Pegg, A.E. 1986. Recent advances in the biochemistry of polyamines in eukaryotes. Biochem. J. 234: 249–262.

    CAS  Google Scholar 

  19. Pegg, A.E. 1988. Polyamine metabolism and its importance in neoplastic growth and as a target for chemotherapy. Cancer Res. 48: 759–774.

    CAS  Google Scholar 

  20. Katz, A., and Kahana, C. 1987. Transcriptional activation of mammalian ornithine decarboxylase during stimulated growth. Mol. Cell. Biol. 7: 2641–2643.

    CAS  Google Scholar 

  21. Feinstein, S.C., Dana, S.L., McConlogue, L., Shooter, E.M., and Coffin, P. 1985. Nerve growth factor rapidly induces ornithine decarboxylase in PC 12 rat pheochromocytoma cells. Proc. Natl. Acad. Sci. U.S.A. 82: 5761–5765.

    CAS  Google Scholar 

  22. Boutwell, R.K., O’Brien, T.G., Verma, A.K., Weekes, R.G., DeYoung, Y.M., Ashendel, C.L., and Astrup, E.G. 1979. The induction of ornithine decarboxylase activity and its control in mouse skin epidermis. Adv. Enz. Reg. 17: 89–112.

    CAS  Google Scholar 

  23. Verma, A.K., and Boutwell, R.K. 1987. Inhibition of carcinogenesis by inhibitors of putrescine biosynthesis. In Inhibition of polyamine metabolism. Biological significance and basis for new therapies, ed. P.P. McCann, A.E. Pegg, and A. Sjoerdsma, eds. Orlando, Fl: Academic Press. Pp. 249–258.

    Google Scholar 

  24. Gilmour, S.K., Avdalovic, N., Madara, T., and O’Brien, T.G. 1985. Induction of ornithine decarboxylase by 12-O-tetradecanoylphorbol-13-acetate in hamster fibroblasts. J. Biol. Chem. 260: 16439–16444.

    CAS  Google Scholar 

  25. Gilmour, S.K., Verma, A.K., Madara, T., O’Brien, T.G. 1987. Regulation of ornithine decarboxylase gene expression in mouse epidermis and epidermal tumors during two-stage tumorigenesis. Cancer Res. 47: 1221–1225.

    CAS  Google Scholar 

  26. Yuspa, S.H., Morgan, D., Lichti, U., Spangler, E.F., Michael, D., Kilkeny, A., and Hennings, H. 1986. Cultivation and characterization of cells derived from mouse skin papillomas induced by an initiation-promotion protocol. Carcinogenesis 7: 949–958.

    CAS  Google Scholar 

  27. Kulesz-Martin, M.F., Koehler, B., Hennings, H., and Yuspa, S.H. 1980. Quantitative assay for carcinogen altered differentiation in mouse epidermal cells. Carcinogenesis 1: 995–1006.

    CAS  Google Scholar 

  28. Hennings, H., Michael, D., Lichti, U., and Yuspa, S.H. 1987. Response of carcinogen-altered mouse epidermal cells to phorbol ester tumor promoters and calcium. J. Invest. Dermatol. 88: 60–65.

    CAS  Google Scholar 

  29. Pegg, A.E., and McCann, P.P. 1982. Polyamine metabolism and function. Am. J. Physiol. 243: C212 - C221.

    CAS  Google Scholar 

  30. Porter, C.W., and Sufrin, J.R. 1986. Interference with polyamine biosynthesis and/or function by analogs of polyamines or methionine as a potential anticancer chemotherapeutic strategy. Anticancer Res. 6: 525–542.

    CAS  Google Scholar 

  31. Klinken, S.P., Castilla, M.J., and Thorgiersson, S.S. 1986. Effect of inhibitors of ornithine decarboxylase on retrovirus induced transformation of murine erythroid precursors in vitro. Cancer Res. 46: 6246–6249.

    CAS  Google Scholar 

  32. Verma, A.K. 1988. Inhibition of tumor promoter 12-O-tetradecanoylphorbol-13acetate-induced synthesis of epidermal ornithine decarboxylase messenger RNA and diacylglycerol-promoter mouse skin tumor formation by retinoic acid. Cancer Res. 48: 2168–2173.

    CAS  Google Scholar 

  33. Maniatis, T., Fritsch, E.F., and Sambrook, J. 1982. Molecular cloning: A laboratory manual. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory.

    Google Scholar 

  34. Hsieh, J.T., and Verma, A.K. 1988. Involvement of protein kinase C in the transcriptional regulation of ornithine decarboxylase gene expression by 12-O-tetradecanoylphorbol-13-acetate in T24 human bladder carcinoma cells. Arch. Biochem. Biophys. 262: 326–336.

    CAS  Google Scholar 

  35. Gilmour, S.K., and O’Brien, T.G. 1989. Regulation of ornithine decarboxylase gene expression in normal and transformed hamster embryo fibroblasts following stimulation by 12-O-tetradecanoylphorbol-13-acetate. Carcinogenesis 10: 157–162.

    CAS  Google Scholar 

  36. Seely, J.E., Poso, H., and Pegg, A.E. 1982. Effect of androgens on turnover of ornithine decarboxylase in mouse kidney. J. Biol. Chem. 257: 7549–7553.

    CAS  Google Scholar 

  37. Greenberg, M.E., and Ziff, E.B. 1984. Stimulation of 3T3 cells induces transcription of the c-fos protooncogene. Nature (London) 311: 433–437.

    CAS  Google Scholar 

  38. Chinsky, J.M., Maa, M.-C., Ramamurthy, V., and Kellems, R.E. 1989. Adenosine deaminase gene expression. Tissue-dependent regulation of transcriptional elongation. J. Biol. Chem. 264: 14561–14565.

    CAS  Google Scholar 

  39. Hunter, T. 1984. The proteins of oncogenes. Sci. Am. 251: 70–79.

    CAS  Google Scholar 

  40. Weinberg, R.A. 1985. The action of oncogenes in the cytoplasm and nucleus. Science 230: 770–776.

    CAS  Google Scholar 

  41. Uehara, Y., Murakami, Y., Suzukake-Tsuchiya, K., Moriya, Y., Sano, H., Shibata, K., and Omura, S. 1988. Effects of herbimycin derivatives on src oncogene function in relation to antitumor activity. J. Antibiot. 41: 831–834.

    CAS  Google Scholar 

  42. King, C.R., Kraus, M.H., and Aaronson, S.A. 1985. Amplification of a novel verbB-related gene in a human mammary carcinoma. Science 229: 974–978.

    CAS  Google Scholar 

  43. Tanaka, T., Slamon, D.J., Battifora, H., and Cline, M.J. 1986. Expression of p21 ras oncoproteins in human cancers. Cancer Res. 46: 1465–1470.

    CAS  Google Scholar 

  44. Kung, H.-S., Smith, M.R., Bekisi, E., Manne, V., and Stacey, D.W. 1986. Reversal of transformed phenotype by monoclonal antibodies against Ha-ras p21 proteins. Exp. Cell Res. 162: 363–371.

    CAS  Google Scholar 

  45. de Klein, A., van Kessel, A.G. Grosveld, G., Bartram, C.R., Hagemeijer, A., Bootsma, D., Spurr, N.K., Heisterkamp, N., Groffen, J., and Stephenson, J.R. 1982. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature (London) 300: 765–767.

    Google Scholar 

  46. Leder, A., Pattengale, P.K., Kuo, A., Stewart, T.A., and Leder, P. 1986. Consequences of widespread deregulation of the c-myc gene in transgenic mice: Multiple neoplasms and normal development. Cell 45: 485–495.

    CAS  Google Scholar 

  47. Maguire, H.C., Jr., and Greene, M.I. 1989. The neu (c-erb B-2) oncogene. Sem. Oncol. 16: 148–155.

    CAS  Google Scholar 

  48. Huber, B.E. 1989. Therapeutic opportunities involving cellular oncogenes: Novel approaches fostered by biotechnology. FASEB J. 3: 5–13.

    CAS  Google Scholar 

  49. Laemmli, U.K. 1970. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature (London): 227: 680–685.

    CAS  Google Scholar 

  50. Towbin, H., Staehelin, T., and Gordon, J. 1979. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: Procedure and some applications. Proc. Natl. Acad. Sci. U.S.A. 76: 4350–4354.

    CAS  Google Scholar 

  51. Seshradri, T., and Campisi, J. 1990. Repression of c-fos transcription and an altered genetic program in senescent human fibroblasts. Science 247: 205–259.

    Google Scholar 

  52. Thiele, C.J., Cohen, P.S., and Israel, M.A. 1988. Regulation of c-myb expression in human neuroblastoma cells during retinoic acid-induced differentiation. Mol. Cell. Biol. 8: 1677–1683.

    CAS  Google Scholar 

  53. Linevsky, J., Cohen, M.B., Hartman, K.D., Knode, M.C., and Glazer, R.I. 1985. Effect of Neplanocin A on differentiation, nucleic acid methylation, and c-myc mRNA expression in human promyelocytic leukemia cells. Mol. Pharmacol. 28: 45–50.

    CAS  Google Scholar 

  54. Hunter, T., and Cooper, J.A. 1985. Protein-tyrosine kinases. Annu. Rev. Biochem. 54: 897–930.

    CAS  Google Scholar 

  55. Hunter, T. 1987. A thousand and one protein kinases. Cell 50: 823–829.

    CAS  Google Scholar 

  56. Zioncheck, T.F., Harrison, M.L., and Gaehlen, R.L. 1986. Purification and characterization of a protein-tyrosine kinase from bovine thymus. J. Biol. Chem. 261: 15637–15643.

    CAS  Google Scholar 

  57. Geahlen, R.L., Koonchanok, N.M., and McLaughlin, J.L. 1989. Inhibition of protein-tyrosine kinase activity by flavonoids and related compounds. J. Nat. Prod. 52: 982–986.

    CAS  Google Scholar 

  58. O’Farrell, P.H. 1975. High resolution two-dimensional electrophoresis of proteins. J. Biol. Chem. 250: 4007–4021.

    Google Scholar 

  59. Freshney, R.I. 1987. The transformed phenotype. In Culture of animal cells. New York: Alan R. Liss. Pp. 197–206.

    Google Scholar 

  60. Volm, M., Wayss, K., Kaufmann, M., and Mattern, J. 1979 Pretherapeutic detection of tumour resistance and the results of tumour chemotherapy. Eur. J. Cancer 15: 983–993.

    CAS  Google Scholar 

  61. Swanson, S.M., and Pezzuto, J.M. 1990. Bioscreening for antitumor activity: Evaluation of cytotoxic potential and ability to inhibit macromolecule biosynthesis. In Drug bioscreening, Drug evaluation techniques in pharmacology, E.B. Thompson, ed. New York: VCH. Pp. 273–397.

    Google Scholar 

  62. Twardzik, D.R. 1985. Differential expression of transforming growth factor alpha during prenatal development of the mouse. Cancer Res. 45: 5413–5416.

    CAS  Google Scholar 

  63. Cuthbertson, R.A., and Klintworth, G.K. 1988. Transgenic mice-A gold mine for furthering knowledge in pathobiology. Lab. Invest. 58: 484–502.

    CAS  Google Scholar 

  64. Southern, E.M. 1975. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J. Mol. Biol. 98: 503–517.

    CAS  Google Scholar 

  65. Andres, A.-C., Schonenberger, C.-A., Groner, B., Henninghausen, L., LeMeur, M., and Gerlinger, P. 1987. Ha-ras oncogene expression directed by a milk protein gene promoter: Tissue specificity, hormonal regulation, and tumor induction in transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 84: 1299–1303.

    CAS  Google Scholar 

  66. Ezzell, C. 1988. First ever animal patent issued in United States. Nature (London) 332: 668.

    Google Scholar 

  67. Holt, J.T., Gopal, T.V., Moulton, A.D., and Nienhuis, A.W. 1986. Inducible production of c-fos antisense RNA inhibits 3T3 cell proliferation. Proc. Natl. Acad. Sci. U.S.A. 83: 4794–4798.

    CAS  Google Scholar 

  68. Nishikura, K., and Murray, J.M. 1987. Antisense RNA of proto-oncogene c-fos blocks renewed growth of quiescent 3T3 cells. Mol. Cell. Biol. 7: 639–649.

    CAS  Google Scholar 

  69. Chambers, A.F., and Denhardt, D.T. 1990. Abatement of gene expression using antisense oligodeoxynucleotides. Pharmaceut. Technol. February: 24–28.

    Google Scholar 

  70. Gorman, C.M., Moffat, L.F., and Howard, B.H. 1982. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol. Cell. Biol. 2: 1044–1051.

    CAS  Google Scholar 

  71. de Wet, J.R., Wood, K.V., DeLuca, M., Helinski, D.R., and Subramani, S. 1987. Firefly luciferase gene: Structure and expression in mammalian cells. Mol. Cell. Biol. 7: 725–737.

    Google Scholar 

  72. Hudson, L.G., Ertl, A.P., Gill, G.N. 1990. Structure and inducible regulation of the human c-erb B2/neu promoter. J. Biol. Chem. 265: 4389–4393.

    CAS  Google Scholar 

  73. Bargmann, C.I., and Weinberg, R.A. 1988. Increased tyrosine kinase activity associated with the protein encoded by the activated neu oncogene. Proc. Natl. Acad. Sci. U.S.A. 85: 5394–5398.

    CAS  Google Scholar 

  74. Evans, R.M. 1988. The steroid and thyroid hormone receptor superfamily. Science 240: 889–895.

    CAS  Google Scholar 

  75. Thompson, C.C., and Evans, R.M. 1989. Transactivation by thyroid hormone receptors: Functional parallels with steroid hormone receptors. Proc. Natl. Acad. Sci. U.S.A. 86: 3494–3498.

    CAS  Google Scholar 

  76. Hard, T., Kellenbach, E., Boelens, R., Maler, B.A., Dahlman, K., Freedman, L.P., Carlstedt-Duke, J., Yamamoto, K.R., Gustafsson, J.-A., and Kaptein, R. 1990. Solution structure of the glucocorticoid receptor DNA-binding domain. Science 249: 157–160.

    CAS  Google Scholar 

  77. Giguere, V., Ong, E.S., Segui, P., and Evans, R.M. 1987. Identification of a receptor for the morphogen retinoic acid. Nature (London) 330: 624–629.

    CAS  Google Scholar 

  78. Evans, R.M. 1989. The v-erbA oncogene is a thyroid hormone receptor antagonist. Int. J. Cancer. 4: suppl. 26–28.

    Google Scholar 

  79. Umesono, K., and Evans, R.M. 1989. Determinants of target gene specificity for steroid/thyroid hormone receptors. Cell 57: 1139–1146.

    CAS  Google Scholar 

  80. Damm, K., Thompson, C.C., and Evans, R.M. 1989. Protein encoded by v-erbA functions as a thyroid-hormone receptor antagonist. Nature (London) 339: 593–597.

    CAS  Google Scholar 

  81. Muller, W.E.G., Okamoto, T., Reuter, P., Ugarkovic, D., and Schroder, H.C. 1990. Functional characterization of Tat protein from human immunodeficiency virus. J. Biol. Chem. 265: 3803–3808.

    CAS  Google Scholar 

  82. Nelbock, P., Dillon, P.J., Perkins, A., and Rosen, C.A. 1990. A cDNA for a protein that interacts with the human immunodeficiency virus Tat transactivator. Science 248: 1650–1653.

    CAS  Google Scholar 

  83. Krogstad, D.J., Schlesinger, P.H., Herwaldt, B.L. 1988. Antimalarial agents: Mechanism of chloroquine resistance. Antimicrob Agents Chemother. 32: 799–801.

    CAS  Google Scholar 

  84. Fuqua, S.A.W., Moretti-Rojas, I.M., Schneider, S.L., and McGuire, W.L. 1987. P-Glycoprotein expression in human breast cancer cells. Cancer Res. 47: 2103–2106.

    CAS  Google Scholar 

  85. Bradley, G., Juranka, P.F., and Ling, V. 1988. Mechanism of multidrug resistance. Biochim Biophys. Acta 948: 87–128.

    CAS  Google Scholar 

  86. Gottesman, M.M., and Pastan, I. 1988. Resistance to multiple chemotherapeutic agents in human cancer cells. Trends Pharm. Sci. 9: 54–58.

    CAS  Google Scholar 

  87. Kartner, N., and Ling, V. 1989. Multidrug resistance in cancer. Sci. Am. 260: 44–51

    CAS  Google Scholar 

  88. Thiebaut, F., Tsuruo, T., Hamada, H., Gottesman, M.M., Pastan, I., and Willingham, M.C. 1987. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc. Natl. Acad. Sci. U.S.A. 84: 7735–7738.

    CAS  Google Scholar 

  89. Cornwell, M.M., Safa, A.R., Felsted, R.L., Gottesman, M.M., and Pastan, I. 1986. Membrane vesicles from multidrug-resistant human cancer cells contain a specific 150- to 170-kDa protein detected by photoaffinity labeling. Proc. Natl. Acad. Sci. U.S.A. 83: 3847–3850.

    CAS  Google Scholar 

  90. Juliano, R.L., and Ling, V. 1976. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochem. Biophys. Acta 455: 152–162.

    CAS  Google Scholar 

  91. Kartner, N., Riordan, J.R., and Ling, V. 1983. Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science 221: 1285–1288.

    CAS  Google Scholar 

  92. Ueda, K., Cornwell, M.M., Gottesman, M.M., Pastan, I., Roninson, I.B., Ling, V., and Riordan, J.R. 1986. The mdr 1 gene, responsible for multi-drug resistance, codes for P-glycoprotein. Biochem. Biophys. Res. Commun. 141: 956–962.

    CAS  Google Scholar 

  93. Fojo, A., Akiyama, S., Gottesman, M.M., and Pastan, I. 1985. Reduced drug accumulation in multiply drug-resistant human KB carcinoma cell lines. Cancer Res. 45: 3002–3007.

    CAS  Google Scholar 

  94. Beck. W.T., Cirtain, M.C., and Lefko, J.L. 1983. Energy-dependent reduced drug binding as a mechanism of Vinca alkaloid resistance in human leukemic lymphoblasts. Mol. Pharmacol. 24: 485–492.

    Google Scholar 

  95. Cornwell, M.M., Tsuruo, T., Gottesman, M.M., and Pastan, I. 1987. ATP-binding properties of P-glycoprotein from multidrug-resistant KB cells. FASEB J. 1: 51–54.

    CAS  Google Scholar 

  96. Horio, M., Gottesman, M.M., and Pastan, I. 1988. ATP-dependent transport of vinblastine in vesicles from human multidrug-resistant cells. Proc. Natl. Acad. Sci. U.S.A. 85: 3580–3584.

    CAS  Google Scholar 

  97. Deuchars, K.L., and Ling, V. 1989. P-Glycoprotein and multidrug resistance in cancer chemotherapy. Sem. Oncol. 16: 156–165.

    CAS  Google Scholar 

  98. Deuchars, K.L., Du, R.-P., Naik, M., Evernden-Porelle, D., Kanner, N., van der Bliek, A.M., and Ling, V. 1987. Expression of hamster P-glycoprotein and multi-drug resistance in DNA-mediated transformants of mouse LTA cells. Mol. Cell. Biol. 7: 718–724.

    CAS  Google Scholar 

  99. Sugimoto, Y., and Tsuruo, T. 1987. DNA-mediated transfer and cloning of a human multidrug-resistant gene of adriamycin-resistant myelogenous leukemia K562. Cancer Res. 47: 2620–2625.

    CAS  Google Scholar 

  100. Ueda, K., Cardarelli, C., Gottesman, M.M., and Pastan, I. 1987. Expression of a full-length cDNA for the human “MDR1” gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc. Natl. Acad. Sci. U.S.A. 84: 3004–3008.

    CAS  Google Scholar 

  101. Gros, P., Neriah, Y.B., Croop, J.M., and Housman, D.E. 1986. Isolation and expression of a complementary DNA that confers multidrug resistance. Nature (London) 323: 728–731.

    CAS  Google Scholar 

  102. Shen, D.-W., Fojo, A., Roninson, LB., Chin, J.E., Siffir, R., Pastan, I., and Gottesman, M.M. 1986. Multidrug resistance of DNA-mediated transformants is linked to transfer of the human mdrl gene. Mol. Cell. Biol. 6: 4039–4044.

    CAS  Google Scholar 

  103. Gros, P., Fallows, D.A., Croop, J.M., and Housman, D.E. 1986. Chromosome-mediated gene transfer of multidrug resistance. Mol. Cell. Biol. 6: 3785–3790.

    CAS  Google Scholar 

  104. Goldstein, L.J., Galski, H., Fojo, A., Willingham, M., Lai, S.-L., Gazdar, A., Pirkir, R., Green, A. Crist, W., Brodeur, G.M., Lieber, M., Cossman, J., Gottesman, M.M., and Pastan, I. 1989. Expression of a multidrug resistance gene in human cancers. J. Natl. Cancer Inst. 81: 116–124.

    CAS  Google Scholar 

  105. Cano-Gauci, D.F., and Riordan, J.R. 1987. Action of calcium antagonists on multidrug resistant cells. Specific cytotoxicity independent of increased cancer drug accumulation. Biochem. Pharmacol. 36: 2115–2123.

    CAS  Google Scholar 

  106. Tsuruo, T., lida, H., Tsukagoshi, S., and Sakurai, Y. 1982. Increased accumulation of vincristine and adriamycin in drug-resistant P388 tumor cells following incubation with calcium antagonists and calmodulin inhibitors. Cancer Res. 42: 4730–4703.

    CAS  Google Scholar 

  107. Tsuruo, T., and lida, H. 1986. Effects of cytochalasins and colchicine on the accumulation and retention of daunomycin and vincristine in drug resistant tumor cells. Biochem. Pharmacol. 35: 1087–1090.

    CAS  Google Scholar 

  108. Zamora, J.M., and Beck, W.T. 1986. Chloroquine enhancement of anticancer drug cytotoxicity in multiple drug resistant human leukemia cells. Biochem. Pharmacol. 35: 4303–4310.

    CAS  Google Scholar 

  109. Krogstad, D.J., Gluzman, I.Y., Kyle, D.E., Oduola, A.M.J., Martin, S.K., Milhous, W.K., and Schlesinger, P.H. 1987. Efflux of chloroquine from Plasmodium falciparum: Mechanism of chloroquine resistance. Science 238: 1283–1285.

    CAS  Google Scholar 

  110. Bellamy, W.T., Dalton, W.S., Kailey, J.M., Gleason, M.C., McCloskey, T.M., Don, R.T., and Alberts, D.S. 1988. Verapamil reversal of doxorubicin resistance in multidrug-resistant human myeloma cells and association with drug accumulation and DNA damage. Cancer Res. 48: 6303–6308.

    Google Scholar 

  111. Inaba, M., Kobayashi, H., Sakurai, Y., and Johnson, R.K. 1979. Active efflux of daunorubicin and adriamycin in sensitive and resistant sublines of P388 leukemia. Cancer Res. 39: 2200–2203.

    CAS  Google Scholar 

  112. Tapiero, H., Munck, J.-N., Fourcade, A., and Lampidis, T.J. 1984. Cross-resistance to rhodamine 123 in adriamycin-and daunorubicin-resistant Friend leukemia cell variants. Cancer Res. 44: 5544–5549.

    CAS  Google Scholar 

  113. Munck, J.-N., Fourcade, A., Bennoum, M., and Tapiero, H. 1985. Relationship between the intracellular level and growth inhibition of a new anthracycline 4’-Otetrahydropyranyl-adriamycin in Friend leukemia cell variants. Leukemia Res. 9: 289–296.

    CAS  Google Scholar 

  114. Neyfakh, A.A. 1988. Use of fluorescent dyes as molecular probes for the study of multidrug resistance. Exp. Cell. Res. 174: 168–176.

    CAS  Google Scholar 

  115. Lalande, M.E., Ling, V., and Miller, R.G. 1981. Hoechst 33342 dye uptake as a probe of membrane permeability changes in mammalian cells. Proc. Natl. Acad. Sci. U.S.A. 78: 363–367.

    CAS  Google Scholar 

  116. Neyfakh, A.A., Dmitrevskaya, T.V., and Serpinskaya, A.S. 1988. The membrane transport system responsible for multidrug resistance is operating in nonresistant cells. Exp. Cell. Res. 178: 513–517.

    CAS  Google Scholar 

  117. Akiyama, S.-I., Cornwell, M.M., Kuwano, M., Pastan, I., and Gottesman, M.M. 1988. Most drugs that reverse multidrug resistance also inhibit photoaffinity labeling of P-glycoprotein by a vinblastine analog. Mol. Pharmacol. 33: 144–147.

    CAS  Google Scholar 

  118. Safa, A.R. 1988. Photoaffinity labeling of the multidrug-resistance-related P-glycoprotein with photoactive analogs of verapamil. Proc. Natl. Acad. Sci. U.S.A. 85: 7187–7191.

    CAS  Google Scholar 

  119. Shen, D., Cardarelli, C., Hwang, J., Cornwell, M., Richert, N., Ishii, S., Pastan, I., and Gottesman, M.M. 1986. 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.

    CAS  Google Scholar 

  120. Greenberger, L.M., Williams, S.S., Georges, E., Ling, V., and Band-Horwitz, S. 1988. Electrophoretic analysis of P-glycoproteins produced by mouse J774.2 and Chinese Hamster Ovary multidrug-resistant cells. J. Natl. Cancer Inst. 80: 506–510.

    CAS  Google Scholar 

  121. Kartner, N., Evernden-Porelle, D., Bradley, G., and Ling, V. 1985. Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies. Nature (London) 316: 820–823.

    CAS  Google Scholar 

  122. Beck, W.T. 1983. Vinca alkaloid resistant phenotype in cultured human leukemia lymphoblasts. Cancer Treat. Rep. 67: 875–881.

    CAS  Google Scholar 

  123. Danks, M.K., Metzger, D.W., Ashmun, R.A., and Beck, W.T. 1985. Monoclonal antibodies to glycoproteins of Vinca alkaloid-resistant human leukemic cells. Cancer Res. 45: 3220–3224.

    CAS  Google Scholar 

  124. Volm, M., Efferth, T., and Lathan, B. 1987. Detection of murine SI80 cells expressing a multidrug resistance phenotype using different in vitro test systems and a monoclonal antibody. Arzneim-Forsch. 37 (2): 862–867.

    CAS  Google Scholar 

  125. Fojo, A.T., Uead, K., Slamon, D.J., Poplack, D.J., Gottesman, M.M., and Pastan, I. 1987. Expression of a multidrug-resistance gene in human tumors and tissues. Proc. Natl. Acad. Sci. U.S.A. 84: 265–269.

    CAS  Google Scholar 

  126. Hitchins, R.N., Harman, D.H., Davey, R.A., and Bell, D.R. 1988. Identification of a multidrug-resistance associated antigen (P-glycoprotein) in normal human tissues. Eur. J. Cancer Clin. Oncol. 24: 449–454.

    CAS  Google Scholar 

  127. Biedler, J.L., Riehm, H., Peterson, R.H.F., and Spengler, B.A. 1975. Membrane-mediated drug resistance and phenotypic reversion to normal growth behavior of Chinese Hamster Cells. J. Natl. Cancer Inst. 55: 671–677.

    CAS  Google Scholar 

  128. Bates, S.E., Mickley, L.A., Chen, Y.-N., Richert, N., Rudick, J., Biedler, J., and Fojo, A.T. 1989. Expression of a drug resistance gene in human neuroblastoma cell lines: Modulation by retinoic acid-induced differentiation. Mol. Cell. Biol. 9: 4337–4344.

    CAS  Google Scholar 

  129. Mickley, L.A., Bates, S.E., Richert, N.D., Currier, S., Tanaka, S., Foss, F., Rosen, N., and Fojo, A.T. 1989. Modulation of the expression of a multidrug resistance gene (mdr-1/P-glycoprotein) by differentiating agents. J. Biol. Chem. 264: 18031–18040.

    CAS  Google Scholar 

  130. Bell, D.R., Gerlack, J.H., Kartner, N., Buick, R.N., and Ling, V. 1985. Detection of p-glycoprotein in ovarian cancer: A molecular marker associated with multidrug resistance. J. Clin. Oncol. 3: 311–315.

    CAS  Google Scholar 

  131. Beck, W.T. 1987. The cell biology of multiple drug resistance. Biochem. Pharmacol. 36: 2879–2887.

    CAS  Google Scholar 

  132. Richert, N., Akiyama, S., Shen, D., Gottesman, M.M., and Pastan, I. 1985. Multiply drug-resistant human KB carcinoma cells have decreased amounts of a 75 kDa and a 72 kDa glycoprotein. Proc. Natl. Acad. Sci. U.S.A. 82: 2330–2333.

    CAS  Google Scholar 

  133. van der Bliek, A.M., van der Velde-Koerts, T., Ling, V., and Borst, P. 1986. Overexpression and amplification of five genes in a multidrug-resistant Chinese Hamster Ovary cell line. Mol. Cell. Biol. 6: 1671–1678.

    Google Scholar 

  134. Akiyama, S., Fojo, A., Hanover, J.A., Pastan, I., and Gottesman, M.M. 1985. Isolation and genetic characterization of human KB cell lines resistant to multiple drugs. Som. Cell. Mol. Gen. 11: 117–126.

    CAS  Google Scholar 

  135. Hu, J.M., and Hsuing, G.D. 1989. Evaluation of new antiviral agents. 1. In vitro perspectives. Antiviral Res. 11: 217–232.

    Google Scholar 

  136. Field, A.K., Davis, M.E., DeWitt, C.M., Perry, H.C., Schofield, T.L., Karkas, J.D., Germershausen, J., Wagner, A.F., Cantone, C.L., MacCoss, M., and Tolman, R.L. 1986. Efficacy of 2’-nor-cyclic GMP in treatment of experimental herpes virus infections. Antiviral Res. 6: 329–341.

    CAS  Google Scholar 

  137. Hu, J.M., and Hsuing, G.D. 1988. Studies on two new antiviral agents against guinea pig lymphotropic herpesvirus infection in vitro (abstract). Antiviral Res. 9: 83.

    Google Scholar 

  138. Collins, P., and Bauer, D.J. 1977. Relative potencies of anti-herpes compounds. Ann. N.Y. Acad. Sci. 284: 49–59.

    CAS  Google Scholar 

  139. Harada, S., Koyanagi, Y., and Yamamoto, N. 1985. Infection of HTLV-III/LAV in HTLV-1-carrying cell MT-2 and MT-4 and application in a plaque assay. Science 229: 563–566.

    CAS  Google Scholar 

  140. Nakashima, H., Matsui, T., Harada, S., Kobayashi, N., Matsuda, A., Ueda, T., and Yamamoto, N. 1986. Inhibition of replication and cytopathic effect of human T-cell lymphotropic virus type III/ lymphadenopathy-associated virus by 3’-deoxythymidine in vitro. Antimicrob. Agents Chemother. 30: 933–937.

    CAS  Google Scholar 

  141. Montefiore, D.C., Robinson, W.E., Jr., Schuffman, S.S., and Mitchell, W.M. 1988. Evaluation of antiviral drugs and neutralizing antibodies to human immunodeficiency virus by a rapid and sensitive microliter infection assay. J. Clin. Microbiol. 26: 231–235.

    Google Scholar 

  142. Abou-Karam, M., and Shier, W.T. 1990. A simplified plaque reduction assay for antiviral agents from plants. Demonstration of frequent occurrence of antiviral activity in higher plants. J. Nat. Prod. 53: 340–344.

    CAS  Google Scholar 

  143. Pauwels, R., Balzarini, J., Baba, M., Snoeck, R., Schols, D., Herdewijn, P., Desmyter, J., and DeClerq, E. 1988. Rapid and automated tetrazolium-based colori-metric assay for the detection of anti-HIV compounds. J. Virol. Methods 20: 309–321.

    CAS  Google Scholar 

  144. Vince, R., Hua, M., Brownell, J., Daluge, S., Lee, F., Shannon, W.M., Lavelle, G.C. Qualls, J., Weislow, O.S., Kiser, R., Canonico, P.G., Schultz, R.H., Narayanan, V.L., Mayo, J.G., Shoemaker, R.H., and Boyd, M.R. 1988. Potent and selective activity of a new carbocyclic nucleoside analog (Carbovir: NSC 614846) against human immunodeficiency virus in vitro. Biochem. Biophys. Res. Commun. 156: 1046–1053.

    CAS  Google Scholar 

  145. Weislow, O.S., Kiser, R., Fine, D.L., Bader, J., Shoemaker, R.H., and Boyd, M.R. 1989. New soluble-formazan assay for HIV-1 cytopathic effects: Application

    Google Scholar 

  146. to high-flux screening of synthetic and natural products for AIDS-antiviral activity. J. Natl. Cancer Inst. 81:577–586.

    Google Scholar 

  147. Paull, K.D., Shoemaker, R.H., Boyd, M.R., Parsons, J.L., Risbood, P.A., Barbera, W.A., Sharma, M.N., Baker, D.C., Hand, E., Scudiero, D.A., Monks, A., Alley, M.C., and Grote, M. 1988. The synthesis of XTT-A new tetrazolium reagent that is bioreducible to a water-soluble formazan. J. Heterocyclic Chem. 25: 911–914.

    CAS  Google Scholar 

  148. Goodchild, J., Agrawal, S., Civeira, M.P., Sarin, P.S., Sun, D., and Zamecnik, P.C. 1988. Inhibition of human immunodeficiency virus replication by antisense oligodeoxynucleotides. Proc. Natl. Acad. Sci. U.S.A. 85: 5507–5511.

    CAS  Google Scholar 

  149. Sarin, P.S., Agrawal, S., Civeira, M.P., Goodchild, J., Ikeuchi, T., and Zamecnik, P.C. 1988. Inhibition of acquired immunodeficiency syndrome virus by oligodeoxynucleoside methylphosphonates. Proc. Natl. Acad. Sci. U.S.A. 85: 7448–7451.

    CAS  Google Scholar 

  150. Mitsuya, H., Popovic, M., Yarchoan, R., Matsushita, S., Gallo, R., and Broder, S. 1984. Suramin protection of T cells in vitro against infectivity and cytopathic effect of HTLV-III. Science 226: 172–174.

    CAS  Google Scholar 

  151. DeClercq, E. 1986. Chemotherapeutic approaches to the treatment of the acquired immune deficiency syndrome (AIDS). J. Med. Chem. 29: 1561–1569.

    CAS  Google Scholar 

  152. Spedding, G., Ratty, A., and Middleton, E., Jr. 1989. Inhibition of reverse transcriptases by flavonoids. Antiviral Res. 12: 99–110.

    CAS  Google Scholar 

  153. Tan, G.T., Pezzuto, J.M. Kinghorn, A.D., and Hughes, S.H. 1991. Evaluation of natural products as inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. J. Nat. Prod. 54: 143–154.

    CAS  Google Scholar 

  154. Hizi, A., McGill, C., and Hughes, S.H. 1988. Expression of soluble, enzymatically active, human immunodeficiency virus reverse transcriptase in Escherichia coli and analysis of mutants. Proc. Natl. Acad. Sci. U.S.A. 85: 1218–1222.

    CAS  Google Scholar 

  155. Clark, P.K., Ferris, A.L., Miller, D.A., Hizi, A., Kim, K.-W., Deringer-Boyer, S.M., Mellini, M.L., Clark, A.D., Jr., Arnold, G.F., Lebherz, W.B., III, Arnold, E., Muschik, G.M., and Hughes, S.H. 1990. HIV-1 reverse transcriptase purified from a recombinant strain of Escherichia coli. AIDS Res. Hum. Retroviruses 6: 753–761

    CAS  Google Scholar 

  156. Schinazi, R.F., Erikkson, B.F.H., and Hughes, S.H. 1989. Comparison of inhibitory activities of various antiretroviral agents against particle-derived and recombinant human immunodeficiency virus type 1 reverse transcriptases. Antimicrob. Agents Chemother. 33: 115–117.

    CAS  Google Scholar 

  157. Lifson, J.D., and Engleman, E.G. 1989. Role of CD4 in normal immunity and HIV infection. Immunol. Rev. 109: 93–117.

    CAS  Google Scholar 

  158. Sperber, S.J., and Hayden, F.G. 1989. Protective effect of rhinovirus receptor blocking antibody in human fibroblast cells. Antiviral Res. 12: 231–238.

    CAS  Google Scholar 

  159. Krausslich, H.-G., and Wimmer, E. 1988. Viral proteinases. Annu. Rev. Biochem. 57: 701–754.

    CAS  Google Scholar 

  160. Orr, D.C., Long, A.C., Kay, J., Dunn, B.M., and Cameron, J.M. 1989. Hydrolysis of a series of synthetic peptide substrates by the human rhinovirus 14 3C proteinase, cloned and expressed in Escherichia coli. J. Gen. Virol. 70: 2931–2942.

    CAS  Google Scholar 

  161. Long, A.C., Orr, D.C., Cameron, J.M., Dunn, B.M., and Kay, J. 1989. A consensus sequence for substrate hydrolysis by rhinovirus 3C proteinase. FEBS Lett. 235: 75–78.

    Google Scholar 

  162. Sainsbury, J.R.C., Sherbet, G.V., Farndon, J.R., and Harris, A.L. 1985. Epidermal-growth-factor receptors and oestrogen receptors in human breast cancer. Lancet 16: 364–368.

    Google Scholar 

  163. Schusdziarra, V., Rewes, B., Lenz, N., Maier, V., and Pfeiffer, E.F. 1983. Carbohydrates modulate opiate receptor mediated mechanisms during postprandial endocrine function. Regul. Peptides 7: 243–252.

    CAS  Google Scholar 

  164. Ulmann, A., Teutsch, G., and Philibert, D. 1990. RU 486. Sci. Am. 262: 42–48.

    Google Scholar 

  165. Waldmann, T.A. 1986. The structure, function, and expression of interleukin-2 receptors on normal and malignant lymphocytes. Science 232: 727–732.

    CAS  Google Scholar 

  166. Weite, K., and Mertelsmann, R. 1985. Human interleukin-2: Biochemistry, physiology, and possible pathogenic role in immunodeficiency syndromes. Cancer Invest. 3: 35–49.

    Google Scholar 

  167. Sutherland, E.W. 1972. Studies on the mechanism of hormone action. Science 177: 401–408.

    CAS  Google Scholar 

  168. Darnell, L., Lodish, H., and Baltimore, D. 1986. Cell-to-cell signalling: Hormones and receptors. Molecular cell biology. New York: Scientific American Books. Pp. 667–713.

    Google Scholar 

  169. Nishizuka, Y. 1984. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature (London) 308: 693–697.

    CAS  Google Scholar 

  170. Nishizuka, Y. 1988. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature (London) 334: 661–665.

    CAS  Google Scholar 

  171. Dreher, M.L., and Hanley, M.R. 1988. Multiple modes of protein kinase C regulation and their significance in signalling. Trends Pharm. Sci. 9: 114–115.

    CAS  Google Scholar 

  172. Parker, P.J., Coussens, L., Totty, N., Rhee, L., Young, S., Chen, E., Stahel, S., Waterfield, M.D., and Ullrich, A. 1986. The complete primary structure of protein kinase C-the major phorbol ester receptor. Science 233: 853–859.

    CAS  Google Scholar 

  173. Castagna, M., Takai, Y., Kaibuchi, K., Sano, K., Kikkawa, U., and Nishizuka, Y. 1982. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J. Biol. Chem. 257: 7847–7851.

    CAS  Google Scholar 

  174. Nakadate, T., Jeng, A.Y., and Blumberg, P.M. 1988. Comparison of protein kinase C functional assays to clarify mechanisms of inhibitor action. Biochem. Pharmacol. 37: 1541–1545.

    CAS  Google Scholar 

  175. Leach, K.L., and Blumberg, P.M. 1985. Modulation of protein kinase C activity and [3H]phorbol 12,13-dibutyrate binding by various tumor promoters in mouse brain cytosol. Cancer Res. 45: 1958–1963.

    CAS  Google Scholar 

  176. de Vries, D.J., Herald, C.L., Pettit, G.R., and Blumberg, P.M. 1988. Demonstration of subnanomolar affinity of bryostatin 1 for the phorbol ester receptor in rat brain. Biochem. Pharmacol. 37: 4069–4073.

    Google Scholar 

  177. Beutler, J.A., Alvarado, A.B., McCloud, T.G., and Cragg, G.M. 1989. Distribution of phorbol ester bioactivity in the Euphorbiaceae. Phytother. Res. 3: 188–192.

    CAS  Google Scholar 

  178. Foon, K.A. 1989. Biological response modifiers: The new immunotherapy. Cancer Res. 49: 1621–1639.

    CAS  Google Scholar 

  179. Zullo, J.N., and Faller, D. V. 1988. P21 V-ras inhibits induction of c-myc and c-fos expression by platelet-derived growth factor. Mol. Cell. Biol. 8: 5080–5085.

    CAS  Google Scholar 

  180. Pantazis, P., Pelicci, P.G., Dalla-Favera, R., and Antoniades, H.N. 1985. Synthesis and secretion of proteins resembling platelet-derived growth factor by human glioblastoma and fibrosarcoma cells in culture. Proc. Natl. Acad. Sci. U.S.A. 82: 2404–2408.

    CAS  Google Scholar 

  181. Schecter, A.L., Stern, D.F., Vaidyanathan, L., Decker, S.J., Drebin, J.A., Greene, M.I., and Weinberg, R.A. 1984. The neu oncogene: An erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature (London) 312: 513–516.

    Google Scholar 

  182. Muller, R., Bravo, R., Burckhardt, J., and Curren, T. 1984. Induction of c-fos gene and protein by growth factors precedes activation of c-myc. Nature (London) 312: 716–720.

    CAS  Google Scholar 

  183. Chang, R.S.L., and Lotti, V.J. 1986. Biochemical and pharmacological characterization of an extremely potent and selective non-peptide cholecystokinin antagonist. Proc. Natl. Acad. Sci. U.S.A. 83: 4923–4926.

    CAS  Google Scholar 

  184. Gregory, H. 1975. Isolation and structure of urogastrone and its relationship to epidermal growth factor. Nature (London) 257: 325–327.

    CAS  Google Scholar 

  185. Lamers, C.B.H.W., and Jansen, J.B.M.J. 1988. Role of gastrin and cholecystokinin in tumors of the gastrointestinal tract. Eur. J. Cancer Clin. Oncol. 24: 267–273.

    CAS  Google Scholar 

  186. Beauchamp, R.D., Townsend, C.M., Jr., Singh, P., Glass, E.J., and Thompson, J.C. 1985. Proglumide, a gastrin receptor antagonist, inhibits growth of colon cancer and enhances survival in mice. Ann. Surg. 202: 303–308.

    CAS  Google Scholar 

  187. Magous, R., and Bali, J.P. 1983. Evidence that proglumide and benzotript antagonize secretogogue stimulation of isolated gastric parietal cells. Reg. Peptides 7: 233–241.

    CAS  Google Scholar 

  188. Wong, R.S., and Passar, E. Jr. 1989. Growth factors, oncogenes and the autocrine hypothesis. Surg. Gynecol. Obstet. 168: 468–473.

    CAS  Google Scholar 

  189. Horowitz, J.M., Friend, S.H., Weinberg, R.A., Whyte, P., Buchkovich, K., and Harlow, E. 1988. Anti-oncogenes and the negative regulation of cell growth. Cold Spring Harbor Symp. Quant. Biol. 53: 843–847.

    CAS  Google Scholar 

  190. Defeo-Jones, D., Tai, J.Y., Wegrzyn, R.J., Vuocolo, G.A., Baker, A.E., Payne, L.S., Garsky, V.M., Oliff, A., and Riemen, W.M. 1988. Structure-function analysis of synthetic and recombinant derivatives of transforming growth factor alpha. Mol. Cell. Biol. 8: 2999–3007.

    CAS  Google Scholar 

  191. Todaro, G.J., DeLarco, J.E., Fryling, C., Johnson, P.A., and Sporn, M.B. 1981. Transforming growth factors (TGFs): Properties and possible mechanisms of action. J. Supramol. Struct. Cell. Biochem. 15: 287–301.

    CAS  Google Scholar 

  192. Hirata, Y., and Orth, D.N. 1979. Epidermal growth factor (urogastrone) in human fluids: Size heterogeneity. J. Clin. Endocrinol. Metab. 48: 673–679.

    CAS  Google Scholar 

  193. Coffey, R.J., Jr., Derynck, R., Wilcox, J.N., Bringman, T.S., Goustin, A.S., Moses, H.L., and Pittelkow, M.R. 1987. Production and auto-induction of transforming growth factor-alpha in human keratinocytes. Nature (London) 328: 817–820.

    CAS  Google Scholar 

  194. Derynck, R., Goeddel, D.V., Ullrich, A., Gutterman, J.U., Williams, R.D., Bringman, T.S., and Berger, W.H. 1987. Synthesis of messenger RNAs for transforming growth factors alpha and beta and the epidermal growth factor receptor by human tumors. Cancer Res. 47: 707–712.

    CAS  Google Scholar 

  195. Sherwin, S.A., Twardzik, D.R., Bohn, W.H., Cockley, K.D., and Todaro, G.J. 1983. High-molecular weight-transforming growth factor activity in the urine of patients with disseminated cancer. Cancer Res. 43: 403–407.

    CAS  Google Scholar 

  196. Downward, J., Yarden, Y., Mayes, E., Scrace, G., Totty, N., Stockwell, P., Ullrich, A., Schlesinger, J., and Waterfield, M.D. 1984. Close similarity of epidermal growth factor receptor and v-erbB oncogene protein sequences. Nature (London) 307: 521–527.

    CAS  Google Scholar 

  197. Riemen, M.W., Wegrzyn, R.J., Baker, A.E., Hurni, W.M., Bennett, C.D., Oliff, A., and Stein, R.B. 1987. Isolation of multiple biologically and chemically diverse species of epidermal growth factor. Peptides 8: 877–885.

    CAS  Google Scholar 

  198. Nebert, D.W., and Gonzalez, F.J. 1987. P450 genes: Structure, evolution and regulation. Annu. Rev. Biochem. 56: 945–993.

    CAS  Google Scholar 

  199. Guengerich, F.P. 1988. Roles of cytochrome P-450enzymes in chemical carcinogenesis and cancer chemotherapy. Cancer Res. 48: 2946–2954.

    CAS  Google Scholar 

  200. Gonzalez, F.J., Jaiswal, A.K., and Nebert, D.W. 1986. P-450 genes: Evolution, regulation, and relationship to human cancer and pharmacogenetics. Cold Spring Harbor Symp. Quant. Biol. 51: 879–890.

    CAS  Google Scholar 

  201. Guengerich, F.P. 1989. Polymorphism of cytochrome P-450 in humans. Trends Pharm. Sci. 10: 107–109.

    CAS  Google Scholar 

  202. Wolf, C.R. 1986. Cytochrome P-450s: Polymorphic multigene families involved in carcinogen activation. Trends Genet. 2: 209–214.

    CAS  Google Scholar 

  203. Nebert, D.W., Eisen, H.J., Negishi, M., Lang, M.A., and Hjelmland, L.M. 1981. Genetic mechanisms controlling the induction of polysubstrate monooxygenase (P450) activities. Annu. Rev. Pharmacol. Toxicol. 21: 431–462.

    CAS  Google Scholar 

  204. Waterman, M.R., and Estabrook, R.W. 1983. The induction of microsomal electron transport enzymes. Mol. Cell. Biochem. 53, 54: 267–278.

    Google Scholar 

  205. Renton, K.W., Keyler, D.E., and Mannering, G.J. 1979. Suppression of the inductive effects of phenobarbital and 3-methylcholanthrene on ascorbic acid synthetic and hepatic cytochrome P-450-linked monooxygenase systems by the interferon inducers, poly rI rC and tilorone. Biochem. Biophys. Res. Commun. 88: 1017–1023.

    CAS  Google Scholar 

  206. Frey, A.B., Rosenfeld, M.G., Dolan, W.J., Adesnik, M., and Kreibich, G. 1984. Induction of cytochrome P-450 isozymes in rat hepatoma-derived cell cultures. J. Cell Physiol. 120: 169–180.

    CAS  Google Scholar 

  207. Nowak, D., Schmidt-Preuss, U., Jorres, R., Liebke, F., and Rudiger, H.W. 1988. Formation of DNA adducts and water-soluble metabolites of benzo[a]pyrene in human monocytes is genetically controlled. Int. J. Cancer 41: 169–173.

    CAS  Google Scholar 

  208. Relling, M.V., Evans, W.E., Fonne-Pfister, R., and Meyer, U.A. 1989. Anticancer drugs as inhibitors of two polymorphic cytochrome P-450 enzymes, debrisoquin and mephenytoin hydroxylase, in human liver microsomes. Cancer Res. 49: 68–71.

    CAS  Google Scholar 

  209. Nebert, D.W. 1981. Possible clinical importance of genetic differences in drug metabolism. Br. Med. J. 283: 537.

    CAS  Google Scholar 

  210. Whitlock, J.P., Jr. 1986. The regulation of cytochrome P-450 gene expression. Annu. Rev. Pharmacol. Toxicol. 26: 333–369.

    Google Scholar 

  211. Baird, W.M., Zennie, T.M., Ferin, M., Chae, Y.-H., Hatchell, J., and Cassady, J.M. 1988. Glucolimnanthin, a plant glucosinolate, increases the metabolism and DNA binding of benzo[a]pyrene in hamster embryo cell cultures. Carcinogenesis 9: 657–660.

    CAS  Google Scholar 

  212. Pruess-Schwartz, D., and Baird, W.M. 1986. Benzo[a]pyrene: DNA adduct formation in early-passage Wistar rat embryo cell cultures: Evidence for multiple pathways of activation of benzo[a]pyrene. Cancer Res. 46: 545–552.

    CAS  Google Scholar 

  213. Hesse, S., Cumpelik, O., Mezger, M., Kiefer, F., and Wiebel, F.J. 1990. Glutathione conjugation protects some, but not all, cell lines against DNA binding of benzo[a]pyrene metabolites. Carcinogenesis 11: 485–487.

    CAS  Google Scholar 

  214. Chung, F.-L., Wang, M., and Hecht, S.S. 1985. Effects of dietary indoles and isothiocyantes on N-nitrosodimethylamine and 4-(methylnitrosoamino)-1-(3-pyridyl)-1 butanone alpha-hydroxylation and DNA methylation in rat liver. Carcinogenesis 6: 539–543.

    CAS  Google Scholar 

  215. Ioannides, C., and Parke, D.V. 1987. The cytochromes P-448-A unique family of enzymes involved in chemical toxicity and carcinogenesis. Biochem. Pharmacol. 36: 4197–4207.

    CAS  Google Scholar 

  216. Nebert, D.W., Nelson, D.R., Adesnik, M., Coon, M.J. Estabrook, R.W., Gonzalez, F.J., Guengerich, F.P., Gunsalus, I.C., Johnson, E.F., Kemper, B., Levin, W., Phillips, I.R., Sato, R., and Waterman, M.R. 1989. The P450 superfamily: Updated listing of all genes and recommended nomenclature for the chromosomal loci. DNA 8: 1–13.

    CAS  Google Scholar 

  217. Nebert, D.W. 1979. Genetic differences in the induction of monooxygenase activities by polycyclic aromatic compounds. Pharmacol. Ther. 6: 395–417.

    CAS  Google Scholar 

  218. Gonzalez, F.J., Tukey, R.H., and Nebert, D.W. 1984. Structural gene products of the Ah locus. Transcriptional regulation of cytochrome P,-450 and P3–450 mRNA levels by 3-methylcholanthrene. Mol. Pharmacol. 26: 117–121.

    CAS  Google Scholar 

  219. Nebert, D. W., and Jones, J.E. 1989. Regulation of the mammalian cytochrome P,450 (CYPA1) gene. Int. J. Biochem. 21: 243–252.

    CAS  Google Scholar 

  220. Poland, A., Glover, E., and Kende, A.S. 1976. Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. J. Biol. Chem. 251: 4936–4946.

    CAS  Google Scholar 

  221. Guenthner, T.M., and Nebert, D.W. 1977. Cytosolic receptor for aryl hydrocarbon hydroxylase induction by polycyclic aromatic compounds. J. Biol. Chem. 252: 8981–8989.

    CAS  Google Scholar 

  222. Bigelow, S.W., and Nebert, D.W. 1982. The Ah regulatory gene product. Survey of nineteen polycyclic aromatic compounds’ and fifteen benzo[alpyrene metabolites’ capacity to bind to the cytosolic receptor. Toxicol. Lett. 10: 109–118.

    CAS  Google Scholar 

  223. Paolini, M., Bauer, C., Biagi, G.L., and Cantelli-Forti, G. 1989. Do cytochromes P-448 and P-450 have different functions? Biochem. Pharmacol. 38: 2223–2225.

    CAS  Google Scholar 

  224. Gonzalez, F.J., and Nebert, D.W. 1985. Autoregulation plus upstream positive and negative control regions associated with transcriptional activation of the mouse P,450 gene. Nucleic Acids Res. 13: 7269–7288.

    CAS  Google Scholar 

  225. Jones, P.B.C., Galeazzi, D.R., Fisher, J.M., and Whitlock, J.P., Jr. 1985. Control of cytochrome P1–450 gene expression by dioxin. Science 227: 1499–1502.

    CAS  Google Scholar 

  226. Miskimins, W.K., Roberts, M.P., McClelland, A., and Ruddle, F.H. 1985. Use of a protein-blotting procedure and a specific DNA probe to identify nuclear proteins that recognize the promoter region of the transferrin receptor gene. Proc. Natl. Acad. Sci. U.S.A. 82: 6741–6744.

    CAS  Google Scholar 

  227. Mehta, R.G., Cernz, V.L., Madigan, M., and Moon, R.C. 1984. Modification of mouse mammary gland organ culture technique. J. Tissue Culture Methods 8: 27–30.

    Google Scholar 

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Authors
  1. Cindy K. Angerhofer
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  2. John M. Pezzuto
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Editors and Affiliations

  1. Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, 60612, Chicago, Illinois, USA

    John M. Pezzuto Ph.D. (Professor and Interim Head, Associate Director) (Professor and Interim Head, Associate Director)

  2. Specialized Cancer Center, University of Illinois College of Medicine at Chicago, 833 South Wood Street, 60612, Chicago, Illinois, USA

    John M. Pezzuto Ph.D. (Professor and Interim Head, Associate Director) (Professor and Interim Head, Associate Director)

  3. Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, 60612, Chicago, Illinois, USA

    Michael E. Johnson Ph.D. (Professor and Interim Director) (Professor and Interim Director)

  4. College of Pharmacy, University of Illinois at Chicago, 1737 West Taylor Street, Suite 203, 60612, Chicago, Illinois, USA

    Henri R. Manasse Jr. Ph.D. (Professor, Interim Vice Chancellor for Health Services) (Professor, Interim Vice Chancellor for Health Services)

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© 1993 Springer Science+Business Media Dordrecht

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Angerhofer, C.K., Pezzuto, J.M. (1993). Applications of Biotechnology in Drug Discovery and Evaluation. In: Pezzuto, J.M., Johnson, M.E., Manasse, H.R. (eds) Biotechnology and Pharmacy. Springer, Dordrecht. https://doi.org/10.1007/978-94-015-8135-6_13

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  • DOI: https://doi.org/10.1007/978-94-015-8135-6_13

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  • Print ISBN: 978-0-412-03871-6

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