Review Journal of The Korean Ger iatr ics Soci 2004:8(3):

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1 Review Journal of The Korean Ger iatr ics Soci 2004:8(3): Rece nt New Tre nds of Anticance r Drug The rapy Beom- Seok Yang, Ph. D, Biomedical Research Center, Korea Inst i tut e of Science and Technology 1. ( ) %, %, % % ,000, ,500 1). 1/3 : 39-1, : : bsyang@kist.re.kr, % , Gleevec, Herceptin, 2003 Iressa, 2004 Belcade, Avastin 30.,, 30,. 30,., 128 Vol ume 8, Nomber 3

2 Bum- Suk Yang , (oncogene) (tumor suppressor gene), 80 2,3)., (apoptosis),., (apoptosis), positive negative regulation. positive, negative regulation,,,, mass,., positive negative. (mutation) 3).,, (uncont- rolled growth). DNA, DNA deletion insertion,.,.,. DNAmutation, 4). DNA DNA,. DNA, p53 5). DNA,,. 5070%. p53. 6). BRCA1BRCA2, DNA 7). DNA 100% Sept ember

3 Recent New Tr ends of Ant i cancer Dr ug Ther apy. BRCA1BRCA2 5%. BRCA1BRCA2, 6. BRCA1 BRCA2., predisposed". BRCA1, BRCA2 WT(wilms tumor) 2) ,, 1970, 2 25%. 30,. FDA. DNA, DNA, DNA ,., 30 25%. DNA,. 90 p53, DNA 8,9). p53 DNA, NCI 5070% p53, p53. p53., p53,,. 90. (microtubule) G2/M, (cell cycle check point) 10). DNA. DNA 1., 30,, 130 Vol ume 8, Nomber 3

4 Bum- Suk Yang. DNA. 8090,,, ,, 2000 Gleevec Herceptin, Iressa, Avastin, Belcade ) Gleevec(Imatinib mesylate) Chronic myeloleukemia(cml) chromosome 9 chromosome 22 chromosome 60, 80 translocationchromosome 22 c-abl, abl MIT 11). 90 abl 2, Gleevec, 2002 FDA CML 12). Gleevec.,, signal transduction, 13).,, ATP.,. 4, 700, 300,.,. N- c- pocket, ATP ATP,,.,. abl,, Grb2 11). Grb2 ras, ras /,,. Gleevecabl ATP ATP abl 12). CML abl. Gleevec abl (apoptosis). GleevecCML. Gleevec CML.,,. CML 3040% CML.. CML Sept ember

5 Recent New Tr ends of Ant i cancer Dr ug Ther apy, 1 abl 14). Gleevecabl, c-kit. c-kit gastrointestinal stromal tumor(gist), GIST 15). Gleevec. 2) Iressa (Gefitinib) - Iressa, (epidermal growth factor, EGF) Receptor tyrosine kinase family EGFR(epidermal growth factor receptor) 16). EGFR c-, Iressa EGFR ATP ATP EGFR. Gleevecabl ATP targeting. Receptor tyrosine kinase EGFR family 17,18). Receptor tyrosine kinase,,.,. Receptor tyrosine kinase c- Receptor tyrosine kinase, c-, c-. Receptor tyrosine kinase EGFR, VEGFR, insulin receptor, PDGFR,. EGFR Her2/neu 4 family EGFR family., EGFR,,,. IressaEGFR 20 nmic50 EGFR family Her2/neu 1uMIC50 EGFR 16). Irresa EGFR (non small cell lung carcinoma) (Table 1). Irresa, 250 mg 13.6% 50%, %.,, 4.6% 29.4%. FDA ).,,, 157, Table 1. EGFR express ion in human tumo rs Tumors s howing high EGFR expression High expression generally associated with NSCLC Prostate Gastric Breast Colorectal Pancreatic Ovarian 40 80% 40 80% 33 74% % 25 77% 30 50% 35 70% Invas ion Metastasis Late- stage disease Che motherapy res istance Hormone- the rapy res istance Poor outcome 132 Vol ume 8, Nomber 3

6 Bum- Suk Yang Iressa,. Iressa EGFR Tarceva (OSI-774)Onyx Pharmaceutical FDA. 3) Herceptin(Trastuzumab) HerceptinGenentec 2002 EGFR family Her-2/neu Her-2/neu 20). Her-2/neu Iressa EGFR EGFR. Her-2/neu,. EGFR Her-2/neu apoptosis., EGFR. FDA Herceptin Taxol,. Herceptin1 3060,,,,, HER-2/neu. 30%, 1 60,000., HerceptinAdriamycin, cytoxin, taxol. Adriamycin, cytoxin 52% 50%, Adriamycin cytoxin 43% 20%. taxol. taxol 16%, Herceptintaxol 42% 162%. Herceptin,. 4) Velcade (Bortezomib) Velcade 2004 multiple myeloma 1 multiple myeloma 21). 20S proteasome chymotrypsin like protease. 20S proteasome.. 20S proteasome, subunitchymotrypsin like protease 22). 20S protea some. 20S proteasome IkappaB, NF- kappab NF-kappaB NFkappaB. NF-kappaB,. 20S proteasome IkappaB, IkappaBNF-kappaB. 20S proteasome,. Velcade 20S proteasome chymotrypsine like protease. Velcade multiple myeloma 2004 FDA. Velcade, multiple myeloma 37%, 12%. Sept ember

7 Recent New Tr ends of Ant i cancer Dr ug Ther apy 15,000 multiple myeloma 1. Velcade. 23). multiple myeloma,. 5) Avastin (Bevacuzimab) (vascular endotherial cell growth factor, VEGF) 24). endotherial cell VEGFR endotherial cell, VEGFR Receptor tyrosine kinase family, VEGF endotherial cell. VEGF VEGFR2. VEGF VEGFR2. VEGF VEGF Bevacuzimab (trade name 'Avastin')Genentec. Avastinfluorouracil (5-FU)leucovorin 25). 800 Avastin Avastin (selectivity)...,.. Avastin 2004 FDA.,,,,. VEGFR2 3., Avastin VEGFR2 26) % 1990,...,. cancer imaging, Vol ume 8, Nomber 3

8 Bum- Suk Yang FDA...., ),., ) Hunter T. Cooperation between oncogenes. Cell 1991;64: ) Olopade OI, Pichert G. Cancer genetics in oncology practice. Ann Oncol 2001;12: ) Motoyama N, Naka K. DNA damage tumor suppressor genes and genomic instability. Curr Opin Genet Dev 2004;14: ) Levine AJ, Momand J, Finlay CA. The p53 tumour suppressor gene. Nature 1991;351: ) Schwartz D, Rotter V. p53-dependent cell cycle control: response to genotoxic stress. Semin Cancer Biol 1998;8: ) Carter RF. BRCA1, BRCA2 and breast cancer: A concise clinical review. Clin Invest Med 2001;24: ) El-Deiry WS. The role of p53 in chemosensitivity and radiosensitivity. Oncogene 2003;22: ) Rich T, Allen RL, Wyllie AH. Defying death after DNA damage. Nature 2000;407: ) Blagosklonny MV, Fojo T. Molecular effects of paclitaxel: Myths and reality(a critical review). Int J Cancer 1999;83: ) Arlinghaus R, Sun T. Signal transduction pathways in Bcr-Abl transformed cells. Cancer Treat Res 2004;119: ) Hochhaus A. Imatinib mesylate(glivec, Gleevec) in the treatment of chronic myelogenous leukemia(cml) and gastrointestinal stromal tumors(gist). Ann Hematol 2004;83(Suppl 1): S ) Hanks SK, Quinn AM, Hunter T. The protein kinase family: Conserved features and deduced phylogeny of the catalytic domains. Science 1988;241: ) Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous leukemia: Strategies to avoid and overcome resistance. Leukemia 2004;18: ) Joensuu H, Kindblom LG. Gastrointestinal stromal tumors - A review. Acta Orthop Scand 2004;75(Suppl): ) El-Rayes BF, LoRusso PM. Targeting the epidermal growth factor receptor. Br J Cancer 2004;91: ) Kim DW, Lu B, Hallahan DE. Receptor tyrosine kinase inhibitors as anti-angiogenic agents. Curr Opin Investig Drugs 2004; 5: ) Lamorte L, Park M. The receptor tyrosine kinases: Role in cancer progression. Surg Oncol Clin N Am 2001;10: ) Natale RB. Effects of ZD1839(Iressa, gefitinib) treatment on symptoms and quality of life in patients with advanced nonsmall cell lung cancer. Semin Oncol 2004;31(Suppl 9): ) Ross JS, Fletcher JA, Bloom KJ, Linette GP, Stec J, Clark E, et al. HER-2/neu testing in breast cancer. Am J Clin Pathol 2003;120(Suppl):S ) Kane RC, Bross PF, Farrell AT, Pazdur R. Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 2003;8: Sept ember

9 Recent New Tr ends of Ant i cancer Dr ug Ther apy 22) Adams J. The proteasome: A suitable antineoplastic target. Nat Rev Cancer 2004;4: ) Papandreou CN, Logothetis CJ. Bortezomib as a potential reattment for prostate cancer. Cancer Res 2004;64: ) Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: Therapeutic implications. Semin Oncol 2002;29(Suppl 16): ) Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-vegf antibody for treating cancer. Nat Rev Drug Discov 2004;3: ) Rosen LS. Inhibitors of the vascular endothelial growth factor receptor. Hematol Oncol Clin North Am 2002;16: Vol ume 8, Nomber 3