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1 폐암에대한치료약물들 종설 전남대학교의과대학내과학교실김영철, 김규식 Drugs for Lung Cancer Treatment Young-Chul Kim, M. D., Kyu-Sik Kim, M. D Division of Pulmonology, Internal Medicine, Chonnam National University Medical School, Hwasun Hospital 서 폐암은국내에서도이미암사망률제 1위의질환이되었고 1 현재의흡연인구의약 10% 가폐암을앓게됨을예상하면앞으로폐암발생및사망률은지속적으로증가하여 20-30년후에는현재의두배이상까지증가할것으로예측된다. 원격지에전이된 4 병기폐암에대한항암화학치료뿐만아니라최근에는방사선치료중에도항암화학약물을동시에투여하는추세이고수술전후에항암화학치료를추가함으로써더높은치료효과를얻고있어서대부분의폐암환자들에게항암약물치료가필요하게되었다. 비록과거의성적보다는높아졌지만, 최근에사용되는병합화학요법은관해율이 4병기비소세포폐암에서 20-40% 에불과하고관해유지기간은보통 6 개월이내이며중앙생존기간도 10개월이내이다 2. 또한항암화학치료는상당한독성을감내하면서치료를받아야하므로독성이적으면서효과가더좋은약제들의개발이필요하다. 폐암세포는많은유전자, 분자수준의변화들을획득하고있는데 protein tyrosine kinase, protein kinase C, ras/mitogen-activated protein kinase(m- APK) 와같은신호전달체계의이상, 세포주기와세포사를조절하는체계의이상들이단백의과발현이 론 Address for correspondence : Young Chul Kim, M.D., Department of Medicine, Chonnam National University Medical School, Hwasun Hospital 160 Ilsim-ri, Hwasun, Jeollanam-do , Korea Phone : Fax : kyc0923@jnu.ac.kr 나돌연변이와같은형태로써관찰된다 3. 또한혈관신생을촉진하는변화들이관찰되고종양관련항원들이발현되기도한다. 이러한다양한표적들에선택적으로작용하는표적치료약물들이매우빠른속도로개발되고있어서이제는개발되는약물들을모두열거하기도어려울지경이다. 본고에서는 ( 가 ) 현재사용되고있는항암화학약물들에대한간단한정리와함께 ( 나 ) 표적치료약물들을소개하고자한다. 가. 항암화학치료약물들과병합처방들. A. 비소세포폐암국소적인치료 ( 수술, 방사선 ) 가어려운진행된비소세포폐암에대한 1차항암화학치료는 2가지약제를병합하여치료하는것이권장된다. Platinum계약물과 Taxane 또는 Gemcitabine을병합하거나비 Platinum 계 dirannf들의병합도가능하다 4. Platinum 은 Carboplatin 보다는 Cisplatin 이효과면에서약간더우월하므로완치를목적으로하는항암-방사선동시치료나 adjuvant chemotherapy는 Cisplatin 을선호한다 5,6. 진행된비소세포폐암에대한 1차치료로써 ECOG(Eastern Coorporative Oncology Group) 에서발표한 4가지병합처방 (Paclitaxel/Carboplatin, Paclitaxel/Cisplatin, Docetaxel/Cisplatin, Gemcitabine/ Cisplatin) 의비교연구 7 결과어떠한처방도다른처방들에비하여효과및생존기간에있어서우월하지않았다. 그러나최근에한중재분석연구에서 Gemcitabine/platinum 병합치료가다른병합치료들보다생존기간을약간연장함이보고되었고 8, 대한 123

2 YC Kim et al : Drugs for lung cancer treatment 폐암연구회에서는한국인을대상으로무작위배정 3 상연구를진행중이다 9. 고령이거나 ECOG 수행능력지수가 2점인경우는단독치료도가능하다. 또한관해를보이지않는경우 4주기이상치료는하지않으며효과가있는경우도 6주기까지만을치료하도록권장된다. 특히근치목적의방사선치료를함께투여하는경우는 4주기이내로완료하도록권장한다 4. 1차치료이후재발한경우에는 2차치료약물로 Docetaxel 또는 Pemetrexed가인정된다 2. 비소세포폐암에서사용되는몇가지약제들을간단히기술하고투여할때주의할점들을정리한다. Paclitaxel은북미산주목나무에서추출한 taxane 으로 tubulin 의분해를억제하여 microtubule을 stabilize 시키므로세포주기중 M phase에세포독성을발휘한다. 보통 3주간격으로 135~175mg/m 2 로투여되며골수억제, 간기능이상의정도에따라감량하여투여한다. Anaphylaxis 와같은부작용이발생할수있으므로 dexamethasone 10-20mg, diphenhydramine 50mg, 그리고 cimetidine 300mg 또는 ranitidine 50mg을 30분전에정맥주사한다. 5% glucose 또는 0.9% NaCl 수액에혼합조제하여 0.22 micron in-line filter를장착한 non-pvc set( 예, polyethylene) 를이용하여 1시간동안정주한다. Platinum과병합치료하는경우 platinum보다먼저 paclitaxel 을투여하는것이효과가더좋으면서골수억제도적다. Docetaxel 은유럽산주목나무에서추출한 taxane 으로 paclitaxel과마찬가지로 tubulin의분해를억제하여 M phase에세포독성을발휘한다. 보통 3주에 75mg/m 2 로투여되며, 빌리루빈상승이나 1.5배이상의간효소상승이있으면사용하지않는다. 투여후에발생될수있는수액저류 ( 흉수, 복수, 말초부종 ) 와과민반응 ( 저혈압, bronchospasm, rash) 을감소시키기위하여투여전부터 prednisolone을 5 mg씩하루 2번투여한다. 5% glucose 또는 0.9% NaCl 수액에혼합조제하여 1시간동안정주하며, Platinum과병합치료하는경우 platinum보다먼저 docetaxel을투여하는것이효과가더좋으면서골수억제도적다. Gemcitabine은 pyrimidine 길항제로써 DNA polymerase 와 Ribonucleotide reductase를억제하여 S p- hase에세포독성을발휘한다. 보통 3주간격으로 2회 1250mg/m 2 를 0.9% NaCl 100mL에희석하여 1시간이내에투여하고골수억제의정도에따라용량을조절한다. Vinorelbine 은반합성 vinca alkaloid로써 tubulin에결합하여 microtubule의형성을억제하므로 mitotic spindle의형성을억제하여 M-S phase에세포독성을발휘한다. 3주간격으로 30mg/m 2 를 platinum이나 gemcitabine과함께 2회투여하고골수억제나간기능이상의정도에따라투여용량을조절한다. 조제는 5% glucose 또는 0.9% NaCl 수액 50 ml에혼합하여 5-10분동안에정주하고 mL의수액을추가로더주사하여혈관염을예방한다. 혈관외로약물이유출된경우는 250U의 hyaluronidase를 6mL saline 에 mix하여피하주사하고주사부위를따뜻하게하여거상시켜준다. 냉시프와스테로이드는사용하지않는다. Cisplatin 은 DNA에 cross-link 형태로결합하여이중나선구조를변형시키고 DNA 합성을억제한다. 투여전에 1~2 L의수액을미리투여하고약물을투여하는날은소변량을 100 ml/hr 이상유지시키기위해추가적인수액과함께 furosemide 와 mannitol 을함께투여한다. 주사 set에알루미늄은피해야하며, 60~75 mg/m 2 를 0.9% NaCl 수액에혼합하여주사하고신기능과골수억제정도에따라용량을조절한다. Carboplatin 은 Cisplatin 과비교하여신독성등부작용들이적으나골수억제는더심하다. Cisplatin 처럼다량의수액과이뇨제를투여하지않아도되고신장기능에따라용량을조절하여 5% glucose 용액으로혼합하여주사한다. Pemetrexed(Alimta, LY231514, MTA) 는엽산대사에관여하는 3개의효소들 (thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase) 을억제하는최근개발된항대사항암약물이다. Pemetrexed는비소세포폐암을대상으로 2-3상연구들에서 1-2차단독요법으로효과가입증되었다. 또한 2차요법으로써 docetaxel 단독치 124

3 Tuberculosis and Respiratory Diseases Vol. 60. No. 2, Feb 료와비교하였을때도부작용은경미하면서도비슷한효과를보여국내에서도 2차치료약물로곧사용될수있을것이다 10. B. 소세포폐암소세포폐암은아직 Etoposide와 Platinum 병합치료가표준이며 Platinum은 Carboplatin 보다는 Cisplatin이효과면에서더우월하다. 따라서완치를목적으로하는제한기소세포폐암은 Etoposide/Cisplatin(EP) 와동시에방사선치료를시행함으로써 18~24개월의중앙생존기간, 40~50% 의 2년생존, 3% 이내의치료관련사망률을보인다 11. 그러나전이기소세포폐암은완화를목적으로하므로 Etoposide/Carboplatin(EC) 도흔히이용되며, Irinotecan/Cisplatin(IP) 가 EP보다더높은효과를보임이보고되었으나 12 진행되는연구결과들의검증을기다려야한다. Etoposide는 topoisomerase II 억제제로써 S-G2 phase 에세포주기를정지시킨다. 3주간격으로 100 mg/m 2 로 3일동안투여하며골수억제, 신장, 간기능장애정도에따라투여용량을조절한다. Topoisomerase-I 억제제인 Topotecan, Irinotecan 그리고 Bellotecan 이최근개발되어 1차또는재발한소세포폐암을대상으로사용되고있다. S phase 에세포독성을발휘하는약물들로써골수억제, 신기능장애의정도에따라용량을조절하면서투여한다. Irinotecan 은 3~4주주기로 60~100mg/m 2 를 2~3회투여하고, topotecan(1.5mg/m 2 /day) 이나 bellotecan- (0.5 mg/m 2 /day) 은 3주주기로 5% glucose 용액 10-0cc에희석하여 5일간정주한다. 나. 표적치료약물들비소세포또는소세포폐암에대하여최근에개발되고있는표적치료들을대상에따라구분하면 (A) receptor tyrosine kinases(tk), (B) non-receptor T- K, (C) Apoptotic pathway, (D) Angiogenesis, (E) Retinoid acid receptors, (F) Matrix metalloproteinase, (G) Tumor antigen 등이다 13,14. 신호전달체계에서 TK들은폐암에서가장흔히변화가관찰되는 dominant oncogene 들이다. TK는 receptor TK와 n- on-receptor TK로구분된다. Ligands EGF TGF-α Amphiregulin β-cellulin HB-EGF Epiregulin No specific ligands - often acts as dimer partner Heregulins NRG2 NRG3 Heregulins β-cellulin Cysteine-rich Receptor domain Extracellular Membrane Intracellular Tyrosine kinase domain K K K K erbb1 HER1 EGFR erbb2 HER2 neu erbb3 HER3 erbb4 HER4 Figure 1. The EGFR (erbb) family 125

4 YC Kim et al : Drugs for lung cancer treatment A. Growth Factor Receptor Tyrosine Kinase 정상세포와마찬가지로암세포도 growth factor receptor TK들의활성화에의하여증식, 세포사 (apoptosis), 혈관신생, adhesion, motility 등이조절된다. 세포표면에위치하는 receptor TK들은 epidermal growth factor receptor (EGFR, HER1, erbb-1), erbb-2 (HER-2/neu), erbb-3 (HER-3) 그리고 erbb-4 (HER-4) 4가지가알려져있다. 이수용체들은당단백들로써세포바깥에는 N-말단이있어서성장인자와결합하는역할을하고세포막을통과하는 alpha helix를경유하여세포내에위치하는 Tyrosine kinase 활성을갖는 C 말단으로구성된다 ( 그림 1). 성장인자가세포바깥의 N-말단에결합하면같은혹은서로다른종류의 receptor TK들과서로짝을이루어 (dimerization) 세포막내의 TK를활성화시킨다. 그결과 phospholipase C, 또는 ras/mapk 와같은신호전달체계가활성화된다 ( 그림 2). 정상세포들에서는수용체 TK의활성도가세밀하게조절을받고있지만암세포에서는 TK 유전자의증폭, 돌연변 이, 구조적인재구성등의결과로잘억제되지않으면서암세포의특성을보이게된다 15. A-1. HER-1 (EGFR) EGFR 은비소세포폐암을포함한다양한고형암에서과발현되고있다. EGFR의과발현은진행된병기와불량한예후와관련된다. EGFR이활성화되면세포를증식시키고, 세포고사를억제하며, 침투전이하도록하고혈관신생을촉진함으로써결국종양의성장과진행을촉진하게된다. EGFR이활성화되는또다른기전은 EGFR 유전자의돌연변이결과, TK 가활성화된채로존재하거나성장인자와결합하는세포외 domain 이 truncate 되어있어서성장인자의존재와무관하게활성화되기도한다 16. EGFR의활성화를억제하는몇가지약제들이개발되어비소세포폐암에사용되고있는데대표적인약제들은저분자 TK inhibitor(tki), 단클론항체들이다 ( 표 1). 저분자 TKI들은모두경구로투여가능하며피부증상 (dry skin, acneiform rash) 외에부작용은적은편이다 17. Ligand EGFR K K EGFR-TKI PTEN PI3-K AKT py py py STAT3 GRB2 SOS RAS RAF MEK Proliferation / maturation Gene transcription Cell cycle progression P P DNA Myc Cyclin JunFos D1 Myc Cyclin D1 Chemotherapy / radiotherapy Angiogenesis Metastasis resistance MAPK Survival (anti-apoptosis) Figure 2. EGFR signal transduction in tumor cells and EGFR tyrosine kinase inhibitor (EGFR-TKI). The symbol K represents EGFR tyrosine kinase. 126

5 Tuberculosis and Respiratory Diseases Vol. 60. No. 2, Feb Table 1. List of Targeted Therapies Target Generic designation Trade Name Company Receptor TK EGFR Quinazoline ZD1839, Gefitinib Iressa AstraZeneca Quinazoline OSI-774, Erlotinib Tarceva Genentech TK inhibitor CI Pfizer Monoclonal Ab IMC C225, Cetuximab Erbitux BMS HER2/Neu Monoclonal Ab Trastuzumab Herceptin Gentech C-kit TK inhibitor STI571, Imatinib Gleevec Novartis Non Receptor TK Ras Farnesyl transferase Inhibitor R115777, Tipfarnib Zarnestra Johnson & J. SCH 66336, Lonafarnib Sarsar Schering Plough Raf kinase Antisense oligo ISIS 5132 ISIS Kinase inhibitor Bay , Sorafenib Bayer PKC Macrolide lactone Bryostatin Antisense oligo ISIS 3521, Affinitak ISIS Apoptosis CDK CDK inhibitor Flavopiridol PDE PDE inhibitor Exisulind Aptosyn OSI pharma Bcl-2 Antisense oligo. G3139, Oblimersen Na Angiogenesis VEGF Monoclonal Ab Bevacizumab Avastin Genentech Receptor TKI SU5416, SU6668, Sugen ZD6474 AstraZeneca COX-2 COX-2 inhibitor Celecoxib Celebrex Pfizer Aminopeptidase Synthetic fumagillin TNP-470 Retinoid Receptor RXR Retinoid Bexarotene Targretin Ligand MMP Matrix Metaloproteinase Immune Therapy NSCLC cells MMP inhibitor Marimastat British Biotec MMP inhibitor BAY Bayer Irradiated tumor cells engineered to secrete GM-CSF GVAX Cell Genesys Tumor cells Killed M. vaccae SRL172 SR pharma GD3 ganglioside Antiidiotypic Ab BEC2/BCG ImClone sys NCAM Antibody+Ricin N901-bR GRP Mono. Antibody 2A11 A-1-1. Gefitinib Gefitinib(ZD1839, Iressa ) 은 quinazoline계약물로써 EGFR의 TK domain을표적으로하는 TKI이다. 1상임상실험에서 gefitinib 단독치료가비소세포폐암에서가장효과적이었기때문에주로비소세포폐암을대상으로임상연구들이진행되어왔다. IDEAL(Iressa Dose Evaluation in Advanced Lung studies) 18,19 은 EGFR 발현여부를구분하지않고 gefitinib 을단독으로투여한 2상연구들이다. IDEA- L-1 19 에서는 210 명의 IIIB 병기이상의최소한가지항암치료이후재발한비소세포폐암환자들을대상 으로하였다. 하루투여량 250 mg 또는 500 mg을비교하여조사한결과반응율은 (18.4% 와 19 %), 무진행생존기간은 (2.7개월과 2.8 개월 ), 그리고중앙생존기간은 (7.6개월과 8.0개월 ) 로서로비슷하였으나하루 250mg을투여한군에서부작용의빈도가유의하게낮았다. 질병관련증상들의호전은 40~37 % 의환자들에서그리고삶의질지수 (QOL, FACT-L) 또한 24~22 % 에서호전되었다. 무진행생존기간은질병관련증상들의호전이관찰된환자들에서 2배정도연장되었다. IDEAL-2 18 다기관공동연구는 IDEAL-1 과비슷 127

6 YC Kim et al : Drugs for lung cancer treatment 하게계획되어최소한 2 가지항암치료이후재발한 216명의비소세포폐암환자들을대상으로진행되었다. IDEAL-1 과같이두가지약제의용량에따라치료효과는서로다르지않았는데, 반응율은 (12% 와 9%), 중앙생존기간은 (7개월과 6개월 ) 그리고 1년생존율은 (27% 와 24%) 을각각보였다. 질병관련증상의호전은 44~40 % 에서관찰되었고부분관해또는안정화 (stable disease) 를얻은환자들의 96~73% 에서증상의호전이관찰되었고증상의호전이있었던군이그렇지않은군과비교하여유의하게중앙생존기간이연장되었다 (13개월과 5개월 ). 위와같은근거들로써 2003년미국 FDA에 3차요법으로허가되었고미국암학회의치료권고안에도등록되었으며 4, 국내식약청과심평원심사기준에서도 2004년 6월이후로역시 3차요법으로허가되었다. Gefitinib 의효과는비교적항암화학치료에저항을보이는기관지폐포암에특히좋은효과를보인다. 미국에서이루어진 139명의비소세포폐암을대상으로한연구20에서 21명 (15%) 에서부분관해를얻었는데, 기관지폐포암이다른선암들보다 38 vs. 14% 로반응율이높았고, 비흡연자가흡연자에비하여 (36% 와 8%), 여성이남성에비하여 (19% 와 8 %) 반응율이높았다. 이러한반응을예측할수있는특성들은최근국내 21 와대만 22 에서의보고그리고저자들의성적 23 에서도일치하고있다. HER-2를겨냥하는 trastuzumab 은 HER-2/neu- (c-erbb-2) 유전자가증폭된종양에서주로효과를보이지만, gefitinib 의효과는 EGFR 단백의발현정도와는무관하다 23,24. Gefitinib 에효과는 80% 이상에서보통 1개월이내에관찰되며 1주이내에극적인종양관련증상의호전과방사선소견의호전이관찰되기도한다 23. 이러한빠른효과를보이는기전으로 gefitinib 에반응을보이는비소세포폐암세포들은 EGFR의하부신호전달체계인 Akt가인산화 ( 활성화 ) 되어있음이보고되었고 25, gefitinib 에대한효과를보이는종양세포들은 Akt 신호전달체계의활성화결과세포고사가억제되는기전에생존을의존하고있는데 (Oncogene addiction) 26, 다양한방법들로써 Akt를억제하게되면바로세포고사에빠지는것을 보고하였다 27. 또한 gefitinib 에관해를보였던 9명중 8명에서 EGFR 유전자의 TK domain에서돌연변이가발견되었고, 효과가없었던환자들에서는돌연변이가발견되지않았다 28. EGFR의신호전달체계를활성화시키는돌연변이들의결과암세포의생존이 EGFR의활성화에의존하고있다가, EGFR TKI에의하여세포사에이르는것을추정할수있다. 이러한 EGFR 유전자의돌연변이는후속되는연구들에서도확인되고있는데 22,23,29-31, 돌연변이를획득한 kinase의 ATP cleft 구조가변화되면서 gefitinib에더쉽게억제되는것도가능한기전으로제기되었다 26. Gefitinib 에반응하는 EGFR mutation 은 EGFR 유전자의 tyrosine kinase domain 부위인 exon 18, 19, 20, 21에서관찰된다. 국내의보고들 23,31 에서는비소세포폐암조직의약 20% 에서돌연변이가관찰되었고돌연변이가관찰되는경우 90% 이상에서 gefitinib 에임상적인호전을보였다. 그러나관해를보인환자들도결국 15~22개월정도치료과정중에재발이관찰된다. 최근에재발한종양조직에서 EGFR 유전자의 exon 20에새로운돌연변이가발견되어 (T790- M) 32,33 약제내성의한가지기전이알려져서이를극복하기위한연구들이진행중이다. 또한 T790M 돌연변이없이 gefitinib 에불응하면서성장하는종양세포는 gefitinib-egfr complex 가세포내로이동하면서서로해리되어 gefitinib 에내성을보이는기전도보고되었다 34. 또한 EGFR 돌연변이는 K-ras 유전자의돌연변이와서로중첩되지않으면서독립적으로발견되고 K- ras 유전자의돌연변이가있는경우 EGFR TKI에내성을보인다 35. 비흡연자, 여성에서 TKI에감수성이좋은 EGFR 돌연변이가흔한반면에, 흡연자에서는내성을보이는 K-ras 유전자의돌연변이가발견되므로이제는조직형외에도유전자형으로구분하여폐암을분류하고치료에도응용하는시대가도래하고있다. 2004년 12월예비발표된 Iressa Survival Evaluation in Lung cancer (ISEL) 연구에서항암화학치료에실패한비소세포폐암 1692명에서이레사투여 128

7 Tuberculosis and Respiratory Diseases Vol. 60. No. 2, Feb 에따른생존기간의연장은통계적유의수준에도달하지못하였다. 그러나선암환자들의분석에서는이레사투여군에서생존기간이연장되는경향 ( 위험도 0.83, 중앙생존 6.3개월과 5.4개월, p=0.07) 을보였고동양인과비흡연자군을각각대상으로한분석에서는이레사투여군에서생존기간이유의하게연장되었다 36. 그러나 gefitinib 에반응군과비반응군간에는분명한생존기간의차이가관찰되고있으며, 단기간치료로반응을쉽게평가할수있고, 임상상과유전자분석을이용한반응군의예측도어느정도가능한상황에서무작위배정연구결과보다는환자와종양의특성에따른맞춤치료를고려해야할것이다 37. 항암화학치료와 geftinib의병합치료를위한전임상단계의연구들에서는 taxane, gemcitabine, platinum 제제들과 gefitinib 을함께사용하였을때세포독성이크게증가됨이 38,39 보고되어시행된 1상임상시험에서 gefitinib과 carboplatin, paclitaxel 을함께투여한환자들중 7명에서부분관해를얻었고 9명에서는안정화를얻을수있었다 40. 이러한근거로부터미주와유럽에서각각 gefitinib 을 carboplatin/paclitaxel 또는 gemcitabine/cisplatin 치료와병합하거나항암화학치료만시행하는다기관 3상무작위배정연구가진행되었다. 그러나 INTACT(Iressa NSCLC Trials Assessing Combination Treatment) 41,42 라불리는두연구에서각각 1000명이상의환자들을대상으로조사하였으나두가지연구모두치료의반응, 무진행생존기간, 생존에있어서항암화학약물추가의효과를증명하지못하였으므로아직까지단독요법으로만사용되고있다. Gefinitib 뿐만아니라 erlotinib과같이 EGFR을겨냥하는약물들은여드름과비슷한피부발진을보이는데, 피부발진의정도가항암효과와비례하는것으로보고되고있다. INTACT 연구들에서간질성폐렴의빈도는 gefitinib 과항암화학치료를병행한군과항암화학치료만을시행한군간에약 1% 정도로써서로차이가없어서분명한연관관계를결론짓기는어렵다 41,42. 그러나간질성폐렴이일본인에서는약 2% 백인에서는 0.3% 로써전체적으로는 gefitinib 사 용환자들의약 1% 에서관찰되었고이들중약 30% 가간질성폐렴으로사망하게되므로 gefitinib 을사용하는도중에간질성폐렴의발생이관찰되면즉각적으로투여를중단하는것이현재까지는필요하다 43. Gefitinib 은뇌및중추신경계전이병소에도항암효과를보임이보고되고있으나 44-46, 뇌와수막은 gefitinib 사용중폐암이재발하는흔한병소이기도하다 47. A-1-2. Erlotinib Erlotinib(OSI-774, Tarceva ) 은 gefitinib과같은 quinazoline계약물이다. 2상임상연구에서 57명의비소세포폐암환자들에게 erlotinib(150mg/ 일 ) 을단독으로투여하였을때, 12% (1 완전관해, 8 부분관해 ) 의반응율을보였고, 중앙생존기간은 8.4개월, 40% 가 1년이상생존하였다 48. 치료에따른부작용도크지는않았고피부발진과설사가각각 73%, 56% 에서관찰되었다. 이후로 1-2차치료에실패한비소세포폐암환자 731명을대상으로 erlotinib과위약대조군임상시험 (BR21) 이시행되었는데, 반응율은 9% 에불과하였지만, 중앙생존기간이 erlotinib을사용한군 6.7 개월에비하여위약대조군 4.7 개월로써유의한차이를보였다 49. 이자료를근거하여미국식약청은 2차치료부터투여를인정하여, 국내에서도곧사용이가능할전망이다. Erlotinib 역시선암, 비흡연자, EGFR 의발현이치료에좋은반응이예측되는인자들이다 50. Gefitinib 과마찬가지로 erlotinib도 carboplatin/paclitaxel 또는 gemcitabine/cisplatin과병합하는두개의 3상임상연구가계획되어환자모집을마무리한상태이나병합치료의이점은없는것으로보인다. A-1-3. CI-1033 다른약물로 CI-1033는 4가지 EGFR 단백에대한비특이적이면서비가역적인억제약물이다. Gefitinib 과같이 CI-1033 도 mitoxantrone과 topoisomerase I 억제제의세포독성효과를증가시키므로 51 임상연구가진행중이다. 129

8 YC Kim et al : Drugs for lung cancer treatment A-1-4. Monoclonal Antibodies EGFR의세포외구조에대한생쥐유래의유전자가포함된키메릭항체인 Cetuximab (IMC-C225, Erbitux ) 은 EGF receptor TK를완전히억제하여 G1 세포주기에정지시킨다 52. 전임상연구들에서 cetuximab 을 cisplatin, doxorubicin, topotecan, paclitaxel 등항암화학치료제와병합하였을때세포독성이증가됨이보고되었다 명의 1차치료에실패한비소세포폐암환자들에게 Docetaxel 과병합치료를시행한 2상연구에서 4명의부분관해와함께 6명에서안정상태를얻을수있어서 54 3상연구가진행중이다. Cetuximab 과달리 Abx-EGF 는완전한인간형의단클론항체로써특이적으로인간의 EGFR에결합하므로부작용이더적을것으로기대되지만아직연구단계이며 1상임상시험에서 9명중 2명의비소세포폐암에서안정상태를얻어서 55 2상연구로진행중이다. A-2. HER-2 (HER-2/neu, c-erbb-2) HER2/neu 는 c-erbb-2 로도알려져있는또다른 RTK 유전자로써역시 TK 효소활성을가지고있는 185kD의당단백수용체를생산한다. 약 25-30% 의비소세포폐암에서과발현되어발견되는데대부분선암이며 HER2/neu 의과발현은불량한예후와관계된다. 소세포폐암의일부에서도과발현되는데역시짧은생존기간을예측하게하는예후인자이다 56. 이 HER2/neu 에대한인간형의단틀론항체가 trastuzumab (Herceptin ) 으로써전이된유방암에단일치료또는병합치료로써효과를발휘한다. 폐암에대해서도항암화학치료와병합되었을때세포독성이증가함이 57 보고되어임상시험들이진행중이다. 현재까지 2상임상연구들이비소세포폐암을대상으로진행되고있는데, HER-2/neu 를과발현하는비소세포폐암만을대상으로 paclitaxel/carboplatin과함께투여하였을때반응율은 25% 이었고 1년생존율은 42% 를보였다 58. 다른연구에서는 14명을대상 으로 gemcitabine/cisplatin과함께 Herceptin 을투여하여평가가능한 12명중 6명에서부분관해를얻었고 5명의안정화를얻었다 59. 이후로 gemcitabine/cisplatin과 Herceptin을병합하거나항암화학치료만을시행한군을비교연구 60 하였지만 Herceptin 투여군의반응율, 생존기간등이항암화학치료만을시행한군보다오히려낮아서병합치료의잇점은증명할수없었다. 그러나최근 HER2 에대한 sequencing 결과 EGFR과마찬가지로 tyrosine kinase 부위의 HER2 gene에 mutation이발견되어서 mutation 여부에따라서치료효과에차이가있을가능성이제기되었다 61. A-3. C-kit C-kit는 145kDa의 receptor TK이다. 이수용체에결합하는인자 (ligand) 는 stem cell factor(scf) 또는 Steel factor 라고알려져있는 mast cell growth factor이다. C-kit는소세포폐암과비소세포폐암을포함한다양한종양에서활성화되어발견되며, 다양한기전으로 C-kit가활성화되어있다 62. 소세포폐암세포주의 28~81% 에서 c-kit가발현되어있고, 소세포폐암의 70% 에서 c-kit와 SCF가함께높게발현됨이보고되었다 63. 만성골수성백혈병의 Bcr-Abl TK를겨냥하여개발된 TK 억제제인 Imatinib (Gleevec ) 은 c-kit 돌연변이가있는다른종양들에서도효과를발휘한다 16. 그러나 c-kit와그 ligand 의발현이증가된소세포폐암에서도효과를보일지는확실하지않다. 체외실험에서 imatinib은소세포폐암세포주의성장을억제하였으나64, 세포사멸 (cytocital) 보다는세포정지 (cytostatic) 효과를보여주었고 c-kit 발현정도와상관관계를보였다. 항암화학치료와병행할때에상승효과를보일지는아직확인되지않았다. 19명의소세포폐암환자들대상으로 2상임상시험에서 imatinib에반응을보인환자는없었고단지 1 명만이 90일동안안정화를유지하였다. 이들중 28% 에서만 c-kit을면역조직화학적으로발현하고있었기에추가적인연구가필요하다

9 Tuberculosis and Respiratory Diseases Vol. 60. No. 2, Feb B. Non Receptor Tyrosine Kinase 학치료약물과동시치료의효과가연구되고있다 72. B-1. Ras 비소세포폐암을포함한많은암종에서 ras/m- APK 신호전달체계가활성화되어발견되므로이전달체계내의다양한물질들을겨냥한약물들이개발되고있다. 비소세포폐암의약 40% 에서돌연변이가관찰되는 Ras는 ISIS 2503, farnesyl transferase inhibitors(ftis) 그리고 peptide vaccines과같은다양한방법으로억제될수있다 13. 다양한 FTI들 (Tipifarnib, Lonafarnib) 을단독으로또는항암화학치료와함께투여한 1~2 상연구들이발표되고있다 66,67. B-2. Raf Raf kinase를표적으로 antisense molecules인 ISIS 5132는 paclitaxel/carboplatin 과병합치료하였을때길항작용이의심되기도하였다 68. Raf-1 kinase 억제제 BAY (Sorafenib) 은아직연구결과들을기다려보아야한다. B-3. Protein Kinase C Protein Kinase C(PKC) 는 serine/threonine protein kinase로써활성화된 ras로부터신호를받아서전달하여세포의성장, 증식, 분화, 사망등을조절하게된다. PKC level은비소세포폐암등암세포들에서상승되어있어서 69, PKC를억제함으로써세포분화를촉진하고항암제의세포독성을증가시킬수도있다 15. Bryostatin 은해양생물인 Bugula nerutina로부터추출된 macrolide lactone 으로써 PKC를억제하여강력한항암작용을보이며다른항암약물들의효과를증가시키므로 70, Paclitaxel과함께투여하는 2상임상연구가진행되었으나부작용외에상승효과는없었다 71. Antisense oligonucleotides는상보적인 RNA 염기구조를갖는 oligonucleotides를이용하여 mrna가단백으로표현되는과정을억제하는방법이다. Affinitak(ISIS 3521, LY90003) 은 PKC-alpha mrna를선택적으로억제하는 20염기의 antisense oligonucleotide로비소세포폐암을대상으로몇가지항암화 C. Cell Survival and Apoptosis C-1. Cyclin dependent kinase(cdk) 세포주기는수많은단백들의조절을받고있다. G1 기의세포주기로부터 retinoblastoma(rb) 단백을 CDK들이인산화시킴으로써 E2F를분리시켜서 S기로진행된다. CDK가활성화되기위해서는 cyclin(a, B, C, D, E) 단백들의역할이필요한데, Cyclin 들중에서특히 D와 E는폐암에서과발현되어있다. CDK를억제하는 flavopiridol은 CDK의 ATP 결합부위를차단함으로써 CDK 효소를억제하고그결과 RB단백의 E2F분리를억제하여세포주기가진행되지않도록하는약물이다. 그러나비소세포폐암에서 flovopiridol 단독치료결과는실망적인데 20명의 4병기환자들에게초치료로써투여한결과관해를보인경우는없었고 6명에서만안정화를보였다 73. C-2. cgmp phosphodiesterase(pde) Cyclic GMP(cGMP) 는 G-protein 과결합하여신호를전달함으로써세포고사를유도한다 74. cgmp는 PDE에의하여 GTP로인산화되는데 exisulind (Apto\syn ) 는경구투여가가능한 PDE 억제제로써, cgmp 농도를높임으로써암세포의고사를유도한다 75. Exisulind 역시다른항암화학치료약물과상승효과가보고되어 1-2상임상시험에서 docetaxel과함께투여되었을때약 50% 의안정화를얻어서 상연구가진행중이다 77. C-3. P53 유전자염색체 17p13.1에위치하는 P53 유전자는 G1 phase에서세포주기가진행되지않도록역할을하는전사인자 (transcription factor) 인 P53 단백을생산한다. 정상적인 p53은세포의 DNA가손상을받았을때세포의성장을억제시키고 cell cycle을정지시켜서 DNA를복구하도록하고한편으로는세포를고사시키기도한다. P53 유전자가돌연변이를갖고있거나소실되어 p53 단백의정상적인기능을잃게되면세 131

10 YC Kim et al : Drugs for lung cancer treatment 포는 DNA 손상에더취약해지고손상된 DNA를가진채로성장, 분열하게되므로결국암을발생시킬수있어서암억제유전자로분류된다. P53의돌연변이는비소세포폐암의약 60% 에서발견되고특히흡연자에서발생된폐암에더높은빈도로발견된다 78. P53의정상적인기능과항암치료에따른세포고사유도기능이치료효과에필요하므로 p53의기능이소실된암세포에정상 P53 유전자를넣어주는유전자치료가시도되고있다 79. 초기의 1상연구에서는 p53 돌연변이를가지고있는재발된 9명의비소세포폐암환자들에게 retroviral vector에정상 p53을넣어주사하였다 명에서는종양의관해가관찰되었고 3명에서는안정화를볼수있었으나 vector의낮은세포내이입율 (transduction efficiency) 이문제가되었다. 추후로는 adenovirus를이용하여더높은세포내이입율을얻을수있었고 81, 24명의환자들에게 cisplatin과함께 P53을주사한결과 17명에서안정화, 2명에서부분관해를얻을수있었다 82. 그러나다기관 2상임상연구에서병합화학치료와함께 P53을주사하였는데 P53 사용에따른치료효과의상승은관찰되지않았다 83. C-4. Bcl-2 mrna로부터단백의전사를차단하는 antisense oligonucleotide인 Oblimersen sodium(g3139) 은세포고사를억제하는 bcl-2 단백의생성을억제한다. bcl-2의과발현은소세포폐암의 69~90% 에서관찰되는데, bcl-2의과발현이항암화학치료에내성기전의하나로이해되고있다 84. 소세포폐암세포주들을이용한실험들에서 Oblimersen 은세포고사를유도하고항암약물의세포독성을증가시켰다 85,86. Rudin 등은 12 명의항암치료에불응한소세포폐암환자들에게 oblimersen과함께 paclitaxel을투여하였는데 87, 한환자에서관찰된발진외에다른이상반응은없었고, 관해를보인경우는없었으나 2명 (17%) 의환자들에서안정화를얻었다. 이후진행된 1 상연구에서는 14명의전이가있는초치료환자중 12명이 oblimersen과 carboplatin/etoposide 치료에 부분관해를보였다 88. 중앙생존기간은 12.5개월이었지만무작위배정연구가추구되어야할것이므로 Cancer and Leukemia Group B (CALGB) 에서는초치료소세포폐암환자들을대상으로무작위배정 2 상연구를진행중이다. D. Angiogenesis 혈관의신생은암의성장과전이를위해서는필수적으로획득되어야할특성이다. 혈관신생의정도에따라전이, 재발의가능성이달라지고생존기간도달라짐이많은종양에서관찰되므로종양의성장과전이를위해필요한혈관신생은치료의중요한표적이된다. Vascular endothelial growth factor (VEGF) 는강력한혈관신생촉진인자로써비소세포폐암에서발현의증가는불량한예후인자이다. 실험동물들에서는 VEGF 수용체에대한단클론항체와같은혈관신생을억제하는약물들을사용함으로써암의성장을억제할수있다 89. D-1. 단클론항체 VEGF에대한단클론항체로개발된약물이 bevacizumab (Avastin, Genentech) 이다. Bevacizumab을단독또는 carboplatin/paclitaxel과병합하여치료하는무작위배정 2상연구 90 에서 99명환자중 bevacizumab 을병합한군의생존기간, 관해율, 관해유지기간이더연장되었다. 그러나 6명의환자들에서대량각혈이발생되었고그들중 4명이각혈로사망하였다. 이후로각혈을보였던편평상피세포암을제외한 878명의비소세포폐암환자들에게 carboplatin/paclitaxel 과함께 avastin을 1차치료로써투여한 3상연구에서항암화학약물만을투여한군에비하여 avastin 동시투여군의생존기간이연장됨이최근발표되어 91 비소세포폐암에서 triplet 치료가 doublet 치료보다우월함을보인첫번째연구결과가되었다. 다른단클론항체들을이용한연구들도진행중이며 14, 이제는표적치료약물들을병합하는연구들 92,93 도진 132

11 Tuberculosis and Respiratory Diseases Vol. 60. No. 2, Feb 행되고있다. D-2. VEGF receptor TKI VEGF의활성을차단하는또다른방법으로 VE- GF 수용체 tyrosine kinase 억제제들 (SU5416, SU- 6668, ZD6474) 이있어서폐암에서 1~2상연구들이진행되고있으나아직그역할은밝혀지지않은상태이다. D-3. COX-2 억제제 Cyclooxygenase-2(COX-2) 는 arachidonic acid 대사에관여하는효소로써, 폐암을포함한다양한종양에서과발현되어있고, 조기비소세포폐암에서 COX-2의과발현은불량한예후인자이다. COX-2의산물인 prostaglandin E2(PGE-2) 는 VEGF를생성하여암세포성장을촉진하고면역방어체계를억제하며, bcl-2를과발현시키고다향한 matrix metalloproteinase들을과발현시킨다. COX-2 억제제는폐암세포주들에서세포고사를유도하므로 94, COX-2를과발현하는비소세포폐암에서 Celecoxib와같은 COX-2 억제제들은좋은효과가기대된다. Altoki 등은 IB에서 IIIA까지의비소세포폐암환자 29명에게 2주기의 paclitaxel/carboplatin 과함께매일 celecoxib를투여하였다 95. Celecoxib 투여군에서 5명 (17%) 의완전관해를얻은반면에무작위배정은아니지만 celecoxib를함께투여하지않고같은시기에항암화학치료만을시행한 13명의환자들중완전관해는한명도없었다. 그러나전반적인관해율은양군간이각각 65% 와 61% 로유의한차이는없었다. Celecoxib 투여군에서 7명 (24%) 은수술후병리학적으로 microscopic residual disease 만남은상태로확인되었다. 이러한고무적인연구결과에따라 3상연구결과가기대된다. D-4. Endogenous angiogenesis inhibitors 초기의동물실험들에서는 angiostatin과 endostatin 등내인성혈관내피세포억제제들이좋은효과를보여주었으나인체를대상으로한임상실험에서뚜렷한효과는관찰되지않았다 96,97. TNP-470은자연적으로생성되는혈관신생억제제인 fumagillin의합성물로써혈관내피세포의증식에필요한 methionine aminopeptidase 효소를억제한다. 전임상연구에서실험동물에게 TNP-470을투여하면전이를억제하고세포독성약물들과병합하였을때효과가증폭되었다. 32명의고형암환자들에게 paclitaxel과함께 TNP-470를투여한 1상연구에서도고무적인결과가보고되었다 98. 비소세포폐암 16례중에서 60% 는다른항암처방후에 2차이상의치료로써투여되었으나이들중 6 례에서부분관해가관찰되어서추가적인병합치료연구가필요하다. E. Retinoid receptors 비타민 A와같은 Retinoid들은 retinoic acid receptors(rars) 와 retinoid X receptors (RXRs) 라는두가지핵수용체 (nuclear receptor) 를경유하여 transcription factor들을이용한유전자발현을조절하여세포의성장과분화, 면역기능조절에관여한다 99. 때문에 Retinoid 대사조절이상은암의발생에관여될수있는데대표적인예가 acute promyelocytic leukemia(apml) 이다. RAR-alpha gene을포함한염색체전좌 (translocation) 로인하여생성되는 RAR은 retinoic acid에낮은민감도를보여 promyelocyte의분화가억제되면서 APML이발생된다. 따라서 all-trans retinoic acid(atra) 를투여함으로써치료효과를얻을수가있다. RAR과 RXR은비소세포폐암에서발현이저하되어있어서암억제유전자로써의가능성이대두되었다 100. 더불어 RXR은비소세포폐암세포주의성장을억제하는효과가있고, 수술로절제된폐암조직에서 RXR-beta 발현이저하된경우예후가불량함도보고되었다 101. Bexarotene (Targretin ) 은 RXR에선택적으로작용하는 retinoid로써경구로투여되며부작용도적으며면역억제작용도없다. 비소세포폐암에대하여항암화학요법과더불어 Bexarotene 을투여한 1/2상연구 102 에서 50% 의안정화를 25% 의부분관해를얻을수있었다. 이어서진행된무작위이중맹검실험에서도항암화학치료후 133

12 YC Kim et al : Drugs for lung cancer treatment bexarotene 또는위약을투여하였는데, 무병생존기간이 bexarotene군이위약군보다긴경향 (177일과 56일 ) 을보여서추가적인연구가진행중이다 103. F. Extracellular Matrix Matrix metalloproteinases(mmp) 는 extracellular matrix 를분해하는 zinc-dependent endopeptidase 의일종이다 104. 정상적으로는 MMP의활성은정교하게조절을받지만, 종양세포에서는과발현되거나활성화가조절되지않음으로써혈관신생을촉진하여암종의성장과침투, 전이에관여한다 105. 비소세포폐암에서는 MMP-2 와 MMP-9 두가지효소의활성형이주변조직에비해서종양세포에서높게측정되었고, 이러한과발현은불량한예후와관련됨이보고되었다. 몇가지합성형의 matrix metalloproteinase 억제제 (MMPI) 들의세포독성항암약물들과병합효과를관찰한초기의연구들에서는고무적인결과들이보고되었으나, 추적된 3상연구들에서세포독성약물등과병합하였을때생존기간의연장은증명되지않았다 106. 소세포폐암은비소세포폐암에비하여전이가더활발하므로 MMPI의과발현이더중요한역할을할것으로추정되는데, 약 89% 에서 MMP들이발현되며 3, 11, 14번 MMP의과발현은불량한예후인자로보고되었다 107. 개발된 MMPI중경구투여가가능한 marimastat 를소세포폐암의유도화학요법이후에재발까지의시간을연장하려는목적으로시험되었다. 완전또는부분관해를얻었던 532명의소세포폐암환자들에게무작위배정으로 marimastat 를위약대조군과함께투여하였는데 (10 mg 하루 2회경구 ) 108, marimastat 투여군과대조군간에진행기간및생존기간에차이는없으면서 marimastat 투여군에서근골격계독성으로인한삶의질의저하가관찰되었다. 또다른 MMPI로써개발된 BAY 는 700명의소세포폐암환자들을유도화학치료후위약대조군과함께투여되었는데중간결과분석에서더높은부작용과질병의악화율을보여조기에실험이종료되었다. G. Immune Therapy G-1. 종양관련항원들면역체계를조절하여암에대한거부반응을유도하는것은암치료의오랜숙원중의하나이다. 암세포내외에위치하는종양항원들은면역반응을유발할수있는데, 세포표면에위치하는항원들은대식세포, B 세포, 또는수지상세포 (dendritic cells) 와같은 antigen presenting cell(apc) 에의하여 endocytosis 되어서, class II MHC 분자들과함께 T세포에게제공된다. 세포내에위치하는항원들은보통 peptides 형태로처리되어종양세포표면의 class I MHC 분자들과함께 T 세포에게제공된다. 수많은암세포표면항원들이폐암의면역치료대상으로물색되었다. 예를들어비소세포폐암의 80% 에서발견되는 carcinoembryonic antigen(cea) 을복제가불가한 virus vector에 CEA 유전자형태로넣어주는시도가있었다 109. 소세포폐암의면역치료를위한세포외항원들은 ganglioside(fucosyl GM1GM2, GD2, GD3) 가있으며이러한표적들을겨냥한 immune conjugate vaccine 들이연구되고있다. G-2. Autologous tumor vaccines 자신의암세포표면에특이하게발현되는항원을대상으로면역반응을유도하는방법이다. 면역보강제를병합하여투여하여면역반응을유도하는펩티드암백신도있지만, 최근에는암세포에서 cytokine 을분비시키는유전자조절백신을사용하고있다. Cytokine 들은 T 세포를활성화시킬수있는보조적인자극을줄수있는데, 전임상연구들에서는 granulocyte macrophage colony stimulating factor (GM-CSF) 가가장효과적이며특이적으로오래지속하는 CD8+ T 림프구면역반응을유발한다 110. 환자의종양세포를채취하여 GM-CSF 유전자를발현하도록유전자를이입시키고방사선을조사한후다시환자에게투여하는종양백신 (GVAX ) 이기대되는성적을보이고있다. 4병기비소세포폐암만을대상으로한 1상연구에서, 백신을투여하였을 134

13 Tuberculosis and Respiratory Diseases Vol. 60. No. 2, Feb 때 25명중 18명의환자들에서면역반응이유도되었다 111. 백신을투여하기전에이미수술적으로완전히종양이제거된두명의환자는 43 개월과 42개월째재발의증거없이유지되고있고다른 5명의환자들은최소한 3개월이상안정화상태에있음이보고되었다. 또다른 1-2상임상연구에서는 83명의환자들로부터종양세포를채취하여 67명에서성공적으로백신을생산할수있었는데 112, 33명의진행된비소세포폐암중 3명과기관지폐포암 2명에서 6, 18개월그리고 22개월이상지속한완전관해를얻을수있었다. Mycobacterium vaccae균을가열살균처리한용액인 SRL172는종양세포와함께투여하였을때강력한면역유발효과가있다. 28명의소세포폐암환자들에게항암치료와함께 SRL172를투여하였을때투여군에서중앙생존이더연장되는경향을보였다 113. 이후로비소세포폐암에서 3상연구가진행되었는데항암화학치료에 SRL172를추가함에따른생존기간의연장은없었으나투여군에서삶의질이더호전됨이보고되었다 114. 소세포폐암에서발현되는 GD3 ganglioside를모방한 anti-idiotypic antibody (BEC2) 는생체내에서 GD3 ganglioside에대한항체생산을유도한다 명의표준적치료를마친소세포폐암환자들에게 2.5mg의 BEC2와 BCG를 10주동안 5차례피하주사하였다 116. 모든환자들이 BEC2에대한항체를생산하였고, 5명에서는 GD3에대한항체를생산하였으며, 치료에따른부작용은경미하였다. 중앙생존기간은 21개월이었고질병진행기간은전이기환자 8명에서 11개월, 7명의제한기환자들은아직도달하지않았다. 위와같은고무적인결과에따라제한기소세포폐암으로표준치료를마친환자들에게 BEC2/BCG 또는단순추적관찰하는 3상연구가진행되었으나양군간에생존, 무병생존기간에차이는없었다 (G. Giaccone et al. Abstract #7020, ASCO, 2004). G-3. Anti-NCAM blocked ricin fusion protein 소세포페암세포에서발현되는특이항원인 CD56 (neural cell adhesion molecule, NCAM) 에대한특이항체를제작하여독소 (diphtheria toxin 또는 ricin) 와결합하여사용할수있다. N901은 NCAM에대한항체로써 blocked Ricin(N901-bR) 과 conjugation 시킨약물이다. 21명의전이기소세포폐암에게투여된 1 상연구에서 1명의부분관해가관찰되었으나 117, 후속된연구 118 에서중증의부작용으로더이상개발은진행되지않고있다. G-4. Anti-gastrin releasing peptide antibodies 쥐로부터만들어진단클론항체 2A11은 gastrin releasing peptide(grp) 를인식하여세포주와동물실험에서자가성장촉진기능을차단한다. 12명의소세포폐암을대상으로 MoAb 2A11를사용한 2상연구에서 4개월간지속한완전관해 1명과 3명의안정화를얻을수있었다 119. 결 아직치료가어려운폐암에대하여새로운약물및치료방법들이절실히요구되고있어서, 특이표적들을겨냥한새로운치료방법들이활발하게연구개발되고있다. 특히이제는조직형뿐만아니라유전자또는분자수준의특성으로폐암을구분하여이해하고치료에도응용하는시대가도래하고있다. 그러나이러한표적치료들은단독으로효과가기대되기보 다는다른치료방법들과다양한방법으로병합이필요하다. 따라서임상에서는각각의치료방법들에대한효과를예측할수있는지표들을찾는연구들과함께적절한병합치료방법들의개발이추구되어야할것이다. 론 참고문헌 1. Seo JH, Jeong CS. Death rate statistics of Korea, Korea National Statistical Office; Reck M, Gatzemeier U. Chemotherapy in stage-iv NSCLC. Lung Cancer 2004;45(Suppl 2):S Fong KM, Sekido Y, Minna JD. Molecular pathogenesis of lung cancer. J Thorac Cardiovasc Surg 1999; 135

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