Tyrosine kinases in disease: Overview of kinase inhibitors as therapeutic agents and current drugs in clinical trials

Expert Opinion on Investigational Drugs

Volumn 7, Issue 4, 1998, Pages 553-573

  Strawn, Laurie m ^a   Shawver, Laura k ^a  

^a SUGEN INC   (United States)

Author keywords

angiogenesis; cancer; fibrosis; growth factors; indolinones; isoxazoles; psoriasis; pyrimidines; quinazolines; restenosis; tyrosine kinases

Indexed keywords

EID: 85017325712     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.7.4.553     Document Type: Review

References (180)

1. DRUKER BJ, MAMON HJ, ROBERTS TM: Oncogenes, growth factors, and signal transduction. New Engl. J. Med. (1989) 321: 1383 – 1391.
2. BASERGA R: Oncogenes and the strategy of growth fac-tors. Cell (1994) 79: 927 – 930.
3. SPORN MB, ROBERTS AB: Autocrine growth factors and cancer. Nature (1985) 313: 745 – 747.
4. PLOWMAN GD, ULLRICH A, SHAWVER LK: Receptor tyro-sine kinases as targets for drug intervention. Drug News Perspect. (1994) 7: 334 – 339.
5. TRAXLER PM: Protein tyrosine kinase inhibitors in can-cer treatment. Exp. Opin. Ther. Patents (1997) 7: 571 – 588.
6. TRAXLER P, FURET P, METT H et al.: Design and synthe-sis of novel tyrosine kinase inhibitors using a pharma-cophore model of the ATP-binding site of the EGF-R. J. Pharm. Belg. (1997) 52: 88 – 96.
7. BURKE TR, Jr., YAO Z-J, SMYTH MS, YE B:Phosphotyrosyl-based motifs in the structure-based design of protein-tyrosine kinase-dependent signal transduction inhibitors. Curr. Pharm. Des. (1997) 3: 291 – 304.
8. KLOHS WD, FRY DW, KRAKER AJ: Inhibitors of tyrosinekinase. Curr. Opin. Oncol. (1997) 9: 562 – 568.
9. CLAESSON-WELSH L: Platelet-derived growth factor re-ceptor signals. J. Biol. Chem. (1994) 269: 32023 – 32026.
10. SORIANO P: Abnormal kidney development and hema-tological disorders in PDGF I3-receptor mutant mice. Genes Dev. (1994) 8: 1888 – 1896.
11. SORIANO P: The PDGFa receptor is required for neural crest cell development and for normal patterning of the somites. Development (1997) 124: 2691 – 2700.
12. LINDAHL P, JOHANSSON BR, LEVEEN P, BETSHOLTZ C: Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science (1997) 277: 242 – 245.
13. RICHARDSON WD, PRINGLE N, MOSLEY MJ, WESTER-MARK B, DUBOIS-DAICQ M: A role for platelet-derived growth factor in normal gliogenesis in the central nervous system. Cell (1988) 53: 309 – 319.
14. ELLISON JA, SCULLY SA, DE VELLIS J: Evidence for neu-ronal regulation of oligodendrocyte development: cel-lular localization of platelet-derived growth factor alpha receptor and A-chain mRNA during cerebral cor-tex development in the rat. J. Neurosci. Res. (1996) 45: 28 – 39.
15. ROSS R, RAINES EW, BOWEN-POPE DF: The biology ofplatelet-derived growth factor. Cell (1986) 46: 155 – 169.
16. DOOLITTLE RF, HUNKAPILLAR MW, HOOD LE et al: Sim-ian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science (1983) 221: 275 – 276.
17. WATERFIELD MD, SCRACE GT, WHITTLE N et al: Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sar-coma virus. Nature (1983) 304: 35 – 39.
18. HSU S, HUANG F, FRIEDMAN E: Platelet-derived growthfactor-B increased colon cancer cell growth in vivo by a paracrine effect. J. Cell. Physic)]. (1995) 165: 239 – 245.
19. HARSH GR, KEATING MT, ESCOBEDO JA, WILLIAMS LT:Platelet derived growth factor (PDGF) autocrine com-ponents in human tumor cell lines. J. Neuro-Oncol (1990) 8: 1 – 12.
20. LEVEEN P, CLAESSON-WELSH L, HELDIN C-H, WESTER-MARK B, BETSHOLTZ C: Expression of messenger RNAs for platelet-derived growth factor and its receptors in human sarcoma cell lines. Int. J. Cancer (1990) 46: 1066 – 1070.
21. NISTER M, LIBERMANN TA, BETSHOLTZ C et al.: Expres-sion of messenger RNAs for platelet-derived growth factor and transforming growth factor-a and their re-ceptors in human malignant glioma cell lines. Cancer Res. (1988) 48: 3910 – 3918.
22. NISTER M, CLASSON-WELSH L, ERIKSSON A, HELDIN C-H, WESTERMARK B: Differential expression of platelet-derived growth factor receptors in human malignant glioma cell lines. J. Biol. Chem. (1991) 266: 16755 – 16763.
23. HENRIKSEN R, FUNA K, WILANDER E et al.: Expressionand prognostic significance of platelet-derived growth factor and its receptor in epithelial ovarian neo-plasms. Cancer Res. (1993) 53: 4550 – 4554.
24. HERMANSSON M, NISTER M, BETSHOLTZ C et al.: Endo-thelial cell hyperplasia in human glioblastoma: coex-pression of mRNA for platelet-derived growth stimulation. Proc. Natl. Acad. ScL USA (1988) 85: 7748 – 7752.
25. HERMANSSON M, FUNA K, HARTMAN M et al.: Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and pro-tein suggests the presence of autocrine and paracrine loops. Cancer Res. (1992) 52: 3213 – 3219.
26. PLATE KH, BREIER G, FARRELL CL, RISAU W: Platelet-derived growth factor receptor-13 is induced during tu-mor development and upregulated during tumor pro-gression in endothelial cells in human gliomas. Lab. Invest. (1992) 67: 529 – 534.
27. STRAWN LM, MANN E, ELLIGER SS et al.: Inhibition ofglioma cell growth by a truncated platelet-derived growth factor-13 receptor. J. Biol. Chem. (1994) 269: 21215 – 21222.
28. SHAMAH SM, STILES CD, GUHA A: Dominant-negativemutants of platelet-derived growth factor revert the transformed phenotype of human astrocytoma cells. Mol Cell Biol. (1993) 13: 7203 – 7212.
29. VASSBOTN FS, ANDERSSON M, WESTERMARK B, HELDINC-H, OSTMAN A: Reversion of autocrine transforma-tion by a dominant negative platelet-derived growth factor mutant. Mol. Cell Biol. (1993) 13: 4066 – 4076.
30. HADAR DP, POMERANTZ KB: Signal transduction in atherosclerosis: integration of cytokines and the eico-sanoid network. FASEB J (1992) 6: 2933 – 2941.
31. SCHWARTZ SM, DEBLOIS D, O'BRIEN ERM: Soil for athe-rosclerosis and restenosis. Circ. Res. (1995) 77: 445 – 465.
32. MAJESKY MW, REIDY MA, BOWEN-POPE DF etal: PDGF ligand and receptor gene expression during repair of arterial injury. J. Cell Biol. (1990) 111: 2149 – 2158.
33. JOHNSON DE, WILLIAMS LT: Structural and functional diversity in the FGF receptor multigene family. Adv. Cancer Res. (1993) 60: 1 – 41.
34. BASILICO C, MOSCATELLI D: The FGF family of growth factors and oncogenes. Adv. Cancer Res. (1992) 59: 115 – 165.
35. MIYAMOTO M, NARUO K-I, SEKO C et al.: Molecularcloning of a novel cytokine cDNA encoding the ninth member of the fibroblast growth factor family, which has a unique secretion property. Mol Cell Biol. (1993) 13: 4251 – 4259.
36. COULIER F, PONTAROTTI P, ROUBIN R et al.: Of worms and men: an evolutionary perspective on the fibro-blast growth factor (FGF) and FGF receptor families. J. Moi Evol. (1997) 44: 43 – 56.
37. YAMAGUCHI TP, HARPAL K, HENKEMEYER M, ROSSANT J: fgfr-1 is required for embryonic growth and meso-dermal patterning during mouse gastrulation. Genes Dev. (1994) 8: 3032 – 3044.
38. WERNER S, WEINBERG W, LIAO X etal.: Targeted expres-sion of a dominant-negative FGF receptor mutant in the epidermis of transgenic mice reveals a role of FGF in keratinocyte organization and differentiation. EMBO J (1993) 12: 2635 – 2643.
39. ROUSSEAU F, BONAVENTURE J, LEGEAI-MALLET L et al.: Mutations in the gene encoding fibroblast growth fac-tor receptor-3 in achondroplasia. Nature (1994) 371: 252 – 254.
40. SHIANG R, THOMPSON LM, ZHU Y-Z etal.: Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell (1994) 78: 335 – 342.
41. NASKI MC, WANG Q, XU J, ORNITZ DM: Graded activa-tion of fibroblast growth factor receptor 3 by muta-tions causing achondroplasia and thanatophoric dysplasia. Nature Gen. (1996) 13: 233 – 237.
42. BUNTROCK P, JENTZSCH KD, HEDER G: Simulation of wound healing, using brain extract with fibroblast growth factor (FGF) activity. 1. Quantitative and bio-chemical studies into formation of granulation tissue. Exp. Pathol. (1982) 21: 46 – 53.
43. MARTIN P: Wound healing - aiming for perfect skin re-generation. Science (1997) 276: 75 – 81.
44. WERNER S, SMOLA H, LIAO X etal: The function of KGF in morphogenesis of epithelium and reepithelializa-tion of wounds. Science (1994) 266: 819 – 822.
45. FOLKMAN J, KLAGSBRUN M: Angiogenic factors. Science (1987) 235: 442 – 447.
46. SCHOTT RJ, MORROW LA: Growth factors and angio-genesis. Cardiovasc. Res. (1993) 27: 1155 – 1161.
47. SINGH RK, LLANSA N, BUCANA CD et al.: Cell density-dependent regulation of basic fibroblast growth factor expression in human renal cell carcinoma cells. Cell Growth Differ. (1996) 7: 397 – 404.
48. NAKAMOTO T, CHANG C, LI A, CHODAK GW: Basic fi-broblast growth factor in human prostate cancer cells. Cancer Res. (1992) 52: 571 – 577.
49. IIDA S, KATOH 0, TOKUNAGA A, TERADA M: Expression of fibroblast growth factor gene family and its recep-tor gene family in the human upper gastrointestinal tract. Biochem. Biophys. Res. Commun. (1994) 199: 1113 – 1119.
50. KAIPAINEN A, VLAYKOVA T, HATVA E et al.: Enhanced expression of the Tie receptor tyrosine kinase mRNA in the vascular endothelium of metastatic melanomas. Cancer Res. (1994) 54: 6571 – 6577.
51. YAMAGUCHI F, SAYA H, BRUNER JM, MORRISON RS: Dif-ferential expression of two fibroblast growth factor-receptor genes is associated with malignant © Ashley Publications Ltd. All rights reserved.Exp. Opin. Invest. Drugs (1998) 7(4) progression in human astrocytomas. Proc. Natl. Acad. Sci. USA (1994) 91: 484 – 488.
52. LU J, NISHIZAWA Y, TANAKA A et al: Inhibitory effect of antibody against basic fibroblast growth factor on an-drogen- or glucocorticoid-induced growth of shionogi carcinoma 115 cells in serum-free culture. Cancer Res. (1989) 49: 4963 – 4967.
53. TAKAHASHI JA, FUKUMOTO M, KOZAI Y et al Inhibi- tion of cell growth and tumor genesis of human glio-blastoma cells by a neutralizing antibody against human basic fibroblast growth factor. FEBS Lett. (1991) 288: 65 – 71.
54. UNDER V, REIDY MA: Expression of basic fibroblastgrowth factor and its receptor by smooth muscle cells and endothelium in injured rat arteries. Circ. Res. (1993) 73: 589 – 595.
55. UNDER V, REIDY MA: Proliferation of smooth musclecells inhibited by an antibody against basic fibroblast growth factor. Proc. Natl. Acad. Sci. USA (1991) 88: 3739 – 3743.
56. QUINN TP, PETERS KG, DE VRIES C, FERRARA N, WIL-LIAMS LT: Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc. Natl. Acad. Sci. USA (1993) 90: 7533 – 7537.
57. MILLAUER, B, WIZIGMANN-VOOS S, SCHNORCH H et al.: High affinity VEGF binding and developmental ex-pression suggest Flk-1 as a major regulator of vasculo-genesis and angiogenesis. Cell (1993) 72: 835 – 846.
58. TERMAN BI, CARRION ME, KOVACS E et al.: Identifica-tion of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene (1991) 6: 1677 – 1683.
59. SHIBUYA M, YAMAGUCHI S, YAMANE A et al: Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene MO closely related to the fms family. Oncogene (1990) 5: 519 – 524.
60. DE VRIES C, ESCOBEDO JA, UENO H et al.: The fins-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science (1992) 255: 989 – 991.
61. PAJUSOLA K, APRELIKOVA 0, KORHONEN J et al.: FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multi-ple human tissues and cell lines. Cancer Res. (1992) 52: 5738 – 5743.
62. FERRARA N: The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res. Treat. (1995) 36: 127 – 137.
63. CONNOLLY DT: Vascular permeability factor: a unique regulator of blood vessel function. J. Cell. Biochem. (1991) 47: 219 – 223.
64. OLOFSSON B, PAJUSOLA K, KAIPAINEN A et al: Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc. Natl. Acad. Sci. USA (1996) 93: 2576 – 2581.
65. JOUKOV V, PAJUSOLA K, KAIPAINEN A et al.: A novel vas-cular endothelial growth factor, VEGF-C, is a ligand for the F1t4 (VEGFR-3) and KDR (VEGFR-2) receptor tyro-sine kinases. EMBO J (1996) 15: 290 – 298.
66. LEE J, GRAY A, YUAN J et al.: Vascular endothelial growth factor related protein: a ligand and specific ac-tivator of the tyrosine kinase receptor F1t4. Cell Biol. (1996) 93: 1988 – 1992.
67. JAKEMAN LB, ARMANINI M, PHILLIPS HS, FERRARA N: De-velopmental expression of binding sites and messen-ger ribonucleic acid for vascular endothelial growth factor suggests a role for this protein in vasculogenesis and angiogenesis. Endocrinology (1993) 133: 848 – 859.
68. BREIER G, ALBRECHT U, STERRER S, RISAU W: Expres-sion of vascular endothelial growth factor during em-bryonic angiogenesis and endothelial cell differentiation. Development (1992) 114: 521 – 532.
69. SHALABY F, ROSSANT J, YAMAGUCHI TP et al.: Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature (1995) 376: 62 – 66.
70. HANANHAN D, FOLKMAN J: Patterns and emerging mechanisms of the angiogenic switch during tumori-genesis. Cell (1996) 86: 353 – 364.
71. CLAFFEY KP, BROWN LF, DEL AGUILA LF et al.: Expres-sion of vascular permeability factor/vascular endothe-lial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis. Cancer Res. (1996) 56: 172 – 181.
72. MYOKEN Y, KAYADA Y, OKAMOTO T et al.: Vascular en-dothelial cell growth factor (VEGF) produced by A-431 human epidermoid carcinoma cells and identification of VEGF membrane binding sites. Proc. Natl. Acad. Sci. USA (1991) 88: 5819 – 5823.
73. PLATE KH, BREIER G, WEICH HA, RISAU W: Vascular en-dothelial growth factor is a potential tumour angio-genesis factor in human gliomas in vivo. Nature (1992) 359: 845 – 848.
74. PLATE KH, BREIER G, WEICH HA, MENNEL HD, RISAU W: Vascular endothelial growth factor and glioma angio-genesis: coordinate induction of VEGF receptors, dis-tribution of VEGF protein and possible in vivo regulatory mechanisms. Int. J. Cancer (1994) 59: 520 – 529.
75. HATVA E, BOHLING T, JAASKELAINEN J et al.: Vascular growth factors and receptors in capillary hemangio-blastomas and hemangiopericytomas. Am. J. Pathol (1996) 148: 763 – 775.
76. TOI M, HOSHINA S, TAKAYANAGI T, TOMINAGA T: Asso-ciation of vascular endothelial growth factor expres-sion with tumor angiogenesis and with early relapse in primary breast cancer. Jpn. J. Cancer Res. (1994) 85: 1045 – 1049.
77. ANAN K, MORISAKI T, KATANO M et al.: Vascular endo-thelial growth factor and platelet-derived growth fac-tor are potential angiogenic and metastatic factors in human breast cancer. Surgery (1996) 119:333-339. © Ashley Publications Ltd. All rights reserved.Exp. Opin. Invest. Drugs (1998) 7(4)
78. YOSHIJI H, GOMEZ DE, SHIBUYA M, THORGEIRSSON UP: Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Res. (1996) 56: 2013 – 2016.
79. BROWN LF, BERSE B, JACKMAN RW et al.: Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res. (1993) 53: 4727 – 4735.
80. TAKAHASHI Y, KITADAI Y, BUCANA CD, CLEARY KR, EL-LIS LM: Expression of vascular endothelial growth fac-tor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. (1995) 55: 3964 – 3968.
81. TAKAHASHI A, SASAKI H, KIM SJ et al.: Markedly in-creased amounts of messenger RNAs for vascular en-dothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. (1994) 54: 4233 – 4237.
82. SALEH M, STACKER SA, WILKS AF: Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence. Cancer Res. (1996) 56: 393 – 401.
83. CHENG SY, HUANG HF, NAGANE M et al: Suppression of glioblastoma angiogenicity and tumorigenicity by in-hibition of endogenous expression of vascular endo-thelial growth factor. Proc. Natl. Acad. Sci. USA (1996) 93: 8502 – 8507.
84. KIM KJ, LI B, WINER J et al: Inhibition of vascular endo-thelial growth factor-induced angiogenesis sup-presses tumour growth in vivo. Nature (1993) 362: 841 – 844.
85. ASANO M, YUKITA A, MATSUMOTO T, KONDO S, SUZUKI H: Inhibition of tumor growth and metastasis by an im-munoneutralizing monoclonal antibody to human vascular endothelial growth factor/vascular perme-ability factor 121. Cancer Res. (1995) 55: 5296 – 5301.
86. MILLAUER B, SHAWVER LK, PLATE KH, RISAU W, ULLRICH A: Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature (1994) 367: 576 – 579.
87. MILLAUER B, LONGHI MP, PLATE KH et al: Dominant-negative inhibition of Flk-1 suppresses the growth of many tumor types in vivo. Cancer Res. (1996) 56: 1615 – 1620.
88. WIZIGMANN-VOOS S, BREIER G, RISAU W, PLATE KH: Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res. (1995) 55: 1358 – 1364.
89. DETMAR M, BROWN LF, CLAFFEY KP et al.: Overexpres-sion of vascular permeability factor/vascular endothe-lial growth factor and its receptors in psoriasis. J. Exp. Med. (1994) 180: 1141 – 1146.
90. AIELLO LP, AVERY RL, ARRIGG PG et al.: Vascular endo-thelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. New Engl. J. Med. (1994) 331: 1480 – 1487.
91. ULLRICH A, COUSSENS L, HAYFLICK JS et al.: Human epi-dermal growth factor receptor cDNA sequence and ab-errant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature (1984) 309: 418 – 425.
92. THREADGILL DW, DLUGOSZ AA, HANSEN LA et al.: Tar-geted disruption of mouse EGF receptor effect of ge-netic background on mutant phenotype. Science (1995) 269: 230 – 234.
93. SIBILIA M, WAGNER EF: Strain-dependent epithelial de-fects in mice lacking the EGF receptor. Science (1995) 269: 234 – 238.
94. FUNATOMI H, ITAKURA J, ISHIWATA T et al: Amphiregu-lin antisense oligonucleotide inhibits the growth of T3M4 human pancreatic cancer cells and sensitizes the cells to EGF receptor-targeted therapy. Int. J. Cancer (1997) 72: 512 – 517.
95. NIIKURA H, SASANO H, SATO S, YAJIMA A: Expression of epidermal growth factor-related proteins and epider-mal growth factor receptor in common epithelial ovarian tumors. Int. J. Gynecol. Pathol (1997) 16: 60 – 68.
96. RAMP U, JAQUET K, REINECKE P et al: Functional intact-ness of stimulatory and inhibitory autocrine loops in human renal carcinoma cell lines of the clear cell type. Urol. (1997) 157: 2345 – 2350.
97. NAEF M, YOKOYAMA M, FRIESS H, BUCHLER MW, KORC M: Co-expression of heparin-binding EGF-like growth factor and related peptides in human gastric carci-noma. Int. J. Cancer (1996) 66: 315 – 321.
98. INUI Y, HIGASHIYAMA S, KAWATA S et al: Expression of heparin-binding epidermal growth factor in human hepatocellular carcinoma. Gastroenterology (1994) 107: 1799 – 1804.
99. NICHOLSON RI, MCCLELLAND RA, FINLAY P et al.: Rela-tionship between EGF-R c-ervB-2 protein expression and Ki67 immunostaining in breast cancer and hor-mone sensitivity. Eur. J. Cancer (1993) 29A: 1018 – 1023.
100. LIBERMANN TA, NUSBAUM HR, RAZON N et al: Amplifi-cation, enhanced expression and possible rearrange-ment of EGF receptor gene in primary human brain tumours of glial origin. Nature (1985) 313: 144 – 147.
101. MASUI H, KAWAMOTO T, SATO JD et al: Growth inhibi-tion of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal anti-bodies. Cancer Res. (1984) 44: 1002 – 1007.
102. BASELGA J, MENDELSOHN J: The epidermal growth fac-tor receptor as a target for therapy in breast carci-noma. Breast Cancer Res. Treat. (1994) 29: 127 – 138.
103. GOTTLIEB AB, CHANG CK, POSNETT DN, FANELLI B, TAM JP: Detection of transforming growth factor alpha in normal, malignant, and hyperproliferative human keratinocytes. J. Exp. Merl. (1988) 167: 670 – 675.
104. COFFEY RJ, Jr., DERYNCK R, WILCOX JN et al: Production and auto-induction of transforming growth factor-alpha in human keratinocytes. Nature (1987) 328:817-820. © Ashley Publications Ltd. All rights reserved.Exp. Opin. Invest. Drugs (1998) 7(4)
105. ELDER JT, FISHER GJ, LINDQUIST PB et al.: Overexpres-sion of transforming growth factor alpha in psoriatic epidermis. Science (1989) 243: 811 – 814.
106. VASSAR R, FUCHS E: Transgenic mice provide new in-sights into the role of TGF-a during epidermal devel-opment and differentiation. Genes Dev. (1991) 5: 714 – 727.
107. FINZI E, HARKINS R, HORN T: TGF-a is widely expressed in differentiated as well as hyperproliferative skin epi-thelium. J. Invest. Dermatol. (1991) 96: 328 – 332.
108. NANNEY LB, MAGID M, STOSCHECK CM, KING LE, Jr.: Comparison of epidermal growth factor binding and receptor distribution in normal human epidermis and epidermal appendages. J. Invest. Dermatol. (1984) 83: 385 – 393.
109. GREEN MR, COUCHMAN JR: Differences in human skin between the epidermal growth factor receptor distri-bution detected by EGF binding and monoclonal anti-body recognition. J. Invest. Dermatol. (1985) 85: 239 – 245.
110. ELLIS DL, KAFKA SP, CHOW JC et al.: Melanoma, growth factors, acanthosis nigricans, the sign of Leser-Trelét, and multiple acrochordons. New Engl. J. Med. (1987) 317: 1582 – 1587.
111. VALYI-NAGY I, JENSEN PJ, ALBELDA SM, RODECK U: Cytokine-induced expression of transforming growth factor-alpha and the epidermal growth factor receptor in neonatal skin explants. J. Invest. Dermatol (1992) 99: 350 – 356.
112. BEN-BASSAT H, VARDI DV, GAZIT A et al.: Tyrphostins suppress the growth of psoriatic keratinocytes. Exp. Dermatol. (1995) 4: 82 – 88.
113. BARGMANN CI, HUNG M-C, WEINBERG RA: The neu on-cogene encodes an epidermal growth factor receptor-related protein. Nature (1986) 319: 226 – 230.
114. BARGMANN CI, HUNG M-C, WEINBERG RA: Multiple in-dependent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185. Cell (1986) 45: 649 – 657.
115. COUSSENS L, YANG-FENG TL, LIAO Y-C et al.: Tyrosine kinase receptor with extensive homology to EGF re-ceptor shares chromosomal location with neu onco-gene. Science (1985) 230: 1132 – 1139.
116. YAMAMOTO T, IKAWA S, AKIYAMA T et al.: Similarity of protein encoded by the human c-erb-B-2 gene to epi-dermal growth factor receptor. Nature (1986) 319: 230 – 234.
117. DI FIORE PP, PIERCE JH, KRAUS MH et al: erbB-2 is a po-tent oncogene when overexpressed in NIH/3T3 cells. Science (1987) 237: 178 – 182.
118. HUDZIAK RM, SCHLESSINGER J, ULLRICH A: Increased expression of the putative growth factor receptor, p185HER2, causes transformation and tumorigenesis of NIH 3T3 cells. Proc. Natl. Acad. ScL USA (1987) 84: 7159 – 7163.
119. GOLDMAN R, LEVY RB, PELES E, YARDEN Y: Heterodi-merization of the erbB-1 and erbB-2 receptors in hu-man breast carcinoma cells: a mechanism for receptor transregulation. Biochemistry (1990) 29: 11024 – 11028.
120. PELES E, YARDEN Y: Neu and its ligands: from an onco-gene to neural factors. Bioessays (1993) 15: 815 – 824.
121. RIESE DJ, VAN RAAIJ TM, PLOWAMAN GD et al: The cellu-lar response to neuregulins is governed by complex interactions of the erbB receptor family. Mol. Cell Biol. (1995) 15: 5770 – 5776.
122. TZAHAR E, WATERMAN H, CHEN X et al.: A hierarchical network of interreceptor interactions determines sig-nal transduction by neu differentiation fac-tor/neuregulin and epidermal growth factor. MM. Cell Biol. (1996) 16: 5276 – 5287.
123. REESE DM, SLAMON DJ: Her-2/neu signal transduction in human breast and ovarian cancer. Stem Cells (1997) 15: 1 – 8.
124. ROSS JS, SHEEHAN CE, HAYNER-BUCHAN AM et al: Prog-nostic significance of HER-2/neu gene amplification status by fluorescence in situ hybridization of prostate carcinoma. Cancer (1997) 79: 2162 – 2170.
125. KAPITANOVIC S, RADOSEVIC S, KAPITANOVIC M et al.: The expression of p185(HER-2/neu) correlates with the stage of disease and survival in colorectal cancer. Gastroenterology (1997) 112: 1103 – 1113.
126. HUDZIAK RM, LEWIS GD, SHALABY MR et al.: Amplified expression of the HER2/ERBB2 oncogene induces re-sistance to tumor necrosis factor-a in NIH 3T3 cells. Proc. Natl. Acad. ScL USA (1988) 85: 5102 – 5106.
127. FADY C, GARDNER AM, GERA JF, LICHTENSTEIN A: Interferon-induced increase in sensitivity of ovarian cancer targets to lysis by lymphokine-activated killer cells: selective effects on HER2/neu-overexpressing cells. Cancer Res. (1992) 52: 764 – 769.
128. DREBIN JA, LINK VC, STERN DF, WEINBERG RA, GREENE MI: Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell (1995) 41: 695 – 706.
129. BACUS SS, STANCOVSKI I, HUBERMAN E et al.: Tumor-inhibitory monoclonal antibodies to the HER-2/neu receptor induce differentiation of human breast can-cer cells. Cancer Res. (1992) 52: 2580 – 2589.
130. STANCOVSKI I, HURWITZ E, LEITNER 0 et al: Mechanis-tic aspects of the opposing effects of monoclonal anti-bodies to the ERBB2 receptor on tumor growth. Proc. Natl. Acad. ScL USA (1991) 88: 8691 – 8695.
131. BASELGA J, TRIPATHY D, MENDELSOHN J et al.: Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J. Clin. Oncol. (1996) 14: 737 – 744.
132. KOCH CA, ANDERSON D, MORAN MF, ELLIS C, PAWSON T: SH2 and SH3 domains: elements that controlinteractions of cytoplasmic signaling proteins. Science (1991) 252: 668 – 673.
133. XU W, HARRISON SC, ECK MJ: Three-dimensional struc-ture of the tyrosine kinase c-Src. Nature (1997) 385: 595 – 602.
134. KYPTA RM, GOLDBERG Y, ULUG ET, COURTNEIDGE SA: Association between the PDGF receptor and members of the src family of tyrosine kinases. Cell (1990) 62: 481 – 492.
135. TWAMLEY GM, KYPTA RM, HALL B, COUTNEIDGE SA: As-sociation of Fyn with the activated platelet-derived growth factor receptor: requirements for binding and phosphorylation. Oncogene (1992) 7: 1893 – 1901.
136. MORI S, RONNSTRAND L, YOKOTE KN et al: Identifica-tion of two juxtamembrane autophosphorylation sites in the PDGF 3-receptor; involvement in the interaction with Src family tyrosine kinases. EMBO J. (1993) 12: 2257 – 2264.
137. HANSEN K, JOHNELL M, SIEGBAHN A et al: Mutation of a Src phosphorylation site in the PDGF 13-receptor leads to increased PDGF-stimulated chemotaxis but de-creased mitogenesis. EMBO J (1996) 15: 5299 – 5313.
138. TWAMLEY-STEIN GM, PEPPERKKOK R, ANSORGE W, COURTNEIDGE SA: The Src family tyrosine kinases are required for platelet-derived growth factor-mediated signal transduction in NIH 3T3 cells. Proc. Natl. Acad. ScL USA (1993) 90: 7696 – 7700.
139. MUTHUSWAMY SK, MULLER W: Direct and specific in-teraction of c-Src with Neu is involved in signaling by the epidermal growth factor receptor. Oncogene (1995) 11: 271 – 279.
140. SORIANO P, MONTGOMERY C, BRADLEY A: Targeted dis-ruption of the c-Src proto-oncogene leads to os-teopetrosis in mice. Cell (1991) 64: 693 – 702.
141. BOLEN JB, VEILLETTE A, SCHWARTZ AM, DESEAU V, RO-SEN N: Activation of pp60c-src protein kinase activity in human colon carcinoma. Proc. Natl. Acad. ScL USA (1997) 84: 2251 – 2255.
142. PARK J, MEISLER Al, CARTWRIGHT CA: c-Yes tyrosine ki-nase activity in human colon carcinoma. Oncogene (1993) 8: 2627 – 2635.
143. PENA SV, MELHEM MF, MEISLER Al, CARTWRIGHT CA: Elevated c-Yes tyrosine kinase activity in permalig-nant lesions of the colon. Gastroenterology (1995) 108: 117 – 124.
144. STALEY CA, PARIKH NU, GALLICK GE: Decreased tumo-rigenicity of a human colon adenocarcinoma cell line by an antisense expression vector specific for c-Src. Cell Growth Differ. (1997) 8: 269 – 274.
145. LOGANZO F, DOSIK JS, Jr., ZHAO Y et al.: Elevated ex-pression of protein tyrosine kinase c-Yes, but not c-Src, in human malignant melanoma. Oncogene (1993) 8: 2637 – 2635.
146. NIKCEVICH DA, FINNEGAN A, CHONG AS-F, WILLIAMS JW, BREMER EG: Inhibition of interleukin 2 (I1-2)-stim-ulated tyrosine kinase activity by leflunomide. Agents Actions (1994) 41: C279–C282.
147. XU X, WILLIAMS JW, BREMER EG, FINNEGAN A, CHONG AS-F: Inhibition of protein tyrosine phosphorylation in T cells by a novel immunosuppressive agent, leflu-nomide. J. Biol. Chem. (1995) 270: 12398 – 12403.
148. XU X, WILLIAMS JW, GONG A, FINNEGAN A, CHONG AS-F: Two activities of the immunosuppressive me-tabolite of leflunomide, A77 1726: inhibition of py-rimidine nucleotide synthesis and protein tyrosine phosphorylation. Biochem. Pharmacol. (1996) 52: 527 – 534.
149. MATTAR T, KOCHHAR K, BARTLETT R, BREMER EG, FIN-NEGAN A: Inhibition of the epidermal growth factor receptor tyrosine kinase activity by leflunomide. FEBS Lett. (1993) 334: 161 – 164.
150. ELDER RT, XU X, WILLIAMS JW et al.: The immunosup-pressive metabolite of leflunomide, A77 1726, affects murine T cells through two biochemical mechanisms. Immunol. (1997) 159: 22 – 27.
151. SHAWVER LK, SCHWARTZ DP, MANN E et al.: Inhibition of platelet-derived growth factor-mediated signal transduction and tumor growth by N-[4-trifluoromethy0 -phenyl] 5-methylisoxazole-4-carboxamide. Clin. Cancer Res. (1997) 3: 1167 – 1177.
152. CHERWINSKI HM, BYARS N, BALLARON SJ et al.: Leflu-nomide interferes with pyrimidine nucleotide biosyn-thesis. Inflamm. Res. (1995) 44: 317 – 322.
153. WILLIAMSON RA, YEA CM, ROBSON PA et al.: Dihydro-orotate dehydrogenase is a high affinity binding pro-tein for A77 1726 and mediator of a range of biological effects of the immunomodulatory compound. J. Biol. Chem. (1995) 270: 22467 – 22472.
154. DAVIS JP, CAIN GA, PITTS WJ, MAGOLDA RL, COPELAND RA: The immunosuppressive metabolite of leflu-nomide is a potent inhibitor of human dihydroorotate dehydrogenase. Biochemist-1y (1996) 35: 1270 – 1273.
155. FRY DW, KRAKER AJ, MCMICHAEL et al.: A specific in-hibitor of the epidermal growth factor receptor tyro-sine kinase. Science (1994) 265: 1093 – 1095.
156. REWCASTLE GE, DENNY WA, BRIDGES AJ et al.: Tyrosine kinase inhibitors. 5. Synthesis and structure-activity relationships for 4- Rphenylmethyll amino]- and 4-(phenylamino)quinazolines as potent adenosine 5'-triphosphate binding site inhibitors of the tyrosine kinase domain of the epidermal growth factor recep-tor. J. Med. Chem. (1995) 38: 3482 – 3487.
157. BRIDGES AJ, ZHOU H, CODY DR et al: Tyrosine kinase inhibitors. 8. An unusually steep structure-activity a© Ashley Publications Ltd. All rights reserved.Exp. Opin. Invest. Drugs (1998) 7(4)relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibi-tor of the epidermal growth factor receptor. J. Med. Chem. (1996) 39: 267 – 276.
158. WAKELING AE, BARKER AJ, DAVIES DH et al.: Specific in-hibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines. Breast Cancer Res. Treat. (1996) 38: 67 – 73.
159. KUNKEL MW, HOOK KE, HOWARD CT et al: Inhibition of the epidermal growth factor receptor tyrosine ki-nase by PD153035 in human A431 tumors in athymic nude mice. Invest. New Drugs (1996) 13: 295 – 302.
160. WOODBURN JR, BARKER AJ, GIBSON KH et al: ZD1839, an epidermal growth factor tyrosine kinase inhibitor selected for clinical development. Proc. Am. Assoc. Can-cer Res. (1997) 38: 633.
161. IWATA K, MILLER PE, BARBACCI EG et al.: CP-358,774: a selective EGFR kinase inhibitor with potent antiprolif-erative activity against 11N5 head and neck tumor cells. Proc. Am. Assoc. Cancer Res. (1997) 38: 633.
162. POLLACK VA, SAVAGE DM, BAKER DA et al.: Therapy of human carcinomas in athymic mice by inhibition of EGF receptor-mediated signal transduction with CP-358774: dynamics of receptor inhibition and anti-tumor effects. Proc. Am. Assoc. Cancer Res. (1997) 38: 633.
163. MOYER JD, BARBACCI EG, IWATA KK et al.: Induction of apoptosis and cell cycle arrest by CP-358,774, an in-hibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res. (1997) 57: 4838 – 4848.
164. BUCHDUNGER E, ZIMMERMANN J, METT H et al.: Selec-tive inhibition of the platelet-derived growth factor signal transduction pathway by a protein-tyrosine ki-nase inhibitor of the 2-phenylaminopyrimidine class. Proc. Natl. Acad. USA (1995) 92: 2558 – 2562.
165. WANG JY, PRYWES R, BALTIMORE D: Structure and func-tion of the Abelson murine leukemia virus transform-ing gene. Prog. Clin. Biol. Res. (1983) 119: 57 – 63.
166. SHTIVELMAN E, LIFSHITZ B, GALE RP, CANAANI E: Fused transcript of abl and bcr genes in chronic myelogen-ous leukaemia. Nature (1985) 315: 550 – 554.
167. BUCHDUNGER E, ZIMMERMANN J, METT H et al: Inhibi-tion of the Abl protein-tyrosine kinase in vitro and in vivoby a 2-phenylaminopyrimidine derivative. Cancer Res. (1996) 56: 100 – 104.
168. THOMPSON AM, BRIDGES AJ, FRY DW, KRAKER AJ, DENNY WA: Tyrosine kinase inhibitors. 7. 7-Amino-4-(phenylamino)- and 7-amino-4-Rphenyl-methyfiaminolpyrido[4,3-d]pyrimidines: a new class of inhibitors of the tyrosine kinase activity of the epi-dermal growth factor receptor. J. Merl. Chem. (1995) 38: 3780 – 3788.
169. REWCASTLE GW, PALMER BD, THOMPSON AM et al. Ty-rosine kinase inhibitors. 10. Isomeric 4-[(3-bromophenyfiamino]pyrido[d]-pyrimidines are po-tent ATP binding site inhibitors of the tyrosine kinase function of the epidermal growth factor receptor. J. Merl. Chem. (1996) 39: 1823 – 1835.
170. THOMPSON AM, MURRAY DK, ELLIOTT WL et al.: Tyro-sine kinase inhibitors. 13. Structure-activity relation-ships for soluble 7-substituted 4-[(3-bromophenyfi-amino]pyrido[4,3-d]pyrimidines designed as inhibi-tors of the tyrosine kinase activity of the epidermal growth factor receptor. J. Med. Chem. (1997) 40: 3915 – 3925.
171. REWCASTLE GW, BRIDGES AF, FRY DW, RUBIN JR, DENNY WA: Tyrosine kinase inhibitors. 12. Synthesis and structure-activity relationships for 6-substitututed 4- (p he nylamino) pyrimido [5,4- di pyrimidines de-signed as inhibitors of the epidermal growth factor re-ceptor. J. Med. Chem. (1997) 40: 1820 – 1826.
172. FRY DW, NELSON JM, SLINTAK V et al: Biochemical and antiproliferative properties of 4-[ar(alk)yl-amino]pyridopyrimidines, a new chemical class of po-tent and specific epidermal growth factor receptor tyrosine kinase inhibitor. Biochem. Pharmacol. (1997) 54: 877 – 887.
173. KRAKER AJ, MOORE CW, AMAR AM et al.: Cytoxicity and phosphotyrosine effects of c-src kinase inhibition by substituted pyridopyrimidine tyrosine kinase inhibi-tors in human colon carcinoma cell lines. Proc. Am. As-soc. Cancer Res. (1997) 38: 633.
174. PANEK RL, LU GH, KLUTCHKO SR et al.: In vitro pharma-cological characterization of PD 166285, a new nano-molar potent and broadly active protein tyrosine kinase inhibitor. J. Pharmacol Exp. Ther. (1997) 283: 1433 – 1444.
175. HAMBY JM, CONNOLLY CJ, SCHROEDER MC et al.: Structure-activity relationships for a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. J. Med. Chem. (1997) 40: 2296 – 2303.
176. BUCHDUNGER E, TRINKS U, METT H et al.: 4,5-Dianilinophthalimide: a protein tyrosine kinase in-hibitor with selectivity for the epidermal growth fac-tor receptor signal transduction pathway and potent in vivo antitumor activity. Proc. Natl. Acad. Sci. USA (1994) 91: 2334 – 2338.
177. TRAXLER P, BOLD G, FREI J et al.: Use of a pharma-cophore model for the design of EGF-R tyrosine kinase inhibitors: 4-(phenylamino)pyrazolo[3,4-d]pyrimid-ines. J. Merl. Chem. (1997) 40: 3601 – 3616.
178. HANKE JH, GARDNER JP, DOW RL et al.: Discovery of a novel potent, and src family-selective tyrosine kinase inhibitor. J. Biol. Chem. (1996) 271: 695 – 701.
179. MOHAMMADI M, MCMAHON G, SUN L et al.: Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science (1997) 276: 955 – 960.
180. SHAWVER LK, LIPSON KE, FONG TAT et al.: Receptor ty-rosine kinases as targets for inhibition of angiogene-sis. Drug Disc. Today (1997) 2:50-63.Laurie M Strawn & Laura K Shawver