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Review

Cancer metastasis therapeutic targets and drug discovery: emerging small-molecule protein kinase inhibitors

Pages 1-19 | Published online: 02 Mar 2005

  • BOGENRIEDER T, HERLYN M: Axis of evil: molecular mechanisms of cancer metastasis. Oncogene (2003) 22:6524–6536.
  • ••Excellent review describing the intimatemechanisms contributing to cancer metastasis.
  • HANAHAN D, WEINBERG RA: The hallmarks of cancer. Cell (2000) 100:57–70.
  • ••Excellent review describing the intricatenetwork of biological activities that are orchestrated in various types of cancers.
  • MACALUSO M, PAGGI MG, GIORDANO A: Genetic and epigenetic alterations as hallmarks of the intricate road to cancer. Oncogene (2003) 22:6472–6478.
  • PONDER BAJ: Cancer genetics. Nature (2001) 411:336–341.
  • NYGREN P, LARSSON R: Overview of the clinical efficacy of investigational anticancer drugs. J. Internal Med. (2003) 251:46–75.
  • CHAMBERS AF, GROOM AC, MACDONALD IC: Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer (2002) 2:563–572.
  • KAUFFMAN EC, ROBINSON VL, STADLER WM, SOKOLOFF MH, RINKER-SCHAEFFER CW: Metastases suppression: the evolving role of metastases suppressor genes for regulating cancer cell growth at the secondary site. J. Urology (2003) 169:1122–1133.
  • WOODHOUSE EC, CHUAQUI RF, LIOTTA LA: General mechanisms of metastasis. Cancer (1997) 80:1529–1537.
  • FIDLER LJ: Critical determinants of cancer metastasis: rational for therapy. Cancer Chemother. Pharmacol. (1999) 43:S3–S10.
  • WYCKOFF JB, JONES JG, CONDEELIS JS, SEGALL JE: A critical step in metastasis: in vivo analysis of intravasation at the primary tumor. Cancer Res. (2000) 60:2504–2511.
  • FIDLER LJ: Orthotopic implantation of human colon carcinomas into nude mice provides valuable model for the biology and therapy of metastasis. Cancer Metastasis Rev. (1991) 15:272–306.
  • KOHN EC, LIOTTA LA. Molecular insights into cancer invasion: strategies for prevention and intervention. Cancer Res. (1995) 55:1856–1862.
  • RADINSKY R, ELLIS LM: Molecular determinants in the biology of liver metastasis. Surg. Oncol. Clin. North Am. (1996) 5:215–229.
  • MUNDY GR: Metastasis to bone: causes, consequences and therapeutic opportunities. Nat. Rev. Cancer (2002) 2:584–593.
  • ••Excellent review describing bone metastasisand therapeutic strategies.
  • HOFFMAN RM: Orthotopic metastatic mouse models for anticancer drug discovery and evaluation: a bridge to the clinic. Invest. New Drugs (1999) 17:343–359.
  • CHAMBERS AF, MACDONALD IC, SCHMIDT EE, MORRIS VL, GROOM AC: Clinical targets for anti-metastasis therapy. Adv. Cancer Res. (2000) 79:91–121.
  • THOMAS SM, BRUGGE JS: Cellular functions regulated by Src family kinases. Ann. Rev. Cell. Dev. Biol. (1997) 13:513–609.
  • BLUME-JENSEN P, HUNTER T: Oncogenic kinase signalling. Nature (2002) 411:355–365.
  • ••Excellent review describing the molecularaspects of oncogenic protein kinases at the genetic and cellular levels.
  • DONG Tr, LAMB PW, RINKER-SCHAEFFER CW et al.: KAI1, a metastasis suppressor gene for prostate cancer on human chromasome 11p11.2. Science (1995) 12:884–886.
  • MORRIS VL, SCHMIDT EE, KOOP S et al.: Effects of the disintegrin erisostatin on individual steps of hematogeneous metastasis. Exp. Cell Res. (1995) 219:571–578.
  • HERYNK MH, RADINKSKY R: The coordinated functional expression of epidermal growth factor receptor and c-Met in colorectal carcinoma metastasis. In Vivo (2000) 14:587–596.
  • DE MARZO AM, KNUDSEN B, CHAN-TACK K, EPSTEIN JI: E-cadherin expression as a marker of tumor aggressiveness in routinely processed radical prostatectomy specimens. Urology (1999) 3:707–713.
  • GAO AC, LOU W, DONG JT, ISAACS JT: CD44 is a metastasis suppressor gene for prostatic cancer located on human chromosome 11p13. Cancer Res. (1997) 57:846–849.
  • YOSHIDA BA, DUBAUSKAS Z, CHEKMAREVA MA, CHRISTIANO TR, STADLER WM, RINDKER- SCHAFFER CW: Mitogen-activated protein protein 4/stress-activated protein/ Erc kinase 1 (MKK4/SEK1), a prostate cancer metastasis suppressor gene encoded by human chromosome 17. Cancer Res. (1999) 59:5483–5487.
  • KONISHI N, NAKAOKA S, TSUZUKI T et al.: Expression of nm23-H1 and nm23-H2 proteins in prostate carcinoma. Jpn. J. Cancer Res. (1993) 84:1050–1054.
  • LEE JH, WELCH DR: Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res. (1997) 57:2384–2387.
  • LEE JH, MIELE ME, HICKS DJ et al.: KiSS-I, a novel human malignant melanoma metastasis-suppressor gene. J. Nod Cancer Inez (1996) 88:1731–1777.
  • HABERMANN H, RAY V, HABERMANN W, PRINS GS: Alterations in gap junction protein expression I human benign prostatic hyperplasia and prostate cancer. J. UroL (2002) 167:655–660.
  • NAUMOV GN, WILSON SM, MACDONALD IC et al.: Cellular expression of green fluorescent protein, coupled with high-resolution in vivo videomicroscopy to monitor steps in tumor metastasis. J. Cell Sci. (1999) 112:1835–1842.
  • KUO TH, KUBOTA T, WATANABE M et al.: Liver colonization competence governs colon cancer metastases. Proc. Nail. Acad. Sci. USA (1995) 92:12085–12099.
  • HAHN WC, WEINBERG RA: Modelling the molecular circuitry of cancer. Nat. Rev. Cancer (2002) 2:331–341.
  • NAM NH, PARANG K: Current targets for anticancer drug discovery. Curr. Drug Targets (2003) 4:159–179.
  • EBRALIDZE A, TULCHINSKY E, GRIGORIAN M et al.: Isolation and characterization of a gene specifically expressed in different metastatic cells and whose deduced gene product has a high degree of homology to Ca2*-binding protein family. Gene Dev. (1989) 3:1086–1093.
  • DEAR TN, RAMSHAW IA, KEFFORD RF: Differential expression of a novel gene, WDNM I, in nonmetastatic rat mammary adenocarcinoma cells. Cancer Res. (1988) 48:5203–5209.
  • DEAR TN, MCDONALD DA, KEFFORD RF: Transcriptional down-regulation of a rat gene, WDNM2, in metastatic DMBA-8 cells. Cancer Res. (1989) 49:5323–5328.
  • BASSETT P, BELLOCQ JP, WOLF C et al.: A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinoma. Nature (1990) 348:699–704.
  • FUJITA M, SPRAY DC, CHOI H et aL: Extracellular matrix regulation of cell-cell communication and tissue-specific gene expression in primary liver cultures. Prog. Clin. BioL Res. (1986) 226:333–360.
  • XIA W, UNGER P, MILLER L, NELSON J, GELMAN IH: The Src-suppressed C kinase substrate SSeCKS, is a potential metastasis inhibitor in prostate cancer. Cancer Res. (2001) 61:5644–5651.
  • MIYAKE M, INUFASA H, ADACHI M et aL: Suppression of pulmonary metastasis using adenovirally motility related protein-I (MRP-I/CD9) gene delivery. Oncogene (2000) 19:5221–5226.
  • RADFOR KJ, MALLESCH J, HERSEY P: Suppression of human melanoma cell growth and metastasis by the melanoma associated antigen CD63 (ME491). Int. J. Cancer (1995) 62:631–635.
  • NAKAGAWA T, TANAKA S, SUZUKI H et al.: Overexpression of the csk gene suppresses tumor metastasis in vivo. Int. J Cancer (2000) 88:384–391.
  • FU Z, SMITH PC, ZHANG L et cd.: Effects of Raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. J. Nail. Cancer Inst. (2003) 95:878–889.
  • BISCARDI JS, TICE DA, PARSON SJ: c-Src, receptor tyrosine kinases, and human cancer. Adv. Cancer Res. (1999) 76:61–119.
  • SCHLESSINGER J: New roles for Src kinases in control of cell survival and angiogensis. Cell (2000) 100:293–296.
  • FRAME MC: Src in cancer: deregulation and consequences for cell behaviour. Biochim. Biophys. Acta (2002) 1602:114–130.
  • BOYCE BF, YONEDA T, LOWE C, SORIANO P, MUNDY GR: Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. Clin. Invest. (1992) 90:1622–1627.
  • XING L, VENGAS AM, CHEN A et aL: Genetic evidence for a role for Src family kinases in TNF family receptor signaling and cell survival. Genes Dev. (2001) 15:241–253.
  • PERL AK, WILGENBUS P, DAHL U, SEMB H, CHRISTOFORI G: A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature (1998) 392:190–193.
  • PAUL R, EWING CM, JARRARD DF, ISAACS WB: The cadherin cell-cell adhesion pathway in prostate cancer progression. Br. J. UroL (1997) 79(Suppl.):37–43.
  • MBALAVIELE G, DUNSTAN CR, SASAKI A, WILLIAMS PJ, MUNDY GR, YONEDA T: E-cadherin expression in human breast cancer cells suppresses the development of osteolytic bone metastasis in an experimental metastasis model. Cancer Res. (1996) 56:4063–4070
  • DARNELL JE JR: Transcription factors astargets for cancer therapy. Nat. Rev. Cancer (2002) 10:740–749.
  • CLARK EA, GOLUB TR, LANDER ES, HYNES RO: Genomic analysis of metastasis reveals an essential role for RhoC. Nature (2000) 406:532–535.
  • AVIZIENYTE E, WYKE AW, JONES RJ et al.: Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Nat. Cell Biol. (2002) 8:632–638.
  • SAKAMOTO M, TAKAMURI M, INO Y, MIURU A, GENDA T, HIROHASHI S: Involvement of c-Src in carcinoma cell motility and metastasis. Jpn. J. Cancer Res. (2001) 92:941–946.
  • BOYER B, BOURGEOIS Y, POUPON M-R: Src kinase contributes to the metastatic spread of carcinoma cells. Oncogene (2002) 21:2347–2356.
  • HOOD JD, CHERESH DA: Role of integrins in cell invasion and migration. Nat. Rev. Cancer (2002) 2:91–100.
  • GIANCOTTI FG, RUOSLAHTI E: Integrin signaling. Science (1999) 285:1028–32.
  • FELDING-HABERMANN B, O'TOOLE TE, SMITH JW et al.: Integrin activation controls metastasis in human breast cancer. Proc. NatL Acad. Sci. USA (2001) 98:1853–1858.
  • PRUITT K, DER CJ: Ras and Rho regulation of the cell cycle and oncogenes. Cancer Lett. (2001) 171:1–10.
  • BAR-SAGI D: A Ras by any other name. MoL Cell. Biol. (2001) 21:1441–1443.
  • BOS JL: Ras oncogenes in human cancer: a review. Cancer Res. (1989) 49:4682–4689.
  • MALANEY S, DALY RJ: The ras signaling pathway in mammary tumorigenesis and metastasis. J. Mammary Gland Biol. Neoplasia (2001) 6(1):101–113.
  • VARGHESE HJ, DAVIDSON MT, MACDONALD IC et al.: Activated Ras regulates the proliferation/apoptosis balance and early survival of developing micrometastasis. Cancer Res. (2001) 61:887–891.
  • SAHAI E, MARSHALL CJ: Rho-GTPases and cancer. Nat. Rev. Cancer (2002) 2:133–42.
  • MAREEL M, LEROY A: Clinical, cellular and molecular aspects of cancer invasion. PhysioL Rev. (2000) 83:337–376.
  • TAMANOI F, KATO-STANKIEWICZ J, JIANG C, MACHADO I, THAPAR N: Farnesylated proteins and cell cycle progression. J. Cell Biochem. (2001) 37(Suppl.):64–70.
  • MANNING G, WHYTE DB, MARTINEZ R, HUNTER T, SUDARSANAM S: The protein kinase complement of the human genome. Science (2002) 298:1912–1934.
  • MANNING BD, CANTLEY LC: Hitting the target: emerging technologies in the search for kinase substrates. Sci. STKE (2002) (162):PE49.
  • COLLETT MS, ERIKSON RL: Protein kinase activity associated with the avian sarcoma virus src gene product. Proc. Natl. Acad. Sci. USA (1978) 75:2021–2024.
  • STRAWN LM, SHAWVER LK: Tyrosine kinases in diseases. Overview of kinase inhibitors as therapeutic agents and current drugs in clinical trials. Expert Opin. Investig. Drugs (1998) 7:533–573.
  • TSATSANIS C, SPANDIDOS DA: The role of oncogenic kinases in human cancer. Int. J. Malec. Med. (2000) 5:583–590.
  • COHEN P: Protein kinases-the major drug targets of the twenty-first century? Nat. Rev. Drug Discov. (2002) 1:309–315.
  • DREVS J, MEDINGER M, SCHMIDT-GERSBACH C, WEBER R, UNGER C: Receptor tyrosine kinases: the main targets for new anticancer therapy. Curr. Drug Targets (2003) 4:113–121.
  • BRUNELLESCHI S, PENEGO L, SANTORO MM, GAUDINO G: Receptor tyrosine kinases as target for anti-cancer therapy. Curr. Pharm. Design (2002) 8:1959–1972.
  • FABBRO D, RUETZ S, BUCHDUNGER E et al.: Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. PharmacoL Ther. (2002) 93(2-3):79–98.
  • COHEN GB, REN R, BALTIMORE D: Modular binding domains in signal transduction. Cell (1995) 80:237–248.
  • PAWSON T: Protein modules and signalling networks. (1995) Nature 373:573–580.
  • SAWYER TK, BOHACEK RS, DALGARNO DC et aL: SRC homology-2 inhibitors: peptidomimetic and nonpeptide. Mini-Rev. Med. Chem. (2002) 2:475–488.
  • CIARDIELLO F, TORTORA G: A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res. (2001) 7:2958–2970.
  • MCLEAN GW, AVIZIENYTE E, FRAME MC: Focal adhesion kinase as a potential target in oncology. Expert Opin. Pharmacother. (2003) 4:227–234.
  • JONES RJ, BRUNTON VG, FRAME MC: Adhesion-linked kinases in cancer, emphasis on src, focal adhesion kinase and PI 3-kinase. Eur. j Cancer (2000) 36:1595–1606.
  • SAWYER T, BOYCE B, DALGARNO, IULIUCCI J: Src inhibitors: genomics to therapeutics. Expert Opin. Investig. Drugs (2001) 10:1327–1344.
  • METCALF CA III, VAN SCHRAVENDIJK MR, DALGARNO DC, SAWYER TK: Targeting protein kinases for bone disease: discovery and development of Src inhibitors. Curr. Pharm. Design (2002) 8:2049–2075.
  • SUSA M, MISSBACH, M, GREEN J: Src inhibitors: drugs for the treatment of osteoporosis, cancer or both? Trends PharmacoL Sci. (2000) 21:489–495.
  • MAA M-C, LEU TH, MCCARLEY DJ, SCHATZMAN RC, PARSONS SJ: Potentiation of epidermal growth factor receptor-mediated oncogenesis by c-Src: implications for the etiology of multiple human cancers. Proc. NatL Acad. Sci. USA (1995) 92:6981–6985.
  • MAO W, IRBY R, COPPOLA D et al.: Activation of c-Src by receptor tyrosine kinases in human colon cancer cells with high metastatic potential. Oncogene (1997) 15:3083–3090.
  • IRBY RB, MAO W, COPPOLA D et aL:Activating SRC mutation in a subset of advanced human colon cancers. Nat. Genet (1999) 21:187–190.
  • TALAMONTI MS, ROH MS, CURLEY SA, GALLICK GE: Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer. J. Clin. Invest. (1993) 91:3–60.
  • VAN OIJEN MG, RIJKSEN G, TEN BROEK FW, SLOOTWEG PJ: Overexpression of c-Src in areas of hyperproliferation in head and neck cancer, premalignant lesions and benign mucosal disorders. J. Oral PathoL Med. (1998) 27:147–152.
  • LUTZ MP, ESSE IBIB, FLOSSMANN-KAST BB et al.: Overexpression and activation of the tyrosine kinase Src in human pancreatic carcinoma. Biochem. Biophys. Res. Commun. (1998) 243:503–508.
  • NABEL EG: CDKs and CKIs: molecular targets for tissue remodelling. Nat. Rev. Drug Discov. (2002) 1:587–598.
  • MORGA DO: Cyclin-dependent kinases: engines, clocks, and microprocessors. Ann. Rev. Cell. Dev. Biol. (1997) 13:261–291.
  • SIELECKI TM, BOYLAN JF, BENFIELD PA, TRAINOR GL: Cyclin-dependent kinase inhibitors: useful targets in cell cycle regulation. J. Med. Chem. (2000) 43:1–18.
  • KAMB A, GRUIS NA, WEAVER-FELDHAUS J et al.: A cell cycle regulator potentially involved in genesis of many tumor types. Science (1994) 264:436–440.
  • LI Q, ZHU GD: Targeting serine/threonine protein kinase B/Akt and cell-cycle checkpoint kinases for treating cancer. Curr. Topics Med. Chem. (2002) 2:939–971
  • HILL MM, HEMMINGS BA: Inhibition of protein kinase B/Akt. Implications for cancer therapy. PharmacoL Ther. (2002) 93:243–251.
  • MAYO LD, DONNER DB: The PTEN, Mdrn2, p53 tumor suppressor-oncoprotein network. Trends Biochem. Sci. (2002) 27:462–467.
  • VIVANCO I, SAWYERS CL: The phosphoinositide 3-kinase AKT pathway in human cancer. Nat. Rev. Cancer (2002) 2:489–501.
  • YOGANATHAN N, YEE A, ZHANG Z et al.: Integrin-linked kinase, a promising cancer therapeutic target: biochemical and biological properties. PharmacoL Ther. (2002) 93:233–242.
  • LOS M, BUREK CJ, STROH C, BENEDYK K, HUG H, MACKIEWICZ A: Anticancer drugs of tomorrow: apoptotic pathways as targets for drug design. Drug Discov. Today (2003) 8:67–77.
  • STEIN RC: Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment. Endocr. Relat. Cancer (2001) 8:237–248.
  • CHEN J, FANG Y: A novel pathway regulating the mammalian target of rapamycin (mTOR) signaling. Biochem. PharmacoL (2002) 64:1071–1077.
  • HIDALGO M, ROWINSKI EK: The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene (2000)19:6680–6686.
  • HUANG S, HOUGHTON PJ: Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr. Opin. Investig. Drugs (2002) 3:295–304.
  • MAGEE T, MARSHALL C: New insights into the interaction of Ras with the plasma membrane. Cell (1999) 98:9–12.
  • KERKHOFF E, RAPP UR: Cell cycle targets of Ras/Raf signalling. Oncogene (1998) 17:1457–1462.
  • WEINSTEIN-OPPENHEIMER CR, BLALOCK \In., STEELMAN LS, CHANG F, MCCUBREY JA: The Raf signal transduction cascade as a target for chemotherapeutic intervention in growth factor-responsive tumors. Pharmacol Ther. (2000) 88:229–279.
  • NOTTAGE M, SIU LL: Rationale for Ras and raf-kinase as a target for cancer therapeutics. Curr. Pharm. Des. (2002) 8:2231–2242.
  • DAVIES H, BIGNELL GR, COX C et al.: Mutations of the BRAF gene in human cancer. Nature (2002) 417:949–954.
  • JOHNSON GL, LAPADAT R: Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science (2002) 298: 1911-1912.
  • KATSANAKIS KD, OWEN C, ZOUMPOULIS V: JNK and ERK signaling pathways in multistage mouse carcinogenesis: studies in the inhibition of signaling cascades as a means to understand their in vivo biological role. Anticancer Res. (2002) 22:755–759.
  • FOLKMAN J: Role of angiogenesis in tumor growth and metastasis. Semin. OncoL (2000) 29:15–19.
  • RELF M, LEJEUNE S, SCOTT PA et al.: Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. (1997) 57:963–969.
  • TAYLOR AP, OSORIO L, CRAIG R et aL: Tumor-specific regulation of angiogenic growth factors and their receptors during recovery from cytotoxic therapy. Clin. Cancer Res. (2002) 8:1213–1222.
  • NABESHIMA K, INOUE T, SHIMAO Y, SAMESHIMA T: Matrix metalloproteinases in tumor invasion: role for cell migration. PathoL Intern. (2002) 52:255–264.
  • CHANG C, WERB Z: The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis. Trends Cell. Biol. (2001) 11:S37–S43.
  • JIANG Y, GOLDBERG ID, SHI YE: Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene (2001) 21:2245–2252.
  • GIANNELLI G, ASTIGIANO S, ANTONACI S et al.: Role of a3131 and a634 integrins in tumor invasion. Clin. Exp. Metastasis (2002) 19:217–223.
  • KUMAR CC: Integrin avI33 as a therapeutic target for blocking tumor-induced angiogenesis. Curr. Drug Targets (2003) 4:123–131.
  • ALBELDA SM, METTE SA, ELDER DE et al.: Integrin distribution in malignant melanoma: association of the 133 subunit with tumor progression. Cancer Res. (1990) 50:6757–6764.
  • LIAPIS H, FLATH A, KITAZAWA S: Integrin a433 expression by bone-residing breast cancer metastases. Diagn. MoL PathoL (1996) 5:27–135.
  • PECHEUR I, PEYRUCHAUD 0, SERRE C-M et aL: Integrin avI33 expression confers on tumor cells a greater propensity to metastasize to bone. FASEB (2002) 16:1266–1268.
  • TETI A, MIGLIACCIO S, BARON R: The role of the avI33integrin in the development of osteolytic bone metastases: a pharmacological target for alternative therapy? Calcified Tissue Intern. (2002) 71:293–299.
  • TUCKER GC: Inhibitors of integrins. Curr. Opin. PharmacoL (2002) 2:394–402.
  • COLEMAN RE: Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat. Rev. (2001) 27:165–176.
  • O'KEEFE, RJ, SCHWARZ EM, BOYCE BF: Bone metastasis: an update on mechanisms of bone resorption and therapeutic strategies. Curr. Opin. Orthoped. (2000) 11:353–359.
  • SOUTHBY J, KISSIN MW, DANKS JA et al.: Immunohistochemical localization of parathyroid hormone-related protein in breast cancer. Cancer Res. (1990) 50:7710–7716.
  • POWELL GJ, SOUTHBY J, DANKS JA et al.: Localization of parathyroid hormone-related protein in breast cancer metastasis: increased incidence in bone compared to other sites. Cancer Res. (1991) 51:3059–3061.
  • BRYDEN AA, HOYLAND JA, FREEMONT AJ, CLARKE NW, GEORGE NJ: Parathyroid hormone related peptide and receptor expression in paired primary prostate cancer and bone metastasis. Br .j Cancer (2002) 86:322–325.
  • MIKI T, YANO S, HANBUCHI M, SONE S: Bone metastasis model with multiorgan dissemination of human small-cell lung cancer. OncoL Res. (2001) 12:209–217.
  • ZHANG QX, BORG A, WOLF DM, OESTERREICH S, FUQUA SA: An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res. (1997) 57:1244–1249.
  • DE LARCO JE, WUERTZ BR, ROSNER KA al.: A potential role for IL-8 in the metastatic phenotype of breast carcinoma cells. Am.. J Pathol. (2001) 158:639–646.
  • DOWNEY SE, HOYLAND J, FREEMONT AJ, KNOX F, WALLS J, BRUNDRED NJ: Expression of the receptor for parathyroid hormone-related protein in normal and malignant breast tissue. J. PathoL (1997) 183:212–217.
  • GUISE TA, YIN JJ, TAYLOR SD et aL: Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. Clin. Invest. (1996) 98:1544–1549.
  • GALLWITZ WE, GUISE TA, MUNDY GR: Guanosine nucleotides inhibit different syndromes of PTHrP excess caused by human cancers in vivo. Clin. Invest. (2002) 110:1559–1572.
  • BENDRE MS, GADDY-KURTEN D, MON-FOOTE T et al.: Expression of interleukin 8 and not parathyroid hormone-related protein by human breast cancer cells correlates with bone metastasis in vivo. Cancer Res. (2002) 62:5571–5579.
  • THOMAS RJ, GUISE TA, YIN JJ et al.: Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology (1999) 140:4451–4458.
  • NELSON JB, NABULISI AA, VOGELZANG NJ et al.: Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat. Med. (1995) 1:944–949.
  • GUISE TA, YIN JJ, MOHAMMED KS: Role of endothelin-1 in osteoblastic bone metastases. Cancer (2003) 97:779–784.
  • HARRIS SE, BONEWALD LF, HARRIS MA et al.: Effects of transforming growth factor-I3 on bone nodule formation and expression of bone morphogenic protein 2, osteocalcin, osteopontin, alkaline phosphatase, and type 1 collagen mRNA in longterm cultures of fetal rat calvarial osteoblasts. J Bone Min. Res. (1994) 9:855–863.
  • DAWSON NA: Bisphosphonates: their evolving role in the management of prostate cancer-related bone disease. Curr. Opin. UroL (2002) 12:413–418.
  • GREEN JR, CLEZARDIN P: Mechanisms of bisphosphonate effects on osteoclasts, tumor cell growth, and metastasis. Am. J. Clin. OncoL (2002) 25(6 Suppl. 1):53–59.
  • SASAKI A, BOYCE BF, STORY B et al.: Bisphosphonate risedronate reduces metastatic human breast cancer burden in nude mice. Cancer Res. (1995) 55:3551–3557.
  • DIEL IF, SOLOMAYER EF, COSTA SD et al.: Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N EngL J. Med. (1998) 339:357–363.
  • CARTER P: Improving the efficacy of antibody-based cancer therapies. Nat. Rev. Cancer (2001) 1:118–129.
  • ELLIS LM: A targeted approach for antiangiogenic therapy of metastatic human colon cancer. Am. Surg. (2003) 69:3–10.
  • LEYLAND-JONES B: Trastuzumab: hopes and realities. Lancet OncoL (2002) 3:137–144.
  • GRETEN TF, JAFFEE EM: Cancer vaccines./ Clin. OncoL (1999) 17:1047–1060.
  • TAMM I, KORKEN B, HARTMANN G: Antisense therapy in oncology: new hope for an old idea? Lancet (2001) 358:489–497.
  • WANG H, PRASAD G, BUOLAMWINI JK, ZHANG R: Antisense anticancer oligonucleotide therapeutics. Curr. Cancer Drug Targets (2001) 1:177–196.
  • MCCORMICK F: Cancer gene therapy: fringe or cutting edge? Nat. Rev. Cancer (2001) 1:130–141.
  • BYKOV FJN, ISSAEVA N, SHILOV A et al.: Restoration of tumor suppressor function to mutant p53 by a low-molecular weight compound. Nat. Med (2002) 8:282–288.
  • AINA OH, SROKA TC, CHEN ML, LAM KS: Therapeutic cancer targeting peptides. Biopolymers (2002) 66:184–199.
  • BRUMMELKAMP TR, BERNARDS R: New tools for functional mammalian cancer genetics. Nat. Rev. Cancer (2003) 3:781–788.
  • ANZICK SL, TRENT JM: Role of genomics in identifying new targets for cancer therapy. Oncology (2002) 16(5 Suppl. 4):7–13.
  • HANASH S: Disease proteomics. Nature (2003) 422:226–232.
  • DANCEY J, SAUSVILLE EA: Issues and progress with protein kinase inhibitors for cancer treatment. Nat. Rev. Drug Discov. (2003) 2:296–313.
  • FABBRO D, RUETZ S, BUCHDUNGER E et al.: Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. PharmacoL Ther. (2002) 93:79–98.
  • DE BONO JS, ROWINSKY EK: Therapeutics targeting signal transduction for patients with colorectal carcinoma. Br. Med. Bull. (2002) 64:227–254.
  • ZHU Z, BOHLEN P, WITTE L: Clinical development of angiogenesis inhibitors to vascular endothelial growth factor and its receptors as cancer therapeutics. Curr. Cancer Drug Targets (2002) 2:135–156.
  • BASELGA J, HAMMOND LA: HER-targeted tyrosine-kinase inhibitors. Onco/ogy (2002) 63\(Suppl. 1):6–16.
  • RANSON M, SLIWKOWSKI MX: Perspectives on anti-HER monoclonal antibodies. Onco/ogy (2002) 63\(Suppl. 1):17–24.
  • LIPTON A, SMALL E, SAAD F et al.: The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to parnidronate. Cancer Invest. (2002) 20\(Suppl. 2):45–54.
  • LIPTON A: Bone metastases in breast cancer. Curr. Treat. Options OncoL (2003) 4:151–158.
  • GIANNI L: The future of targeted therapy: combining novel agents. Oncology (2002) 63\(Suppl. 1):47–56.
  • HALUSKA P, DY GK, ADJEI AA: Farnesyl transferase inhibitors as anticancer agents. Eur. Cancer (2002) 38:1685–1700.
  • OHKANDA J, KNOWLES DB, BLASKOVICH MA, SEBTI SM, HAMILTON AD: Inhibitors of protein farnesyltransferase as novel anticancer agents. Curr. Top. Med. Chem. (2002) 2:303–323
  • JOHNSTON SR: Farnesyl transferase inhibitors: a novel targeted therapy for cancer. Lancet OncoL (2001) 2:18–26.
  • SEBOLT-LEOPOLD JS: Development of anticancer drugs targeting the MAP kinase pathway. Oncogene (2000) 19:6594–6599.
  • HIRTE HW, VERGOTE IB, JEFFREY JR et al.: An international multicentre Phase III study of BAY 12–9566 (BAY) versus placebo in patients (pts) with advanced ovarian cancer (OVCA) responsive to primary surgery/paclitaxel + platinum containing chemotherapy. Proc. Am. Soc. Clin. OncoL (2001) 20:A843 (Abstract).
  • EGEBLAD M, WERB Z: New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer (2002) 2:161–174.
  • SPARANO JP, BERNARDO P, GRADISHAR WJ, INGLE JN, ZUCKER S, DAVIDSON NE: Randomized Phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: an Eastern Cooperative Oncology Group trial. Proc. Am. Soc. Clin. OncoL (2002) 21:A173 (Abstract).
  • KING J, CLINGAN P, MORRIS DL: Placebo control double-blind randomised clinical trial of the matrix metalloproteinase inhibitor (MMP) marimastat in patients with inoperable colorectal cancer liver metastasis (CRCLM): significant survival advantage in patients with muscoloskeletal symptoms. Proc. Am. Soc. Clin. OncoL (2002) 21:A537 (Abstract).
  • BRAMHALL SR, ROSEMURGY A, BROWN PD, BOWRY C, BUCKELS JAG: Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J. Clin. OncoL (2001) 19:2447–3455.
  • YANG JC, HAWORTH I, STEINBERG SM, ROSENBERG SA, NOVOTNY W: A randomized double-blind placebo-controlled trial of bevacizumab (anti-VEGF antibody) demonstrating a prolongation in time to progression in patients with metastatic renal cancer. Proc. Am. Soc. Clin. OncoL (2002) 21:A15 (Abstract).
  • GUTHEIL JC, CAMPBELL TN, PIERCE PR et al.: Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin avI33. Clin. Cancer Res. (2000) 6:3056–3061.
  • VOEST EE, BEEREPOOT LV, GROENEWEGAN Get al.: Phase I trial of recombinant angiostatin by twice-daily subcutaneous injection in patients with advanced cancer. Proc. Am. Soc. Clin. OncoL (2002) 21:A322 (Abstract).
  • HERBST RS, HESS KR, TRAN HT et al.: Phase I study of recombinant human endostatin in patients with advanced solid tumors./ Clin. OncoL (2002) 20:3792–3803.
  • POWLES T, PATERSON S, KANIS JA et al.: Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J. Clin. OncoL (2002) 20:3219–3124.
  • FREIJE JM, BALBIN M, PENDAS AM, SANCHEZ LM, PUENTE XS, LOPEXZ-OTIN C: Matrix metalloproteinases and tumor progression. Adv. Exp. Med. Biol. (2003) 532:91–107.
  • HEIKKILA P, TERONEN 0, HIRU MY et al.: Inhibition of matrix metalloproteinase-14 in osteosarcoma cells by clodronate. J. Surg. Res. (2003) 111:45–52.
  • CLEZARDIN P, FOURNIER P, BOISSIER S, PEYRUCHAUD 0: In vitro and in vivo antitumor effects of bisphosphonates. Curr. Med. Chem. (2003) 10:173–180.
  • OADES GM, SENARTNE SG, CLARKE IA, KIRBY RS, COLSTON KW: Nitrogen containing bisphosphonates induce apoptosis and inhibit the mevolonate pathway, impairing Ras membrane localization. J UroL (2003) 170:246–252.
  • DENOYELLE C, HONG L, VANNIER JP, SORIA C: New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and independent effects. Br. J Cancer (2003) 88:1631–1640.
  • DRUKER BJ: 5TI571 (Gleevec/Glivec, imatinib) versus interferon + cytarabine as initial therapy for patients with CML. Results of a randomized study. Proc. Am. Soc. Clin. OncoL (2002) 21:A1.
  • CAPDEVILLE R, BUCHDUNGER E, ZIMMERMANN J, MATTER A: Glivec (5TI571, Imatinib), a rationally developed, targeted anticancer drug. Nat. Rev. Drug Disc. (2002) 1:493–502.
  • BASELGA J, TRIGO JM, BOUHRIS J et al.: Cetuximab (C225) plus cisplatin/ carboplatin is active in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) progressing on a same does and schedule platinum-based regimen. Proc. Am. Soc. OncoL (2002) 21:A900 (Abstract).
  • BURTNESS BA, FLOOD YLW, MATTAR BI, FORASTIERE AA: Phase III trial comparing cisplatin (C) + placebo (P) + epidermal growth factor receptor antibody (EGF-R) C225 in patients (pts) with metastatic/recurrent head and neck cancer (HNC). Proc. Am. Soc. Clin. OncoL (2000) 21:A901 (Abstract).
  • SLAMON DJ, LEYLAND-JONES B, SHAK S et al.: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. EngL J Med (2001) 344:783–792.
  • FUKUOKA M, YANO S, GIACCONE G et al.: Final results from a Phase II trial of ZD1839 ('Iressd) for patients with advanced non-small cell lung cancer (IDEAL 1). Proc. Am. Soc. Clin. OncoL (2002) 21:A1188 (Abstract).
  • NATALE RB, SKARIN A, MADDOX AM et al.: Improvement in symptoms and quality of life from advanced non-small cell lung cancer patients receiving ZD1839 ('Iressd) in IDEAL 2. Proc. Am. Soc. OncoL (2002) 21:A1167 (Abstract).
  • WILKINSON E: Surprise Phase III failure for ZD1839. Lancet OncoL (2002) 3:583.
  • HIDALGO M, SIU LL, NEMUNAITIS J et al.: Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. Clin. OncoL (2001) 19:3267–3279.
  • SUMMY JM, GALLICK GE: Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev. (2003) 22:337–358.
  • WANG Y, METCALF CA III, SHAKESPEARE WC et al.: Bone-targeted 2,6,9-trisubstituted purines: novel inhibitors of Src tyrosine kinase for the treatment of bone diseases. Bioorg. Med. Chem. Lett. (2003) 13:3067–3070.
  • SUNDARAMOORTHI R, SHAKESPEARE WC, KEENAN TP et aL: Bone-targeted Src kinase inhibitors: novel pyrrolo- and pyrazolopyrimidine analogs. Bioorg. Med. Chem. Lett. (2003) 13:3063–3066.
  • VU C, LUKE GP, KAWAHATA N et aL: Bone-targeted pyrido [2,3-d] pyrimidin-7-ones: potent inhibitors of Src tyrosine kinase as novel antiresorptive agents. Bioorg. Med. Chem. Lett. (2003) 13:3071–3074.
  • BOYCE BF, XING L, SHAKESPEARE W et al.: Regulation of bone remodeling and emerging breakthrough drugs for osteoporosis and osteolytic bone metastases. Kdney Int. (2003) 85:52–55.
  • SHAKESPEARE W, WANG Y, METCALF C et al.: Development of a novel bone-targeted Src tyrosine kinase inhibitor AP23451 having potent activity in an animal model of osteolytic bone metastasis. Proc. Am. Acad. Cancer Res. (2003) 44:A3871 (Abstract).
  • BELSCHES-JABLONSKI AP, BISCARDI JS, PEAVY DR, TICE DA ROMNEY DA, PARSONS SJ: Src family kinases and HER2 interactions in human breast cancer cell growth and survival. Oncogene (2001) 20:14674–1475.
  • MENKE A, PHILIPP C, VOGELMANN R et al.: Down-regulation of E-cadherin gene expression by collagen type I and type II in pancreatic cell lines. Cancer Res. (2001) 61:3508–3517.
  • ELICEIRI BP, PAUL R, SCHWARTBERG PL, HOOD JD, LENG J, CHERESH DA: Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol. Cell (1999) 4:915–924.
  • TATTON L, MORLEY GM, CHOPRA R, KHWAJA A: The Src-selective kinase inhibitor PP I also inhibits Kit and Bcr-Abl tyrosine kinases. J. Biol. Chem. (2003) 278:4847–4853.
  • CARLOMAGNO F, VITAGLIANO D, GUIDA T et al.: The kinase inhibitor PPI blocks tumorogenesis induced by RET oncogenes. Cancer Res. (2002) 62:1077–1082.
  • NAM JS, INO Y, SAKAMOTO M, HIROHASHI S: Src family kinase inhibitor PP2 restores the E-cadherin/catenin cell adhesion system in human cancer cells and reduces cancer metastasis. Clin. Cancer Res. (2002) 8:2430–2436.
  • BOSCHELLI DH: 4-Anilino-3-quinolinecarbonitriles: an emerging class of kinase inhibitors. Curr. Top. Med. Chem. (2002) 2:1051–1063.
  • YEZHELYEV M, WAGNER C, KOHL G et al.: In vivo and in vitro effects of a novel Src tyrosine kinase inhibitor on human pancreatic cancer in a nude mouse model. Proc. Am. Acad. Cancer Res. (2003) 44:A1718 (Abstract).
  • KEKHARAM M, NASIR A, KAISER HE, COPPOLA D: Insulin-like growth factor-I receptor activates c-SRC and modifies transformation and motility of colon cancer in vitro. Anticancer Res. (2003) 23:1517–1524.
  • RECCHIA I, RUCCI N, FESTUCCIA C et al.: Pyrrolopyrimidine c-Src inhibitors reduce growth, adhesion, motility and invasion of prostate cancer cells in vitro. Eur. J. Cancer (2003) 39:1927–935.
  • METCALF C III, WANG Y, SHAKESPEARE Wet al.: Discovery of potent and selective Src inhibitors and their development as antitumor and antimetastatic agents. Proc. Am. Acad. Cancer Res. (2003) 44:A1716.
  • O'HARE T, STOFFREGEN EP, ABDULLAH OM et al.: Potent inhibition of Imatinib-resistant variants of Bcr-Abl by a novel dual selective Src/Abl kinase inhibitor AP23464: Implications for CML therapy. Proc. Am. Soc. Hematol. (2003) A59.

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