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Original

Current status of antivascular therapy and targeted treatment in the clinic

, &
Pages 97-110 | Received 19 Sep 2007, Accepted 23 Nov 2007, Published online: 09 Jul 2009

References

  • Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med 1971; 285: 1182–1186
  • Folkman J. Anti-angiogenesis: New concept for therapy of solid tumors. Ann Surg 1972; 175: 409–416
  • Folkman J. Proceedings: Tumor angiogenesis factor. Cancer Res. 1974; 34: 2109–2113
  • Folkman J. Angiogenesis: An organizing principle for drug discovery?. Nat Rev Drug Discov 2007; 6: 273–286
  • Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70
  • Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer 2006; 6: 583–592
  • Harris M. Monoclonal antibodies as therapeutic agents for cancer. Lancet Oncol 2004; 5: 292–302
  • Imai K, Takaoka A. Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer 2006; 6: 714–727
  • Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–1037
  • Schiffer CA. BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N Engl J Med 2007; 357: 258–265
  • Carroll M, Ohno-Jones S, Tamura S, Buchdunger E, Zimmermann J, Lydon NB, Gilliland DG, Druker BJ. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood 1997; 90: 4947–4952
  • Druker BJ, Lydon NB. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 2000; 105: 3–7
  • Goldman JM, Melo JV. Targeting the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1084–1086
  • le Coutre P, Mologni L, Cleris L, Marchesi E, Buchdunger E, Giardini R, Formelli F, Gambacorti-Passerini C. In vivo eradication of human BCR/ABLpositive leukemia cells with an ABL kinase inhibitor. J Natl Cancer Inst 1999; 91: 163–168
  • Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000; 289: 1938–1942
  • Thiesing JT, Ohno-Jones S, Kolibaba KS, Druker BJ. Efficacy of STI571, an abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against bcrabl-positive cells. Blood 2000; 96: 3195–3199
  • Vigneri P, Wang JY. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med 2001; 7: 228–2234
  • Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, Silberman S, Capdeville R, Dimitrijevic S, Druker B, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001; 344: 1052–1056
  • Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JTY, Issels R, van Oosterom A, Hogendoorn PC, Van Glabbeke M, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 2004; 364: 1127–1134
  • Shimizu A, O'Brien KP, Sjoblom T, Pietras K, Buchdunger E, Collins VP, Heldin CH, Dumanski JP, Ostman A. The dermatofibrosarcoma protuberans associated collagen type Ialpha1/platelet-derived growth factor (PDGF) B-chain fusion gene generates a transforming protein that is processed to functional PDGF-BB. Cancer Res 1999; 59: 3719–3723
  • McArthur G. Dermatofibrosarcoma protuberans: Recent clinical progress. Ann Surg Oncol 2007; 14: 2876–2886
  • Curtis CE, Grand FH, Musto P, Clark A, Murphy J, Perla G. Minervini MM, Stewart J, Reiter A, Cross NC. Two novel imatinib-responsive PDGFRA fusion genes in chronic eosinophilic leukaemia. Br J Haematol 2007; 138: 77–81
  • Fletcher S, Bain B. Eosinophilic leukaemia. Br Med Bull 2007; 81-82: 115–127
  • Gotlib J, Cools J, Malone JM, III, Schrier SL, Gilliland DG, Coutre SE. The FIP1L1- PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: Implications for diagnosis, classification, and management. Blood 2004; 103: 2879–2891
  • Kalac M, Quintas-Cardama A, Vrhovac R, Kantarjian H, Verstovsek S. A critical appraisal of conventional and investigational drug therapy in patients with hypereosinophilic syndrome and clonal eosinophilia. Cancer 2007; 110: 955–964
  • Pardanani A, Reeder T, Porrata LF, Li CY, Tazelaar HD, Baxter EJ, Witzig TE, Cross NC, Tefferi A. Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders. Blood 2003; 101: 3391–3397
  • Jovanovic JV, Score J, Waghorn K, Cilloni D, Gottardi E, Metzgeroth G, Erben P, Popp H, Walz C, Hochhaus A, et al. Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Blood 2007; 109: 4635–4640
  • Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005; 353: 172–187
  • Guilhot F, Apperley J, Kim DW, Bullorsky EO, Baccarani M, Roboz GJ, Amadori S, de Souza CA, Lipton JH, Hochhaus A, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 2007; 109: 4143–4150
  • Cheson BD. CHOP plus rituximab - Balancing facts and opinion. N Engl J Med 2002; 346: 280–282
  • Coiffier B. Rituximab therapy in malignant lymphoma. Oncogene 2007; 26: 3603–3613
  • Stephenson J. Researchers optimistic about sea change in cancer treatment. JAMA 2001; 285: 2841–2842
  • Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407: 249–257
  • Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002; 20: 4368–4380
  • Adams RH, Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 2007; 8: 464–478
  • Alitalo K, Tammela T, Petrova TV. Lymphangiogenesis in development and human disease. Nature 2005; 438: 946–953
  • 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: 391–400
  • Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, Griffing S, Bergsland E. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003; 21: 60–65
  • Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S. Combined analysis of efficacy: The addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 2005; 23: 3706–3712
  • Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, Mass R, Perrou B, Nelson B, Novotny WF. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: Results of a randomized phase II trial. J Clin Oncol 2005; 23: 3697–3705
  • Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335–2342
  • Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007; 25: 1539–1544
  • Goldberg RM. Therapy for metastatic colorectal cancer. Oncologist 2006; 11: 981–987
  • Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004; 22: 209–1214
  • Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med 2005; 352: 476–487
  • Drevs J, Siegert P, Medinger M, Mross K, Strecker R, Zirrgiebel U, Harder J, Blum H, Robertson J, Jurgensmeier JM, et al. Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol 2007; 25: 3045–3054
  • McDonald DM, Choyke PL. Imaging of angiogenesis: From microscope to clinic. Nat Med 2003; 9: 713–725
  • Miller JC, Pien HH, Sahani D, Sorensen AG, Thrall JH. Imaging angiogenesis: Applications and potential for drug development. J Natl Cancer Inst 2005; 97: 172–187
  • Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004; 10: 145–147
  • Willett CG, Duda DG, di Tomaso E, Boucher Y, Czito BG, Vujaskovic Z, Vlahovic G, Bendell J, Cohen KS, Hurwitz HI, et al. Complete pathological response to bevacizumab and chemoradiation in advanced rectal cancer. Nat Clin Pract Oncol 2007; 4: 316–321
  • Sandler A. Bevacizumab in non small cell lung cancer. Clin Cancer Res 2007; 13: 4613s–4616s
  • Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: Bevacizumab (avastin) plus carboplatin and paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non small cell lung cancer. Oncologist 2007; 12: 713–718
  • Stinchcombe TE, Socinski MA. Bevacizumab in the treatment of non-small-cell lung cancer. Oncogene 2007; 26: 3691–3698
  • Cabebe E, Wakelee H. Role of anti-angiogenesis agents in treating NSCLC: Focus on bevacizumab and VEGFR tyrosine kinase inhibitors. Curr Treat Options Oncol 2007; 8: 15–27
  • de Castro Junior G, Puglisi F, de Azambuja E, El Saghir NS, Awada A. Angiogenesis and cancer: A cross-talk between basic science and clinical trials (the ‘do ut des’ paradigm). Crit Rev Oncol Hematol 2006; 59: 40–50
  • Los M, Roodhart JM, Voest EE. Target practice: Lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. Oncologist 2007; 12: 443–450
  • Arroyo JG. A 76-year-old man with macular degeneration. JAMA 2006; 295: 2394–2406
  • Steinbrook R. The price of sight–Ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med 2006; 355: 1409–1412
  • Stone EM. A very effective treatment for neovascular macular degeneration. N Engl J Med 2006; 355: 1493–1495
  • Iliev ME, Domig D, Wolf-Schnurrbursch U, Wolf S, Sarra GM.2 Intravitreal bevacizumab (Avastin) in the treatment of neovascular glaucoma. Am J Ophthalmol 2006; 142: 1054–1056
  • Melchert M, List A. The thalidomide saga. Int J Biochem. Cell Biol 2007; 39: 1489–1499
  • Morgan GJ, Krishnan B, Jenner M, Davies FE. Advances in oral therapy for multiple myeloma. Lancet Oncol 2006; 7: 316–325
  • Zervas K, Mihou D, Katodritou E, Pouli A, Mitsouli Ch, Anagnostopoulcs A, Delibasi S, Kyrtsonis M, Anagnostopoulos N, Terpos E, et al. VAD-doxil vs. VAD-doxil plus thalidomide as initial treatment for multiple myeloma: Results of a multicenter randomized trial of the Greek myeloma study group. Ann Oncol 2007; 18: 1369–1375
  • Sridhar SS, Seymour L, Shepherd FA. Inhibitors of epidermal-growth-factor receptors: A review of clinical research with a focus on non-small-cell lung cancer. Lancet Oncol 2003; 4: 397–406
  • Pore N, Jiang Z, Gupta A, Cerniglia G, Kao GD, Maity A. EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms. Cancer Res 2006; 66: 3197–3204
  • Nahta R, Esteva FJ. Trastuzumab: Triumphs and tribulations. Oncogene 2007; 26: 3637–3643
  • Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17: 2639–2648
  • Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002; 20: 719–726
  • Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783–792
  • Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353: 1673–1684
  • Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353: 1659–1672
  • Baselga J, Perez EA, Pienkowski T, Bell R. Adjuvant trastuzumab: A milestone in the treatment of HER-2-positive early breast cancer. Oncologist 2006; 11 Suppl. 1: 4–12
  • Pritchard Kl, Shepherd LE, O'Malley FP, Andrulis IL, Tu D, Bramwell VH, Levine MN. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 2006; 354(20)2103–2111
  • Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, et al. Two-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: A randomised controlled trial. Lancet 2007; 369: 29–36
  • Engel RH, Kaklamani VG. HER2-positive breast cancer: Current and future treatment strategies. Drugs 2007; 67: 1329–1341
  • Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006; 355: 2733–2743
  • Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belanj CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with nonsmall cell lung cancer: A randomized trial. JAMA 2003; 290: 2149–2158
  • Giaccone G. The role of gefitinib in lung cancer treatment. Clin Cancer Res 2004; 10: 4233s–4237s
  • Bell DW, Lynch TJ, Haserlat SM, Harris PL, Okimoto RA, Brannigan BW, Sgroi DC, Muir B, Riemenschneider MJ, Lacona RB, et al. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: Molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol 2005; 23: 8081–8092
  • Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123–132
  • Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007; 7: 169–181
  • Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, Milanowski J, Karnicka-Mlodkowski H, Pesek M, Serwatowski P, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: The Tarceva Lung Cancer Investigation Trial. J Clin Oncol 2007; 25: 1545–1552
  • Karamouzis MV, Grandis JR, Argiris A. Therapies directed against epidermal growth factor receptor in aerodigestive carcinomas. JAMA 2007; 298: 70–82
  • Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351: 337–345
  • Saltz LB, Meropol NJ, Loehrer PJ, Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004; 22: 1201–1208
  • Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P, Mirtsching B, Cohn AL, Pippas AW, Azarnia N, et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 2006; 24: 4914–4921
  • Chung KY, Shia J, Kemeny NE, Shah M, Schwartz GK, Tse A, Hamilton A, Pan D, Schrag D, Schwartz L, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 2005; 23: 1803–1810
  • Khambata-Ford S, Garrett CR, Meropol NJ, Basik M, Harbison CT, Wu S, Wong TW, Huang X, Takimoto CH, Godwin AK, et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 2007; 25: 3230–3237
  • Galizia G, Lieto E, De Vita F. Orditura M, Castellano P, Troiani T, Imperatore V, Ciardiello F. Cetuximab, a chimeric human mouse antiepidermal growth factor receptor monoclonal antibody, in the treatment of human colorectal cancer. Oncogene 2007; 26: 3654–3660
  • Hildebrandt B, le Coutre P, Nicolaou A, Koble K, Riess H, Dorken B. Cetuximab: Appraisal of a novel drug against colorectal cancer. Recent Results Cancer Res 2007; 176: 135–143
  • Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007; 25: 1658–1664
  • Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF Côte JF, Tomasic G, Penna C, Ducreux M, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006; 66: 3992–3995
  • Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, Siena S, Bardelli A. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 2007; 67: 2643–2648
  • Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, Bastit L, Killian A, Sesboüé R, Tuech JJ, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer 2007; 96: 1166–1169
  • Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25: 1960–1966
  • Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: Role of the HIF system. Nat Med 2003; 9: 677–684
  • Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med 2005; 353(23)2477–2490
  • Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol 2005; 23: 1028–1043
  • Brugarolas J. Renal-cell carcinoma–molecular pathways and therapies. N Engl J Med 2007; 356: 185–187
  • Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an antivascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349: 427–434
  • Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding G, et al. Sunitinib in patients with metastatic renal cell carcinoma. 2. Jama 2006; 295: 2516–2524
  • Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, et al. Sunitinib vs. interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: 115–124
  • Hainsworth JD, Sosman JA, Spigel DR, Edwards DL, Baughman C, Greco A. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 2005; 23: 7889–7896
  • Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, Gore M, Desai AA, Patnaik A, Xiong HQ, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006; 24: 2505–2512
  • Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: 125–134
  • Raffetto JD, Khalil RA. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol 2007; 7, Online Jul
  • Gasparini G, Longo R, Toi M, Ferrara N. Angiogenic inhibitors: A new therapeutic strategy in oncology. Nat Clin Pract Oncol 2005; 2: 562–577
  • Hidalgo M, Eckhardt SG. Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 2001; 93: 178–193
  • Thorpe PE. Vascular targeting agents as cancer therapeutics. Clin. Cancer Res 2004; 10: 415–427
  • Siemann DW, Chaplin DJ, Horsman MR. Vascular-targeting therapies for treatment of malignant disease. Cancer 2004; 100: 2491–2499
  • Patterson DM, Rustin GJ. Vascular damaging agents. Clin Oncol (R Coll Radiol) 2007; 19: 443–456
  • Denekamp J, Hill SA, Hobson B. Vascular occlusion and tumour cell death. Eur J Cancer Clin Oncol 1983; 19: 271–275
  • Denekamp J. Vascular endothelium as the vulnerable element in tumours. Acta Radiol Oncol 1984; 23: 217–225
  • Hill SA, Lonergan SJ, Denekamp J, Chaplin DJ. Vinca alkaloids: Anti-vascular effects in a murine tumour. Eur J Cancer 1993; 29A(9)1320–1324
  • Eikesdal HP, Bjerkvig R, Dahl O. Vinblastine and hyperthermia target the neovasculature in BT(4)AN rat gliomas: Therapeutic implications of the vascular phenotype. Int J Radiat Oncol Biol Phys 2001; 51: 535–44
  • Eikesdal HP, Bjerkvig R, Mella O, Dahl O. Combretastatin A-4 and hyperthermia: A potent combination for the treatment of solid tumors. Radiother Oncol 2001; 60: 147–154
  • Vincent L, Kermani P, Young LM, Cheng J, Zhang F, Shido K, Lam G, Bompais-Vincent H, Zhu Z, Hicklin DJ, et al. Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling. J Clin Invest 2005; 115: 2992–3006
  • Salmon BA, Siemann DW. Characterizing the tumor response to treatment with combretastatin A4 phosphate. Int J Radiat Oncol Biol Phys 2007; 68: 211–217
  • Griffin RJ, Monzen H, Williams BW, Park H, Lee SH, Song CW. Arsenic trioxide induces selective tumour vascular damage via oxidative stress and increases thermosensitivity of tumours. Int J Hyperthermia 2003; 19: 575–589
  • Murata R, Horsman MR. Tumour-specific enhancement of thermoradiotherapy at mild temperatures by the vascular targeting agent 5,6-dimethylxanthenone-4-acetic acid. Int J Hyperthermia 2004; 20: 393–404
  • ten Hagen TL, Eggermont AM. Changing the pathophysiology of solid tumours: The potential of TNF and other vasoactive agents. Int J Hyperthermia 2006; 22: 241–246
  • Horsman MR. Tissue physiology and the response to heat. Int J Hyperthermia 2006; 22: 197–203
  • Brunstein F, Rens J, van Tiel ST, Eggermont AM, ten Hagen TL. Histamine, a vasoactive agent with vascular disrupting potential, improves tumour response by enhancing local drug delivery. Br J Cancer 2006; 95: 1663–1669
  • Thorpe PE, Chaplin DJ, Blakey DC. The first international conference on vascular targeting: Meeting overview. Cancer Res 2003; 63: 1144–1147
  • Albertsson P, Lennernas B, Norrby K. On metronomic chemotherapy: Modulation of angiogenesis mediated by VEGE-A. Acta Oncol 2006; 45: 144–155
  • Bocci G, Tuccori M, Emmenegger U, Liguori V, Falcone A, Kerbel RS, Del Tacca M. Cyclophosphamide-methotrexate 'metronomic' chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann Oncol 2005; 16: 1243–1252
  • Damber JE, Vallbo C, Albertsson P, Lennernas B, Norrby K. The anti-tumour effect of low-dose continuous chemotherapy may partly be mediated by thrombospondin. Cancer Chemother Pharmacol 2006; 58: 354–360
  • Gasparini G. Metronomic scheduling: The future of chemotherapy?. Lancet Oncol 2001; 2: 733–740
  • Kerbel RS. Antiangiogenic therapy: A universal chemosensitization strategy for cancer?. Science 2006; 312: 1171–1175
  • Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O'Reilly MS, Folkman J. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000; 60: 1878–886
  • Broxterman HJ, Lankelma J, Hoekman K. Resistance to cytotoxic and anti-angiogenic anticancer agents: Similarities and differences. Drug Resist Updat 2003; 6: 111–127
  • Kamat AA, Kim TJ, Landen CN, Jr, Lu C, Han LY, Lin YG, Merritt WM, Thaker PH, Gershenson DM, Bischoff F, et al. Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer. Cancer Res 2007; 67: 281–288
  • Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS. Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem–like cell fraction in glioma xenograft tumors. Cancer Res 2007; 67: 3560–3564
  • Bertolini F, Paul S, Mancuso P, Monestiroli S, Gobbi A, Shaked Y, Kerbel RS. Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res 2003; 63: 4342–4346
  • Bertolini F, Shaked Y, Mancuso P, Kerbel RS. The multifaceted circulating endothelial cell in cancer: Towards marker and target identification. Nat Rev Cancer 2006; 6: 835
  • Rafii S, Lyden D, Benezra R, Hattori K, Heissig B. Vascular and haematopoietic stem cells: Novel targets for anti-angiogenesis therapy?. Nat Rev Cancer 2002; 2: 826–835
  • Jubb AM, Oates AJ, Holden S, Koeppen H. Predicting benefit from anti-angiogenic agents in malignancy. Nat Rev Cancer 2006; 6: 626–635
  • Dewhirst MW, Vujaskovic Z, Jones E, Thrall D. Re-setting the biologic rationale for thermal therapy. Int J Hyperthermia 2005; 21: 779–790
  • Kampinga HH. Cell biological effects of hyperthermia alone or combined with radiation or drugs: A short introduction to newcomers in the field. Int J Hyperthermia 2006; 22: 191–196
  • Wust P, Hildebrandt B, Sreenivasa G, Rau B, Gellermann J, Riess H, Felix R, Schlag PM. Hyperthermia in combined treatment of cancer. Lancet Oncol 2002; 3: 487–497
  • Dahl O, Overgaard J. Hyperthermia. Oxford Textbook of oncology. 2, RL Souhami , IF Tannock, P Hohenberger, J-C Horiot . Oxford University Press, Oxford 2002; 1: 511–525
  • Jackson IL, Batinic-Haberle I, Sonveaux P, Dewhirst MW, Vujaskovic Z. ROS production and angiogenic regulation by macrophages in response to heat therapy. Int J Hyperthermia 2006; 22: 263–273
  • Lyng H, Monge OR, Bohler PJ, Rofstad EK. Relationships between thermal dose and heat-induced tissue and vascular damage after thermoradiotherapy of locally advanced breast carcinoma. Int J Hyperthermia 1991; 7: 403–415
  • Rofstad EK, Brustad T. Response of human malignant melanoma xenografts to hyperthermia: Effect of vascular occlusion. Int J Radiat Oncol Biol Phys 1981; 7: 1685–1687
  • Thrall DE, Larue SM, Pruitt AF, Case B, Dewhirst MW. Changes in tumour oxygenation during fractionated hyperthermia and radiation therapy in spontaneous canine sarcomas. Int J Hyperthermia 2006; 22: 365–373
  • Song CW, Park HJ, Lee CK, Griffin R. Implications of increased tumor blood flow and oxygenation caused by mild temperature hyperthermia in tumor treatment. Int J Hyperthermia 2005; 21: 761–767
  • Fajardo LF, Prionas SD. Endothelial cells and hyperthermia. Int J Hyperthermia 1994; 10: 347–353
  • Fajardo LF, Prionas SD, Kowalski J, Kwan HH. Hyperthermia inhibits angiogenesis. Radiat Res 1988; 114: 297–306
  • Eikesdal HP, Bjorkhaug ST, Dahl O. Hyperthermia exhibits anti-vascular activity in the s.c. BT4An rat glioma: Lack of interaction with the angiogenesis inhibitor batimastat. Int J Hyperthermia 2002; 18: 141
  • Kanamori S, Nishimura Y, Okuno Y, Horii N, Saga T, Hiraoka M. Induction of vascular endothelial growth factor (VEGF) by hyperthermia and/or an angiogenesis inhibitor. Int J Hyperthermia 1999; 15: 267–278
  • Sawaji Y, Sato T, Takeuchi A, Hirata M, Ito A. Anti-angiogenic action of hyperthermia by suppressing gene expression and production of tumour-derived vascular endothelial growth factor in vivo and in vitro. Br J Cancer 2002; 86: 1597
  • Srinivasan JM, Fajardo LF, Hahn GM. Mechanism of antitumor activity of tumor necrosis factor alpha with hyperthermia in a tumor necrosis factor alpha-resistant tumor. J Natl Cancer Inst 1990; 82: 1904–1910
  • Valdagni R, Amichetti M. Report of long-term follow-up in a randomized trial comparing radiation therapy and radiation therapy plus hyperthermia to metastatic lymph nodes in stage IV head and neck patients. Int J Radiat Oncol Biol Phys 1994; 28: 163–169
  • Overgaard J, Gonzalez Gonzalez D, Hulshof MC, Arcangeli G, Dahl O, Mella O, Bentzen SM. Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European Society for Hyperthermic Oncology. Lancet 1995; 345: 540–543
  • Overgaard J, Gonzalez Gonzalez D, Hulshof MC, Arcangeli G, Dahl O, Mella O, Bentzen SM. Hyperthermia as an adjuvant to radiation therapy of recurrent or metastatic malignant melanoma. A multicentre randomized trial by the European Society for Hyperthermic Oncology. Int J Hyperthermia 1996; 12: 3–20
  • Hand JW, Machin D, Vernon CC, Whaley JB. Analysis of thermal parameters obtained during phase III trials of hyperthermia as an adjunct to radiotherapy in the treatment of breast carcinoma. Int J Hyperthermia 1997; 13: 343–364
  • Vernon CC, Hand JW, Field SB, Machin D, Whaley JB, van der Zee J, van Putten WL, van Rhoon GC, van Dijk JD, Gonzalez Gonzalez D, et al. Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: Results from five randomized controlled trials. International Collaborative Hyperthermia Group. Int J Radiat Oncol Biol Phys 1996; 35: 731–744
  • Prosnitz LR, Maguire P, Anderson JM, Scully SP, Harrelson JM, Jones EL, Dewhirst M, Samulski TV, Powers BE, Rosner GL, et al. The treatment of high-grade soft tissue sarcomas with preoperative thermoradiotherapy. Int J Radiat Oncol Biol Phys 1999; 45: 941–949
  • Maguire PD, Samulski TV, Prosnitz LR, Jones EL, Rosner GL, Powers B, Layfield LW, Brizel DM, Scully SP, Harrelson JM, et al. A phase II trial testing the thermal dose parameter CEM43 degrees T90 as a predictor of response in soft tissue sarcomas treated with pre-operative thermoradiotherapy. Int J Hyperthermia 2001; 17: 283–290
  • Issels RD. High-risk soft tissue sarcoma: Clinical trial and hyperthermia combined chemotherapy. Int J Hyperthermia 2006; 22: 235–239
  • Sneed PK, Stauffer PR, McDermott MW, Diederich CJ, Lamborn KR, Prados MD, Chang S, Weaver KA, Spry L, Malec MK, et al. Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost +/− hyperthermia for glioblastoma multiforme. Int J Radiat Oncol Biol Phys 1998; 40: 287–295
  • van der Zee J, Gonzalez Gonzalez D, van Rhoon GC, van Dijk JD, van Putten WL, Hart AA. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: A prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group. Lancet 2000; 355: 1119–1125
  • van der Zee J, van Rhoon GC. Cervical cancer: Radiotherapy and hyperthermia. Int J Hyperthermia 2006; 22: 229–234
  • Harima Y, Nagata K, Harima K, Ostapenko VV, Tanaka Y, Sawada S. A randomized clinical trial of radiation therapy vs. thermoradiotherapy in stage IIIB cervical carcinoma. Int J Hyperthermia 2001; 17: 97–105
  • Westermann AM, Jones EL, Schem BC, van der Steen-Banasik EM, Koper P, Mella O, Uitterhoeve AL, de Wit R, van der Velden J, Burger C, et al. First results of triple-modality treatment combining radiotherapy, chemotherapy, and hyperthermia for the treatment of patients with stage IIB, III, and IVA cervical carcinoma. Cancer 2005; 104: 763–770
  • Colombo R, Da Pozzo LF, Salonia A, Rigatti P, Leib Z, Baniel J, Caldarera E, Pavone-Macaluso M. Multicentric study comparing intravesical chemotherapy alone and with local microwave hyperthermia for prophylaxis of recurrence of superficial transitional cell carcinoma. J Clin Oncol 2003; 21: 4270–4276
  • Issels RD, Lindner LH, Wust P, Hohenberger P, Jauch K, Daugaard S, Mannsmann U, Hiddemann W, Blay J, Verweij J. Regional hyperthermia (RHT) improves response and survival when combined with systemic chemotherapy in the management of locally advanced, high grade soft tissue sarcomas (STS) of the extremities, the body wall and the abdomen: A phase III randomised pros. J Clin Oncol 2007; 10009: 18s
  • Alvarez Secord A, Jones EL, Hahn CA, Petros WP, Yu D, Havrilesky LJ, Soper JT, Berchuck A, Spasojevic I, Clarke-Pearson DL, et al. Phase I/II trial of intravenous Doxil and whole abdomen hyperthermia in patients with refractory ovarian cancer. Int J Hyperthermia 2005; 21: 333–347
  • Johannsen M, Gnevckow U, Taymoorian K, Thiesen B, Waldöfner N, Scholz R, Jung K, Jordan A, Wust P, Loening SA. Morbidity and quality of life during thermotherapy using magnetic nanoparticles in locally recurrent prostate cancer: Results of a prospective phase I trial. Int J Hyperthermia 2007; 23: 315–323
  • Liu P, Zhang A, Xu Y, Xu LX. Study of non-uniform nanoparticle liposome extravasation in tumour. Int J Hyperthermia 2005; 21: 259–270
  • Ponce AM, Viglianti BL, Yu D, Yarmolenko PS, Michelich CR, Woo J, Bally MB, Dewhirst MW. Magnetic resonance imaging of temperaturesensitive liposome release: Drug dose painting and antitumor effects. J Natl Cancer Inst 2007; 99: 53–63
  • Ponce AM, Vujaskovic Z, Yuan F, Needham D, Dewhirst MW. Hyperthermia mediated liposomal drug delivery. Int J Hyperthermia 2006; 22: 205–213
  • Wust P, Gneveckow U, Johannsen M, Böhmer D, Henkel T, Kohmann F, Sehouli J, Felix R, Ricke J, Jordan A. Magnetic nanoparticles for interstitial thermotherapy–feasibility, tolerance and achieved temperatures. Int J Hyperthermia 2006; 22: 673–685
  • Siddiqui F, Ehrhart EJ, Charles B, Chubb L, Li CY, Zhang X, Lame SM, Avery PR, Dewhirst MW, Ullrich RL. Anti-angiogenic effects of interleukin-12 delivered by a novel hyperthermia induced gene construct. Int J Hyperthermia 2006; 22: 587–606
  • Siddiqui F, Li CY, Zhang X, Larue SM, Dewhirst MW, Ullrich RL, Avery PR. Characterization of a recombinant adenovirus vector encoding heat-inducible feline interleukin-12 for use in hyperthermia-induced genetherapy. Int J Hyperthermia 2006; 22: 117–134
  • Zhang S, Xu G, Liu C, Xiao S, Sun Y, Su X, Cai Y, Li D, Xu B. Clinical study of recombinant adenovirus-p53 (Adp53) combined with hyperthermia in advanced cancer (a report of 15 cases). Int J Hyperthermia 2005; 21: 631–636
  • Li GC, He F, Ling CC. Hyperthermia and gene therapy: Potential use of microPET imaging. Int J Hyperthermia 2006; 22: 215–221
  • Branford S, Hughes T, Milner A, Koelmeyer R, Schwarer A, Arthur C, Filshie R, Moreton S, Lynch K, Taylor K. Efficacy and safety of imatinib in patients with chronic myeloid leukemia and complete or near-complete cytogenetic response to interferon-alpha. Cancer 2007; 110: 801–808
  • Epstein SE, Kornowski R, Fuchs S, Dvorak HF. Angiogenesis therapy: Amidst the hype, the neglected potential for serious side effects. Circulation 2001; 104: 115–119
  • Van Glabbeke M, Verweij J, Casali PG, Simes J, Le Cesne A, Reichardt P, Issels R, Judson IR, van Oosterom AT, Blay JY. Predicting toxicities for patients with advanced gastrointestinal stromal tumours treated with imatinib: A study of the European Organisation for Research and Treatment of Cancer, the Italian Sarcoma Group, and the Australasian Gastro-Intestinal Trials Group (EORTC-ISG-AGITG). Eur J Cancer 2006; 42: 2277–2285
  • Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 2007; 7: 475–485
  • Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 2006; 6: 803–812
  • Chien KR. Herceptin and the heart - a molecular modifier of cardiac failure. N Engl J Med 2006; 354: 789–790
  • Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 2007; 7: 332–344
  • Suter TM, Procter M, van Veldhuisen DJ, Muscholl M, Bergh J, Carlomagno C, Perren T, Passalacqua R, Bighin C, Klijn JG, et al. Trastuzumab-Associated Cardiac Adverse Effects in the Herceptin Adjuvant Trial. J Clin Oncol 2007; 25: 3859–3865
  • Scappaticci FA, Fehrenbacher L, Cartwright T, Hainsworth JD, Heim W, Berlin J, Kabbinavar F, Novotny W, Sarkar S, Hurwitz H. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 2005; 91: 173–180
  • Scappaticci FA, Skillings JR, Holden SN, Gerber HP, Miller K, Kabbinavar F, Bergsland E, Ngai J, Holmgren E, Wang J, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 2007; 99: 1232–1239
  • van Heeckeren WJ, Ortiz J, Cooney MM, Remick SC. Hypertension, proteinuria, and antagonism of vascular endothelial growth factor signaling: Clinical toxicity, therapeutic target, or novel biomarker?. J Clin Oncol 2007; 25: 2993–2995
  • Schulze T, Wust P, Gellermann J, Hildebrandt B, Riess H, Felix R, Rau B. Influence of neoadjuvant radiochemotherapy combined with hyperthermia on the quality of life in rectum cancer patients. Int J Hyperthermia 2006; 22: 301–318
  • Haveman J, Van Der Zee J, Wondergem J, Hoogeveen JF, Hulshof MC. Effects of hyperthermia on the peripheral nervous system: A review. Int J Hyperthermia 2004; 20: 371–391
  • Wiggenraad R, Koning C, Westermann C, Jansen C, van der Zee J. Two cases of fatal necrosis of the lesser pelvis in patients treated with combined radiotherapy and hyperthermia for cervical carcinoma. Int J Hyperthermia 2005; 21: 185–192
  • Balzer S, Schneider DT, Bernbeck MB, Jager M, Mils O, Schaper J, Willers R, Krauspe R, Gobel U, Wessalowski R. Avascular osteonecrosis after hyperthermia in children and adolescents with pelvic malignancies: A retrospective analysis of potential risk factors. Int J Hyperthermia 2006; 22: 451–461
  • Gellermann J, Hildebrandt B, Issels R, Ganter H, Wlodarczyk W, Budach V, Felix R, Tunn PU, Reichardt P, Wust P. Noninvasive magnetic resonance thermography of soft tissue sarcomas during regional hyperthermia: Correlation with response and direct thermometry. Cancer 2006; 107: 1373–1382
  • Gellermann J, Wlodarczyk W, Feussner A, Fahling H, Nadobny J, Hildebrandt B, Felix R, Wust P. Methods and potentials of magnetic resonance imaging for monitoring radiofrequency hyperthermia in a hybrid system. Int J Hyperthermia 2005; 21: 497–513
  • Hornsleth SN, Frydendal L, Mella O, Dahl O, Raskmark P. Quality assurance for radiofrequency regional hyperthermia. Int J Hyperthermia 1997; 13: 169–185
  • van Haaren PM, Kok HP, Zum Vorde Sive Vording PJ, van Dijk JD, Hulshof MC, Fockens P, van Lanschot JJ, Crezee J. Reliability of temperature and SAR measurements at oesophageal tumour locations. Int J Hyperthermia 2006; 22: 545–561
  • van Rhoon GC, Wust P. Introduction: Non-invasive thermometry for thermotherapy. Int J Hyperthermia 2005; 21: 489–495
  • Horsman MR, Overgaard J. Hyperthermia: A potent enhancer of radiotherapy. Clin Oncol (R Coll Radiol) 2007; 19: 418–426
  • Norum J, Olsen JA, Wist EA, Lonning PE. Trastuzumab in adjuvant breast cancer therapy. A model based cost-effectiveness analysis. Acta Oncol 2007; 46: 153–164
  • Starling N, Tilden D, White J, Cunningham D. Cost-effectiveness analysis of cetuximab/irinotecan vs. active/best supportive care for the treatment of metastatic colorectal cancer patients who have failed previous chemotherapy treatment. Br J Cancer 2007; 96: 206–212

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