著地提高表達(dá)。KB1037和KB1123在SK-MEL-28 和來自患者GB0270腹壁的黑色素瘤細(xì)胞中提高表達(dá)。
[0115] 預(yù)期的是,本說明書中所討論的任何實(shí)施方案可以通過關(guān)于本發(fā)明的任何方法、 試劑盒、試劑或組合物來實(shí)施,反之亦然。此外,本發(fā)明的組合物可以用于實(shí)現(xiàn)本發(fā)明的方 法。
[0116] 要理解的是,本文所述的具體實(shí)施方案是通過舉例說明而不是限制本發(fā)明的方法 來顯示的。本發(fā)明的主要特征可以在不脫離本發(fā)明范圍的情況下用于各種實(shí)施方案中。本 領(lǐng)域技術(shù)人員將認(rèn)識(shí)到,或者僅僅利用常規(guī)的實(shí)驗(yàn)?zāi)軌虼_定本文所述具體步驟的許多等同 物。這樣的等同物被認(rèn)為是在本發(fā)明的范圍內(nèi),且被權(quán)利要求所涵蓋。
[0117] 本說明書中提到的所有出版物和專利申請(qǐng)表明了本發(fā)明所涉及領(lǐng)域的技術(shù)人員 的水平。所有的出版物和專利申請(qǐng)均引入本文作為參考,其引入的程度如同各個(gè)獨(dú)立的出 版物或?qū)@暾?qǐng)具體并獨(dú)立地被指明引入作為參考。
[0118] 詞語"一個(gè)(a)"或"一種(an)"當(dāng)與權(quán)利要求和/或說明書中的術(shù)語"包含 (comprising) "結(jié)合使用時(shí),可以指"一種",但其也與"一種或多種"、"至少一種"和"一種 或多于一種"的意思相一致。在權(quán)利要求中所使用的術(shù)語"或者"是指"和/或",除非明確 指明僅僅是指替代物,或替代物相互排斥,盡管公開內(nèi)容支持僅僅指替代物及"和/或"的 定義。在整個(gè)本申請(qǐng)中,術(shù)語"大約"用來說明這樣的值,其包括用來測(cè)定所述值的裝置、方 法的誤差的固有變化,或者研宄受試者之間存在的變化。
[0119] 如在本說明書和權(quán)利要求中所使用的,詞語"包含(comprising) "(以及任何形式 的"包含",如"包含(comprise)和包含(comprises) "),"具有(having)"(以及任何形式 的"具有",如"具有(have)"和"具有(has)"),"包括(including)"(以及任何形式的"包 括",如"包括(includes)"和"包括(include)")或"含有(containing)"(以及任何形式 的"含有",如"含有(contains)"和"含有(contain)")是包括的或開放式的,且不排除額 外的,未述及的元素或方法步驟。
[0120] 如本文所使用的術(shù)語"或它們的組合"是指在該術(shù)語之前所列舉項(xiàng)目的全部排列 和組合。例如,"A、B、C或它們的組合"意在包括A、B、C、AB、AC、BC或ABC中的至少一種, 并且如果在特定的上下文中順序是重要的,那么還包括BA、CA、CB、CBA、BCA、ACB、BAC或 CAB。繼續(xù)這個(gè)例子,明顯包括的是包含一種或多種項(xiàng)目或術(shù)語的重復(fù)的組合,如BB、AAA、 MB、BBC、AAABCCCC、CBBAAA、CABABB等等。本領(lǐng)域技術(shù)人員將理解的是,通常對(duì)任何組合中 的項(xiàng)目或術(shù)語的數(shù)目沒有限制,除非從上下文中另外是明顯的。
[0121] 如本文中所使用的,近似值的詞語例如而非限制的,"約"、"大體的"或者"大體上" 是指當(dāng)如此修飾時(shí),應(yīng)理解為不必是絕對(duì)的或者完美的條件,而應(yīng)認(rèn)為該條件對(duì)于本領(lǐng)域 普通技術(shù)人員而言其足夠接近指定該條件作為所呈現(xiàn)的保證。說明書可以變化的程度取決 于可以進(jìn)行多大的變化并且本領(lǐng)域普通技術(shù)人員仍然認(rèn)識(shí)到經(jīng)修改的特征仍然具有想要 的性質(zhì)和未修改的特征的性能。一般來說,同時(shí)針對(duì)當(dāng)前的討論,本文被近似值詞語如"約" 修飾的數(shù)值可以從規(guī)定的數(shù)值變化至少±1、2、3、4、5、6、7、10、12或者15%。
[0122] 根據(jù)本發(fā)明的公開內(nèi)容,在不過度的實(shí)驗(yàn)下可以制備和實(shí)施本文所公開和要求保 護(hù)的全部組合物和/或方法。盡管已經(jīng)以優(yōu)選的實(shí)施方案的形式描述了本發(fā)明的組合物和 方法,但是對(duì)于本領(lǐng)域技術(shù)人員來說明顯的是,在不脫離本發(fā)明的構(gòu)思、精神和范圍的情況 下,可以改變本文所述的組合物和/或方法以及方法的步驟或方法的步驟的順序。對(duì)本領(lǐng) 域技術(shù)人員而言明顯的所有這樣相似的替代和修改被認(rèn)為是在所附的權(quán)利要求所限定的 本發(fā)明的精神、范圍和構(gòu)思內(nèi)。
[0123] 參考f獻(xiàn)
[0124] 在發(fā)明詳述中的粗體的參考文獻(xiàn)號(hào)分別地對(duì)應(yīng)于授權(quán)專利和文獻(xiàn)中的原始編號(hào)。 斜體的編號(hào)是用于專利申請(qǐng)的編號(hào)。隨后的編號(hào)是經(jīng)改正的編號(hào)。
[0125]1. Improved DNA:liposome complexes for increased systemic delivery and gene expression,N. S. Templeton,D. D. Lasic,P. M. Frederik,H. H. Strey,D. D. Roberts, and G.N.Pavlakis,Nature Biotechnology,1997,15,647-652.
[0126] 2. Liposomal delivery of nucleic acids in vivo,N. S. Templeton,DNA and Cell Biology,2002,21. 857-867.
[0127] 3.Successful treatment of primary and disseminated human lung cancers by systemic delivery of tumor suppressor genes using an improved liposome vector,R. Ramesh,T. Saeki,N. S. Templeton,L. Ji,L C. Stephens,I. Ito,D. R. Wilson, Z. Wu,C. D. Branch,J. D. Minna,and J. A. Roth,Molecular Therapy,2001,3, 337-350.
[0128] 4. Openings between defective endothelial cells explain tumor vessel leakiness,H.Hashizume,P.Baluk,S.Morikawa,J.W. McLean,G. Thurston,S. Roberge, R. K. Jain,and D.M. McDonald,AmJ Pathol,2000,156,1363-1380.
[0129] 5. Effect of transvascular fluid exchange on pressure-flow relationship in tumors :a proposed mechanism for tumor blood flow heterogeneity,P. A. Netti, S. Roberge,Y. Boucher,L T.Baxter,and R. K. Jain,Microvasc Res,1996, 52, 27-46.
[0130] 6. Vascular permeability and microencapsulation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows,F(xiàn). Yuan,H. A. Salehi, Y. Boucher,U. S. Vasthare,R. F. Tuma,and R. K. Jain,Cancer Res,1994, 54,4564-4568.
[0131] 7. Vasculogenic mimicry,R. Folberg,and A. J. Maniotis,APMIS,2004,112, 508-525.
[0132] 8. Remodeling of the microenvironment by I melanoma tumor cells, M. J. Hendrix,E. A. Seftor,D. A. Kirschmann,V. Quaranta,and R. E. Seftor,Ann N Y Acad Sci,2003,995,151-161.
[0133] 9.Discovering High-Affinity Ligands for Proteins :SAR by NMR? S. B. Shuker,P. J. Hajduk,R. P. Meadows,and S. W. Fesik,Science,1996, 274,1531-1534.
[0134] 10. Discovery of Potent Nonpeptide Inhibitors of Stromelysin Using SAR by NMR,P. J. Hajduk,G. Sheppard,D. G. Nettesheim,E. T. Olejniczak,S. B. Shuker, R. P. Meadows,D. H. Steinman,G. M. Carrera,P. A. Marcotte,J. Severin,K. Walter,H. Smith, E.Gubbius,R. Simmer,T. F. Holzman,D. W.Morgan,S.K.Davidsen,J. B. Summers,and S. W. Fesik,J. Am. Chem. Soc.,1997,119, 5818-5827.
[0135] 11. One-Dimensional Relaxation-and Diffusion-Edited NMR Methods for Screening Compounds That Bind to Macromolecules,P. J. Hajduk,E. T. Olejniczack,and S. W. Fesik,J. Am. Chem. Soc.,1997,119,12257-1226L
[0136] 12.NMR-Based Discovery of Lead Inhibitors That Block DNA Binding of the Human Papillomavirus E2 Protein?P. J. Hajduk?J. Dinges?G. F. Miknis?M.Merlock? T. Middleton,D. J. Kempf,D. A. Egan,K. A. Walter,T. S. Robins,S. B. Shuker,T. F. Holzman, and S. W. Fesik,J. Med. Chem,1997,40, 3144-3150.
[0137] 13. Structure-Activity Relationships by NMR :A New Procedure for Drug Discovery by a Combinatorial-Rational Approach? H. Kessler? Angew. Chem. Int. Ed. ? 1997,36,829-831.
[0138]14.Stromelysin Inhibitors Designed from Weakly Bound Fragments: Effeets of Linking and Cooperativity,E.T.Olejniczak,P.J. Jahduk,P. A. Marcotte, D. G. Nettesheim? R. P. Meadows? R. Edal ji? T. F. Holzman? and S. W. Fesik? J. Am. Chem. Soc. ? 1997,119,5828-5832.
[0139] 15. Identification of a Small Molecule Inhibitor of the IL-2/ IL_2Ra Receptor Interaction Which Binds to IL-2,J. W. Tilley,L Chen,D. C. Fry, S. D. Emerson,G.D. Powers,D.Biondi,T.Varnell,R.Trilles,R. Guthrie,F(xiàn).Mennonaa, G. Kaplan,R. A. LeMahieu,R. Palermo, and G. Ju,J. Am. Chem. Soc.,1997,119, 7589-7590.
[0140] 16.The SHAPES strategy :an NMR-based approach for lead generation in drug discovery? J. Fejzo? C. A. Lepre? J. W. Peng? G. W. Bemis? Ajay? M. A. Murcko? and J. M. Moore,Chem. Biol.,1999, 5, 755-769.
[0141] 17.Privileged Molecules for Protein Binding Identified from NMR-Based Screening,P. J. Hajduk,M. Bures,J. Praestgaard,and S. W. Fesik,J. Med. Chem.,2000,43, 3443-3447.
[0142] 18. SNAr Cyclizations to Form Cyclic Peptidomimetics ofb-Turns,Y. Feng, Z. Wang,S. Jin,andK. Burgess,J. Am. Chem. Soc.,1998,120,10768-10769.
[0143] 19. Solid Phase SNAr Macrocyclizations to Give Turn-extended-turn Peptidomimetics,Y. Feng,and K. Burgess,Chem. Eur. J.,1999, 5, 3261-3272.
[0144]20.Conformations of Peptidomimetics Formed by SNAr Macrocyclizations: 13-tol6_Membered Ring Systems,Y. Feng,Z. Wang,S. Jin,and K. Burgess,Chem. Eur. J., 1999,5,3273-3278.
[0145] 21.Stereochemical Implications of Diversity in b-Turn Peptidomimetic Libraries,Y. Feng,M. Pattarawarapan,Z. Wang,and K. Burgess,J. Org. Chem.,1999,64, 9175-9177.
[0146] 22. Facile Macrocyclizations to b-Turn Mimics with Diverse Structural, Physical,andConformational Properties,C. Park,and K. Burgess,J. Comb. Chem.,2001, 3,257-266.
[0147] 23. A New Solid-Phase Linker for Suzuki Coupling with Concomitant Macrocyclization :Synthesis of b-Turn Mimics,W. Li,and K. Burgess,Tetrahedron Lett.,1999,40,6527-6530.
[0148] 24. Preferred Secondary Structures as a Possible Driving Force for Macrocyclization,S. Reyes,M. Pattarawarapan,S. Roy,and K. Burgess,Tetrahedron, 2000,56,9809-9818.
[0149] 25. Solid-Phase Syntheses of b-Turn Aualogues To Mimic or Disrupt Protein-Protein Interactions,K. Burgess,Acc. Chem. Res.,2001,34,826-835.
[0150] 25.Long-Lasting Rescue of Age-Associated Deficits in Cognition and the CNS Cholinergic Phenotype by a Partial Agonist Peptidomimetic Ligand of TrkA,M. A. Bruno,P. B. S. Clarke,A. Seltzer,R. Quirion,K. Burgess,A. C. Cuello,and H. U. Saragovi,J. Neuroscience,2004, 24,8009-8018.
[0151] 26. Folkman,J,and Kalluri,R(2004) ? Cancer without disease. Nature 427 : 787.
[0152] 27. Tandle,A,Blazer,DG,3rd,and Libutti,SK (2004) ? Antiangiogenic gene therapy of cancer :recent developments. J Transl Med 2;22.
[0153] 28. Ferrata,N,Hillan,KJ,Gerber,HP,and Novotny,W(2004) ? Discovery and development of bevacizumab,an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3 : 391-400.
[0154] 29. Faivre,S,Demetri,G,Sargent,W,and Raymond,E (2007) ? Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 6:734-745.<