5 Vol. 35, pp. 5 21, 2007 : 19 4 9 DNA 20 Heat shock protein 20 epidermal growth factor EGF EGFR EGFR 5
6 1 DNA DNA I 1 1 DNA DNA P- non-toxic II. 1 EGF epidermal growth factor; TGF transforming growth factor -a 6
7 EGF EGFR EGFR HER human epidermal growth factor HER1 type1 HER4 type4 HER2 human epidermal growth factor receptor type-2 EGFR HER2 2 CML 9 22 Philadelphia BCR-ABL ABL EGFR HER1 gefitinib Iressa, erlotinib Tarceva, cetuximab Erbitux, trastuzumab Herceptin, pertuzumab Omnitarg, KIT-TK imatinib Gleevec, bortezomib Velcade, CA125 oregovomab OvaRex, VEGF bevacizumab Avastin 1. gefitinib Iressa gefitinib Astra Zeneca HER1 EGFR HER1 4-amilinoquinazoline EGFR ATP ATP EGFR Ciardiello 3 OVCAR-3 gefitinib 2 4 gefitinib cisplatin, carboplatin, paclitaxel, docetaxel, topotecan 2 erlotinib Tarceva EGFR-TK erlotinib gefitinib EGFR-TK II II EGFR 34 PR 2 SD 15 PD 16 MST 8.1 3 trastuzumab Herceptin 2 4 4 5 6 10 25 HER2 HER2 Herceptin HER2 HER2 down regulation ADCC antibody dependent cell mediated cytotoxicity Herceptin HER2 114 Vogel 7 Herceptin 26 CR 7 PR 23 Hellström 8 HER 2 OVCAR-3 H3730 Herceptin OVCAR-3 H3730 Herceptin ADCC Naruse 9 cisplatin Herceptin 7
8 2 HER 632 22 580 EGFR 3 Trastuzumab HER2 HER HER HER2 transactivate 8
9 4 Herceptin NK Fc ADCC; Antibody-dependent cell-mediated cytotoxicity HER2 ADCC HER2 Herceptin Herceptin GOG 160 10 837 11.4 95 HER2 41 CR1 2.4 PR2 4.9 Herceptin 7.3 HER2 GOG160 HER2 4.1 4 HER2 Herceptin 9 HER2 9 2 RMG-1 HTOA HER 2 3 HMOA, OVISE, HAC-2 HER2 4 HNOA, HMKOA, MCAS, HTBOA 5 1 11 RMG-1 Herceptin HER2 MTT assay HAC-2 HER2 6 HER2 RMG-1 Herceptin Taxol 7 5 pertuzumab 2C4 2C4 Genentech HER2 binding site HER2 HER dimalization trastuzumab Herceptin binding site Herceptin HER2 Herceptin HER2 21 PR 3 SD 8 9
10 PD 10 12 6. CRM197 HB-EGF EGFR HER1 30 50 EGFR EGFR 7 EGF, TGF-a, amphiregulin AR, Epigen EPI EGFR HB-EGF heparin binding epidermal growth factor-like growth factor, epiregulin ER, beta cellulin BTC 1 Erk2 EGFR, EGFR4 HER4 13 HB-EGF RT-PCR 14 SKOV-3 EGFR HB-EGF HB-EGF HB-EGF HB-EGF CRM197 cross reacting material 197 HB-EGF Buzzi 15 25 CRM197 5 Western blot : RMG-1, HAC-2, OVISE : HNOA, HMOA : MCAS, HMKOA : HTOA : HTBOA 10
11 6 MTT assay Herceptin Geldanamycin RMG-1, HAC-2 stable disease 15 19 4 CRM197 phase I II 7 NK4 HB-EGF HGF c-met c-met NK4 HGF a HGF c-met HGF NK4 HGF c-met VEGF bfgf 16 NK4 NK4 NK4 8 oregovomab OvaRex : CA125 OvaRex CA125 65U ml PFS 24 11 17 2 angiostatin, endostatin matrix metalo-proteinase inhibitor MMP 11
12 7 RMG-1 xenograft RMG-1 MMP FDA bevacizumab Avastin soluble Flt-1 sflt-1: VEGF vascular endothelial growth factor receptor Flt-1 IL-10, SU6668 TSU-68: Z -5 1, 2-dihydro-2- oxo-3h-indol-3-ylidene methyl -2, 4-dimethyl-1Hpyrrole-3-ropanoic acid, VEGF, PDGF, bfgf 1 bevacizumab Avastin : VEGF bevacizumab VEGF IgG 1 isotype VEGF VEGF VEGF bevacizumab delivery 16 18 19 GOG218 2000 1 TC 12
13 TC 2 TC Avastin 3 TC Avastin Avastin 3 2 sflt-1 sflt-1 VEGF receptor Flt-1 VEGF sflt-1 VEGF receptor Flt-1 KDR Flk-1 20 VEGF RMG-1 sflt-1 RMG-1 sflt-1 control RMG-1 sflt-1 control sflt-1 3 IL-10 IL-10 VEGF IL-10 VEGF IL-10 21 4 SU6668 22 SU 6668 VEGF, PDGF, bfgf receptor KDR Flk-1, PDGFRb FGFR 1 3 heat shock proteins: Hsps heat shock proteins: Hsps Hsps Hsps Hsps 4 Hsp 90 Hsp70 Hsp60 small Hsps Hsp90 Hsp70 ATPase Hsps Hsps Hsps 1 Hsp 90 Geldanamycin 17- AAG Hsp90 HER2 AKT BCR- Abl p53 Hsp90 23 Hsp90 Hsp Geldanamycin GA 17-allyl-aminogeldanamycin 17-AAG 24 Hsp90 Hsp70 Hsp60 ATPase 8 25 Hsp90 13
14 8 HSP90 HSP90 HSP70, HSP40, Hop, p23 17 AAG HSP90 HSP90 Hsp90 GA 17-AAG Hsp90 Hsp90 50 Hsp90 GA Hsp90 client protein HER2 HER2 GA HER2 MTT assay HER2 5 6 GA HER 2 GA MTT assay HER2 1 RMG-1 1 HAC-2 2 Hsp70 Hsp BP1 Hsp70 Hsp60 Hsp90 Hsp70 Hsp70 26 Hsp70 UV Hsp70 Hsp90 Raynes 27 heat shock protein binding protein1 Hsp BP1 Hsp 70 Hsp70 Hsp BP1 Hsp70 HER2 GA control 2DLC-MS MS GA control Hsp70 Hsp70 GA 9 HSF-1: heat shock transcription factor1 Hsp90 HSF-1 Hsp90 DNA heat shock element, HSE Hsp70 GA Hsp 90 HSF-1 HSF-1 Hsp Hsp70 Hsp70 14
15 9 GA HSF1 HSP HSF-1: heat shock transcription factor1 Hsp90 HSF-1 Hsp90 DNA heat shock element, HSE Hsp70 Hsp70 RNAi Hsp70 Hsp70 Hsp70 inhibitor 4 1 gefitinib gefitinib EGFR EGFR GRB 2 SOS EGFR GRB 2 SOS 28 HER2 HER3 HER family EGFR AKT MAPK phenotype 29 Natale gefitinib GRG1 gefitinib resistant gene Artega PTEN EGFR 1 30 ZD 6474 VEGFR-2 KDR VEGFR-3 EGFR HER1 gefitinib 31 2 trastuzumab Herceptin trastuzumab HER2 15
16 32 trastuzumab HER2 pertuzumab Omnitarg 2C4 12 HER2 HER 2 Lu 33 IGF-I trastuzumab 10 IGF-I trastuzumab Cdk p27 Kip1 HER2 IGF-I HER2 p27 Kip1 p27 Kip1 trastuzumab HER2 p27 Kip1 p27 Kip1 Cdk2 Cdk IGF-I SKBR3 trastuzumab p27 Kip1 Skp 2 p27 Kip1 Skp 2 p27 Kip1 LLnL IGF-I trastuzumab IGF-I trastuzumab Muc4 Muc4 HER2 trastuzumab 34 Muc4 HER2 HER2 3 imatinib Gleevec imatinib 1 potency ABL BMS-354825 35 BCR-ABL Hsp90 BCR-ABL 10 Herceptin HER2 p27 Kip1 p27 Kip1 Herceptin HER2 p27 Kip1 p27 Kip1 Cdk2 Cdk2 IGF-I Herceptin p27 Kip1 IGF-I imatinib BCR-ABL 17- AAG 36 histone deacetylase: HDAC Hsp90 BCR-ABL 37 Hsp90 point mutation imatinib ABL Src sarcoma ABL imatinib AMN107 aminopyrimidine, NS187 dasanitiv dual Src ABL : BMS-354825 VX-180 Aurora 5 16
17 1 trastuzumab vinorelbine or toxotere MBC trastuzumab vinorelbine toxotere trastuzumab HER2 MBC 68 79 38 39 2 bevacizumab Avastin5-FU leucovoline CPT-11 bevacizumab CRC 5-FU leucovoline CPT-11 bevacizumab P 3 bevacizumab 15.6 20.3 40 In vitro HER1 HER2 VEGFR-2 KDR Kinase insert domain containing receptor c-abl, c- Src, Flt-1 multi-target inhibitor AEE788 PKI166 PTK787 ZK22584 paclitaxel 42 CPT-11 2 ZD6474 ZD6474 VEGFR-2 VEGFR-3 EGFR VEGF normal human umbilical vein endothelial cells: HUVEC xenograft 43 3 cetuximab erlotinib gemcitabin CRC cetuximab gemcitabin erlotinib EGFR 41 6 Multi-target inhibitor cytostatic drug SD stable disease gefinitib multi-target inhibitor 1 AEE788 AEE788 EGFR PKI166 VEGF PTK787 ZK22584 7 1 sorafenib BAY43-9006 : Raf Ras- MAPK Raf VEGFR-2 VEGFR-3 p38 PDGFR Flt- 3 c-kit EGFR phase III gemcitabin paclitaxel carboplatin phase II 44 2 lapatinib GW572016 : EGFR 17
18 HER1 HER2 HER2 20 30 15 30 trastuzumab Herceptin lapatinib phase II 45 3 ZD6474 gefinitib VEGFR-2, 3 EGFR xenograft phase III 44 4 mtor mammalian target of rapamycin Rapamycin mtor 46 47 rapamycin CCI-779 RAD001 AP23573 Rapamycin G 1 Rapamycin PTEN rapamycin rapamycin VEGF VEGF mtor PI3K hypoxia-inducible factor1a HIF-1a HIF Rapamycin rapamycin G 1 arrest Rapamycin prodrug CCI-779 phase II SD stable disease 50 PI3K AKT mtor p70s6k G 1 S rapamycin cyclin1 CDK4 CDC25A Rb G 1 S 5 bortezomib Velcade : bortezomib NF-kB nuclear factor kb IkB p53 p21 p27 Bax 48 NF-kB p53 p21 p27 Bax bortezomib bortezomib 49 43 8 6 5 4 2 1 18
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