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Progress in Chemistry 2010, Vol. 22 Issue (10): 1993-2002 Previous Articles   Next Articles

• Review •

Tumor Angiogenesis Inhibitors

Dong Jin   Yao Shuowei  Xu Yungen**   

  1. (Department of Medicinal Chemistry,China Pharmaceutical University, Nanjing 210009)
  • Received: Revised: Online: Published:
  • Contact: Yungen Xu E-mail:xu_yungen@hotmail.com
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At present, drug inhibition of angiogenesis has become a hot topic in the treatment of tumor and several tumor angiogenesis inhibitors (TAIs) have been marketed. TAIs can suppress tumor growth and metastasis, and even induce tumor regression. Research and development on TAIs holds the promise of supplying drugs with high potency, low toxicity and broad-spectrum antitumor activity for tumor patients. This review summarized recent research progress in TAIs. First of all, indirect TAIs were introduced. Among indirect TAIs, VEGF inhibitor is the most successful TAI currently. Secondly, direct TAIs, which are unlikely switch on the angiogenic rescue program, were introduced. Thirdly, in the miscellaneous TAIs part, thalidomide and its derivatives, whose mechanisms of activity have not been defined well, were described in detail. Finally, several problems encountered in the research and development of TAIs, such as challenge from novel theory of anti-angiogenenic therapy and resistance, were analyzed and discussed, and future research directions were pointed out.

Contents 
1 Introduction
2 Indirect angiogenesis inhibitors
2.1 Inhibitors of VEGF/VEGFR signaling
2.2 Inhibitors of angiopoietin-Tie signaling 
3 Direct angiogenesis inhibitors
3.1 Metronomic chemotherapy
3.2 Inhibitors of endothelial-specific integrin/survival signaling
3.3 Miscellaneous direct angiogenesis inhibitors 
4 Miscellaneous angiogenesis inhibitors 
5 Questions needed to be considered
5.1 Mechanism of angiogenesis
5.2 Resistance of angiogenesis inhibitors
5.3 Clinical study design 
6 Future directions 
7 Conclusions

[1 ] 杨友华( Yang Y H ) . 中国处方药( Journal of China
Prescription Drug) ,2004,8(29) : 33—35
[2 ] Folkman J,Hochberg M J. Exp. Med. ,1973,138: 745—753
[3 ] Bergers G,Benjamin L E. Nat. Rev. Cancer. ,2003,3: 401—
410
[4 ] Ferrara N,Kerbel R S. Nature,2005,438: 967—974
[5 ] 何静( He J) ,冯奉仪( Feng F Y) . 临床药物治疗杂志
( Clinical Medication Journal) ,2005,3(2) : 16—20
[6 ] Gasparini G,Longo R,Toi M,Ferrara N. Nat. Clin. Pract.
Oncol. ,2005,2: 562—577
[7 ] Khosravi S P,Fernández P I. Cancer Invest. ,2008,26: 104—
108
[8 ] Otrock Z K,Mahfouz R A,Makarem J A,Shamseddine A I.
Blood Cells Mol. Dis. ,2007,39: 212—220
[9 ] Dvorak H F. J. Clin. Oncol. ,2002,20: 4368—4380
[10] Augustin H G,Koh G Y,Thurston G,Alitalo K. Nat. Rev.
Mol. Cell Biol. ,2009,10: 165—177
[11] Olsson A K,Dimberg A,Kreuger J,Claesson-Welsh L. Nat.
Rev. Mol. Cell Biol. ,2006,7: 359—371
[12] Veikkola T,Jussila L,Makinen T,Karpanen T,Jeltsch M,
Petrova T V,Kubo H,Thurston G,McDonald D M,Achen M
G,Stacker S A,Alitalo K. EMBO J. ,2001,20: 1223—1231
[13] Kiselyov A, Balakin K V, Tkachenko S E. Expert Opin.
Investig. Drugs,2007,16: 83—107
[14] 陈川( Chen C) ,俞德超(Yu D C) ,腾理送( Teng L S) ,中
国肿瘤生物治疗杂志( Chinese Journal of Cancer Biotherapy) ,
2007,14(3) : 291—300
[15] Ferrara N,Hillan K J,Gerber H P,Novotny W. Nat. Rev.
Drug Discov. ,2004,3: 391—400
[16] Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S,
Pattarini L,Chorianopoulos E,Liesenborghs L,Koch M,de M
M,Autiero M,Wyns S,Plaisance S,Moons L,van Rooijen N,
Giacca M,Stassen J M,Dewerchin M,Collen D,Carmeliet P.
Cell,2007,131: 463—475
[17] Holash J,Davis S,Papadopoulos N,Croll S D,Ho L,Russell
M,Boland P,Leidich R,Hylton D,Burova E,Ioffe E,Huang
T,Radziejewski C,Bailey K,Fandl J P,Daly T,Wiegand S J,
Yancopoulos G D,Rudge J S. Proc. Natl. Acad. Sci. USA,
2002,99: 11393—11398
[18] Posey J A,Ng T C,Yang B,Khazaeli M B,Carpenter M D,
Fox F,Needle M,Waksal H,LoBuglio A F. Clin. Cancer
Res. ,2003,9: 1323—1332
[19] Youssoufian H,Hicklin D J, Rowinsky E K. Clin. Cancer
Res. ,2007,13: 5544s—5548s
[20] Camidge D R,Eckhardt S G,Diab S,Gore L,Chow L,O′
Bryant C,Temmer E,Ervin-Haynes A,Katz T,Fox F,Cohen R
B. J. Clin. Oncol. ,2006,24: 3032—3038
[21] Wu Y,Zhong Z,Huber J,Bassi R,Finnerty B,Corcoran E,Li
H,Navarro E,Balderes P,Jimenez X,Koo H,Mangalampalli V
R,Ludwig D L,Tonra J R,Hicklin D J. Clin. Cancer Res. ,
2006,12: 6573—6584
[22] Strumberg D. Drugs Today ( Barc) ,2005,41: 773—784
[23] Wilhelm S,Carter C,Lynch M,Lowinger T,Dumas J,Smith R
A, Schwartz B, Simantov R, Kelley S. Nat. Rev. Drug
Discov. ,2006,5: 835—844
[24] Eisen T,Bukowski R M,Staehler M,Szczylik C,Oudard S,
Stadler W M,Schwartz B,Simantov R,Shan M,Escudier B.
2006 ASCO Annual Meeting Proceedings. Atlanta: J. Clin.
Oncol. ,2006,24: 4524
[25] Matsui J,Funahashi Y,Uenaka T,Watanabe T,Tsuruoka A,
Asada M. Clin. Cancer Res. ,2008,14: 5459—5465
[26] Atkins M,Jones C A,Kirkpatrick P. Nat. Rev. Drug Discov. ,
2006,5: 279—280
[27] Cabebe E,Wakelee H. Drugs Today ( Barc) ,2006,42: 387—
398
[28] Naumova E,Ubezio P, Garofalo A, Borsotti P, Cassis L,
Riccardi E,Scanziani E,Eccles S A,Bani M R,Giavazzi R.
Clin. Cancer Res. ,2006,2: 1839—1849
[29] Patyna S,Laird A D,Mendel D B,O′ farrell A M,Liang C,
Guan H,Vojkovsky T,Vasile S,Wang X,Chen J,Grazzini M,
Yang C Y, Haznedar J O, Sukbuntherng J, Zhong W Z,Cherrington J M,Hu-Lowe D. Mol. Cancer Ther. ,2006,5:
1774—1782
[30] Trudel S,Li Z H,Wei E,Wiesmann M,Chang H,Chen C,
Reece D,Heise C,Stewart A K. Blood,2005,105: 2941—
2948
[31] Hilberg F,Roth G J,Krssak M,Kautschitsch S,Sommergruber
W,Tontsch-Grunt U,Garin-Chesa P,Bader G,Zoephel A,
Quant J,Heckel A,Rettig W J. Cancer Res. ,2008,68:
4774—4782
[32] Teresa T,Tina T,John H,Ciardiello F. Curr. Cancer Ther.
Rev. ,2007,3: 236—241
[33] Wedge S R,Kendrew J,Hennequin L F,Valentine P J,Barry S
T,Brave S R,Smith N R,James N H,Dukes M,Curwen J O,
Chester R,Jackson J A,Boffey S J,Kilburn L L,Barnett S,
Richmond G H,Wadsworth P F,Walker M,Bigley A L,Taylor
S T,Cooper L,Beck S,Jürgensmeier J M,Ogilvie D J. Cancer
Res. ,2005,65: 4389—4400
[34] Garrett C R,Siu L L,El-Khoueiry A B,Buter J,Rocha-Lima C
M,Marshall J L,Kollia G,Velasquez L,Syed S,Feltquate D.
2008 ASCO Annual Meeting Proceedings. Chicago: J. Clin.
Oncol. ,2008,26: 4111
[35] Bhide R S,Lombardo L J,Hunt J T,Cai Z W,Barrish J C,
Galbraith S,Jeyaseelan R Sr,Mortillo S,Wautlet B S,Krishnan
B,Kukral D,Malone H,Lewin A C,Henley B J,Fargnoli J.
Mol. Cancer Ther. ,2010,9: 369—378
[36] Zhang Y,Guessous F,Kofman A, Schiff D,Abounader R.
IDrugs,2010,13: 112—121
[37] Deng M,Huang H,Dirsch O,Dahmen U. Eur. Surg Res. ,
2010,44: 82—95
[38] Morabito A,De M E, Di M M, Normanno N, Perrone F.
Oncologist,2006,11: 753—764
[39] Coxon A,Bush T,Saffran D,Kaufman S,Belmontes B,Rex K,
Hughes P,Caenepeel S,Rottman J B,Tasker A,Patel V,
Kendall R, Radinsky R, Polverino A. Clin. Cancer Res. ,
2009,15: 110—118
[40] Garton A J,Crew A P,Franklin M,Cooke A R,Wynne G M,
Castaldo L,Kahler J,Winski S L,Franks A,Brown E N,
Bittner M A,Keily J F,Briner P,Hidden C,Srebernak M C,
Pirrit C,O′Connor M,Chan A,Vulevic B,Henninger D,Hart
K,Sennello R,Li A H,Zhang T,Richardson F,Emerson D L,
Castelhano A L,Arnold L D,Gibson N W. Cancer Res. ,2006,
66: 1015—1024
[41] Williams R. Expert Opin. Investig. Drugs,2008,17: 1791—
1816
[42] Hutson T E,Bukowski R M. Clin. Genitourin. Cancer,2006,
4: 296—298
[43] Rugo H S,Herbst R S,Liu G,Park J W,Kies M S,Steinfeldt
H M,Pithavala Y K,Reich S D,Freddo J L,Wilding G. J.
Clin. Oncol. ,2005,23: 5474—5419
[44] Hanahan D. Science,1997,277: 48—50
[45] Yu Q. Future Medicine,2005,1: 475—484
[46] Kerbel R S. New Engl. J. Med. ,2008,358: 2039—2049
[47] Lobov I B,Brooks P C,Lang R A. Proc. Natl. Acad. Sci. ,
2002,99: 11205—11210
[48] Zhou B N,Johnson R K,Mattern M R,Fisher P W,Kingston D
G. Org. Lett. ,2001,3: 4047—4049
[49] Hodous B L,Geuns-Meyer S D,Hughes P E,Albrecht B K,
Bellon S,Bready J,Caenepeel S,Cee V J,Chaffee S C,Coxon
A,Emery M,Fretland J,Gallant P,Gu Y,Hoffman D,Johnson
R E,Kendall R,Kim J L,Long A M,Morrison M,Olivieri P
R,Patel V F,Polverino A,Rose P,Tempest P,Wang L,
Whittington D A,Zhao H. J. Med. Chem. ,2007,50: 611—
626
[50] Kerbel R S,Kamen B A. Nat. Rev. Cancer,2004,4: 423—
436
[51] Miller K D,Sweeney C J,Sledge G W. J. Clin. Oncol. ,2001,
19: 1195—1206
[52] Colleoni M,Rocca A,Sandri M T,Zorzino L,Masci G,Nolè F,
Peruzzotti G,Robertson C,Orlando L,Cinieri S,de B F,Viale
G,Goldhirsch A. An. Oncol. ,2002,13: 73—80
[53] Gluck S,Mackinnon J,Lau H,Syme R,Dort J,Gluck D. 2003
ASCO Annual Meeting Proceedings. Chicago: Proc. Am. Soc.
Clin. Oncol. ,2003,22: 2066
[54] Cohn D E,Valmadre S,Resnick K E,Eaton L A,Copeland L
J,Fowler J M. Gynecol. Oncol. ,2006,102: 134—139
[55] Emmenegger U,Man S,Shaked Y,Francia G,Wong J W,
Hicklin D J,Kerbel R S. Cancer Res. ,2004,64: 3994—4000
[56] Hanahan D,Bergers G,Bergsland E J. Clin. Invest. ,2000,
105: 1045—1047
[57] Browder T,Butterfield C E,Krling B M,Shi B,Marshall B,
O′Reilly M S,Folkman J. Cancer Res. ,2000,60: 1878—1886
[58] Huveneers S,Truong H,Danen H J. Int. J. Radiat. Biol. ,
2007,83: 743—751
[59] Schliemann C,Neri D. Biochem. Bioph. Acta. ,2007,1776:
175—192
[60] Loges S, Butzal M, Otten J, Schweizer M, Fischer U,
Bokemeyer C,Hossfeld D K,Schuch G,Fiedler W. Biochem.
Biophys. Res. Commun. ,2007,357: 1016—1020
[61] Perk J,Iavarone A,Benezra R. Nat. Rev. Cancer,2005,5:
603—614
[62] Henke E,Perk J,Vider J,de Candia P,Chin Y,Solit D B,
Ponomarev V,Cartegni L,Manova K,Rosen N,Benezra R.
Nat. Biotechnol. ,2008,26: 91—100
[63] Solomon S D,McMurray J J,Pfeffer M A,Wittes J,Fowler R,
Finn P,Anderson W F,Zauber A,Hawk E,Bertagnolli M. N.
Engl. J. Med. ,2005,352: 1071—1080
[64] Teo S K,Stirling D I,Zeldis J B. Drug Discov. Today,2005,
10: 107—114
[65] Aragon-Ching J B,Li H,Gardner E R,Figg W D. Recent
Patents Anticancer Drug Discov. ,2007,2: 167—174
[66] Ocio E M,Mateos M V,Maiso P,Pandiella A,San-Miguel J F.
Lancet Oncol. ,2008,9: 1157—1165
[67] Schey S A,Fields P,Bartlett J B,Clarke I A,Ashan G,Knight
R D,Streetly M,Dalgleish A G. J. Clin. Oncol. ,2004,22:3269—3276
[68] Kumar S,Raje N, Hideshima T, Ishitsuka K, Roccaro A,
Shiraishi N,Hamasaki M,Yasui H,Munshi N C,Richardson
P,Figg W D,Anderson K C. Leukemia,2005,19: 1253—
1261
[69] Jain R K. Science,2005,307: 58—62
[70] Page-McCaw A,Ewald A J,Werb Z. Nat. Rev. Mol. Cell
Biol. ,2007,8: 221—233
[71] Overall C M,Kleifeld O. Nat. Rev. Cancer,2006,6: 227—
239
[72] Konstantinopoulos P A, Karamouzis M V, Papatsoris A G,
Papavassiliou A G. Int. J. Biochem. Cell Biol. ,2008,40:
1156—1168
[73] Benedito R,Roca C,Srensen I,Adams S,Gossler A,Fruttiger
M,Adams R H. Cell,2009,137: 1124—1135
[74] Eberhard A,Kahlert S,Goede V,Hemmerlein B,Plate K H,
Augustin H G. Cancer Res. ,2000,60: 1388—1393
[75] Casanovas O,Hicklin D,Bergers G,Hanahan D. Cancer Cell,
2005,8: 299—309
[76] Willett C G,Boucher Y,Duda D G,di Tomaso E,Munn L L,
Tong R T,Kozin S V,Petit L,Jain R K,Chung D C,Sahani D
V,Kalva S P,Cohen K S,Scadden D T,Fischman A J,Clark J
W,Ryan D P,Zhu A X,Blaszkowsky L S,Shellito P C,Mino-
Kenudson M, Lauwers G Y. J. Clin. Oncol. , 2005, 23:
8136—8139
[77] Hida K,Klagsbrun M. Cancer Res. ,2005,65: 2507—2510
[78] Rudge J S,Holash J,Hylton D,Russell M,Jiang S,Leidich R,
Papadopoulos N,Pyles E A,Torri A,Wiegand S J,Thurston G,
Stahl N,Yancopoulos G D. Proc. Natl. Acad. Sci. ,2007,
104: 18363—18370
[79] Leighl N B,Paz-Ares L,Douillard J Y,Peschel C,Arnold A,
Depierre A,Santoro A,Betticher D C,Gatzemeier U,Jassem J,
Crawford J,Tu D,Bezjak A,Humphrey J S,Voi M,Galbraith
S,Hann K,Seymour L,Shepherd F A. J. Clin. Oncol. ,2005,
23: 2831—2839

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Abstract

Tumor Angiogenesis Inhibitors