Journal of the Chinese Medical Association
Volume 73, Issue 6 , Pages 281-288, June 2010

Advances in Combination of Antiangiogenic Agents Targeting VEGF-binding and Conventional Chemotherapy and Radiation for Cancer Treatment

  • Li-Song Teng

      Affiliations

    • Department of Surgical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang
    • Corresponding Author InformationCorrespondence to: Dr Li-Song Teng, Department of Surgical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, 79, Qingchun Road, Hangzhou, Zhejiang 310003, China
  • ,
  • Ke-Tao Jin

      Affiliations

    • Department of Surgical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang
    • Department of Surgery, Zhuji Hospital, Zhuji
  • ,
  • Kui-Feng He

      Affiliations

    • Department of Surgical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang
  • ,
  • Hao-Hao Wang

      Affiliations

    • Department of Surgical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang
  • ,
  • Jiang Cao

      Affiliations

    • Sir Run Run Shaw Institute of Clinical Medicine, Zhejiang University: Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang
  • ,
  • De-Cao Yu

      Affiliations

    • Chengdu Kanghong Biotechnology Co. Inc., Chengdu, Sichuan, China

Received 30 November 2009; accepted 14 April 2010.

Article Outline

Despite great efforts and resources being devoted to treatment, the incidence and mortality of numerous cancers have not decreased in recent decades. This is a result of the resistance of cancer cells to chemotherapeutic agents and radio-therapy. The development of antiangiogenic agents that target vascular endothelial growth factor (VEGF) provides a new option for treatment of cancer. Major advances have been achieved with cancer therapy based on antiangiogenic VEGF-targeted agents in the past few years, and some of the recently approved therapies are now being used in daily clinical practice. A further challenge is finding a more efficacious combination of antiangiogenic VEGF-targeted therapies and conventional radio- and chemotherapies. This review outlines the current preclinical and clinical cancer treatments using optimized combinations of antiangiogenic VEGF-targeted agents and conventional radiochemotherapy and highlights that better scheduling for the combination of radiochemotherapy and antiangiogenic VEGF-targeted agents should be developed to achieve better treatment outcomes.

Key Words:  antiangiogenic agents , bevacizumab , VEGF-targeted agents , VEGF-Trap

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References 

  1. Shibuya M . Structure and function of VEGF/VEGF-receptor system involved in angiogenesis . Cell Struct Funct . 2001;26:25–35
  2. Rafii S , Lyden D , Benezra R , Hattori K , Heissig B . Vascular and haematopoietic stem cells: Novel targets for anti-angiogenesis therapy? . Nature Rev Cancer . 2002;2:826–835
  3. Folkman J . Fundamental concepts of the angiogenic process . Curr Mol Med . 2003;3:643–651
  4. Hicklin DJ , Ellis LM . Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis . J Clin Oncol . 2005;23:1011–1027
  5. Ferrara N , Gerber HP , LeCouter J . The biology of VEGF and its receptors . Nat Med . 2003;9:669–676
  6. Senger DR , Galli SJ , Dvorak AM , Perruzzi CA , Harvey VS , Dvorak HF . Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid . Science . 1983;219:983–985
  7. Giaccone G . The potential of antiangiogenic therapy in non-small cell lung cancer . Clin Cancer Res . 2007;13:1961–1970
  8. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, et al  AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients . Cancer Cell . 2007;11:83–95
  9. Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, et al  Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer . Nat Med . 2004;10:145–147
  10. Ferrara N . VEGF as a therapeutic target in cancer . Oncology . 2005;69(Suppl):11–16
  11. Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, et al  VEGF-Trap: a VEGF blocker with potent antitumor effects . Proc Natl Acad Sci USA . 2002;99:11393–11398
  12. Gerber HP , Ferrara N . Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cyto-toxic therapy in preclinical studies . Cancer Res . 2005;65:671–680
  13. Wang Y , Fei D , Vanderlaan M , Song A . Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro . Angiogenesis . 2004;7:335–345
  14. Presta LG, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L, et al  Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders . Cancer Res . 1997;57:4593–4599
  15. Rowe DH, Huang J, Kayton ML, Thompson R, Troxel A, O'Toole KM, et al  Anti-VEGF antibody suppresses primary tumor growth and metastasis in an experimental model of Wilms' tumor . J Pediatr Surg . 2000;35:30–32
  16. Wulff C , Wilson H , Wiegand SJ , Rudge JS , Fraser HM . Prevention of thecal angiogenesis, antral follicular growth, and ovulation in the primate by treatment with vascular endothelial growth factor Trap R1R2 . Endocrinology . 2002;143:2797–2807
  17. Fukasawa M , Korc M . Vascular endothelial growth factor-trap suppresses tumorigenicity of multiple pancreatic cancer cell lines . Clin Cancer Res . 2004;10:3327–3332
  18. Huang J, Frischer JS, Serur A, Kadenhe A, Yokoi A, McCrudden KW, et al  Regression of established tumors and metastases by potent vascular endothelial growth factor blockade . Proc Natl Acad Sci USA . 2003;100:7785–7790
  19. Zhang M , Zhang J , Yan M , Li H , Yang C , Yu D . Recombinant anti-vascular endothelial growth factor fusion protein efficiently suppresses choroidal neovascularization in monkeys . Mol Vis . 2008;14:37–49
  20. Zhang M, Yu D, Yang C, Xia Q, Li W, Liu B, et al. The pharmacology study of a new recombinant human VEGF receptor-fc fusion protein on experimental choroidal neovascularization . Pharm Res . 2009;26:204–210
  21. Mancuso MR, Davis R, Norberg SM, O'Brien S, Sennino B, Nakahara T, et al  Rapid vascular regrowth in tumors after reversal of VEGF inhibition . J Clin Invest . 2006;116:2610–2621
  22. Aita M, Fasola G, Defferrari C, Brianti A, Bello MG, Follador A, et al  Targeting the VEGF pathway: antiangio-genic strategies in the treatment of non-small cell lung cancer . Crit Rev Oncol Hematol . 2008;68:183–196
  23. Jain RK , Duda DG , Clark JW , Loeffler JS . Lessons from phase III clinical trials on anti-VEGF therapy for cancer . Nat Clin Pract Oncol . 2006;3:24–40
  24. Kerbel RS . Antiangiogenic therapy: a universal chemosensitization strategy for cancer? . Science . 2006;312:1171–1175
  25. Gorski DH, Beckett MA, Jaskowiak NT, Calvin DP, Mauceri HJ, Salloum RM, et al  Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation . Cancer Res . 1999;59:3374–3378
  26. Gupta VK, Jaskowiak NT, Beckett MA, Mauceri HJ, Grunstein J, Johnson RS, et al  Vascular endothelial growth factor enhances endothelial cell survival and tumor radioresistance . Cancer J . 2002;8:47–54
  27. Lee CG, Heijn M, di Tomaso E, Griffon-Etienne G, Ancukiewicz M, Koike C, et al  Anti-vascular endothelial growth factor treatment augments tumor radiation response under nor-moxic or hypoxic conditions . Cancer Res . 2000;60:5565–5570
  28. Dings RP, Loren M, Heun H, McNiel E, Griffioen AW, Mayo KH, et al. Scheduling of radiation with angiogenesis inhibitors anginex and Avastin improves therapeutic outcome via vessel normalization . Clin Cancer Res . 2007;13:3395–3402
  29. Lai A, Filka E, McGibbon B, Nghiemphu PL, Graham C, Yong WH, et al  Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability . Int J Radiat Oncol Biol Phys . 2008;71:1372–1380
  30. Czito BG, Bendell JC, Willett CG, Morse MA, Blobe GC, Tyler DS, et al  Bevacizumab, oxaliplatin, and capecitabine with radiation therapy in rectal cancer: phase I trial results . Int J Radiat Oncol Biol Phys . 2007;68:472–478
  31. Ou G, Itasaka S, Zeng L, Shibuya K, Yi J, Harada H, et al. Usefulness of HIF-1 imaging for determining optimal timing of combining bevacizumab and radiotherapy . Int J Radiat Oncol Biol Phys . 2009;75:463–467
  32. Wachsberger PR, Burd R, Cardi C, Thakur M, Daskalakis C, Holash J, et al  VEGF trap in combination with radiotherapy improves tumor control in U87 glioblas-toma . Int J Radiat Oncol Biol Phys . 2007;67:1526–1537
  33. Borgström P , Gold DP , Hillan KJ , Ferrara N . Importance of VEGF for breast cancer angiogenesis in vivo: implications from intravital microscopy of combination treatments with an anti-VEGF neutralizing monoclonal antibody and doxorubicin . Anticancer Res . 1999;19:4203–4214
  34. Soffer SZ, Moore JT, Kim E, Huang J, Yokoi A, Manley C, et al  Combination antiangiogenic therapy: increased efficacy in a murine model of Wilms tumor . J Pediatr Surg . 2001;36:1177–1181
  35. Fox WD, Higgins B, Maiese KM, Drobnjak M, Cordon-Cardo C, Scher HI, et al. Antibody to vascular endothelial growth factor slows growth of an androgen-independent xenograft model of prostate cancer . Clin Cancer Res . 2002;8:3226–3231
  36. Hu L , Hofmann J , Zaloudek C , Ferrara N , Hamilton T , Jaffe RB . Vascular endothelial growth factor immunoneutralization plus Paclitaxel markedly reduces tumor burden and ascites in athymic mouse model of ovarian cancer . Am J Pathol . 2002;161:1917–1924
  37. Wildiers H, Guetens G, De Boeck G, Verbeken E, Landuyt B, Landuyt W, et al  Effect of antivascular endothe-lial growth factor treatment on the intratumoral uptake of CPT-11 . Br J Cancer . 2003;88:1979–1986
  38. Wild R , Dings RP , Subramanian I , Ramakrishnan S . Carboplatin selectively induces the VEGF stress response in endothelial cells: potentiation of antitumor activity by combination treatment with antibody to VEGF . Int J Cancer . 2004;110:343–351
  39. Dickson PV, Hamner JB, Sims TL, Fraga CH, Ng CY, Rajasekeran S, et al  Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xeno-grafts results in improved delivery and efficacy of systemically administered chemotherapy . Clin Cancer Res . 2007;13:3942–3950
  40. Burstein HJ , Demetri GD , Mueller E , Sarraf P , Spiegelman BM , Winer EP . Use of the peroxisome proliferator-activated receptor (PPAR) gamma ligand troglitazone as treatment for refractory breast cancer: a phase II study . Breast Cancer Res Treat . 2003;79:391–397
  41. Ramaswamy B, Elias AD, Kelbick NT, Dodley A, Morrow M, Hauger M, et al  Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients . Clin Cancer Res . 2006;12:3124–3129
  42. Chan D, Allen H, Hu E, Reese D, Patel G, Gottlieb C, et al  Phase II study of docetaxel (D) plus bevacizumab (B) in Her/2 negative metastatic breast carcinoma (MBC) . J Clin Oncol . 2006;24:605s; (abstract 13047). 2006 ASCO Annual Meeting Proceedings Part I.
  43. Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, et al  Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer . J Clin Oncol . 2005;23:792–799
  44. Miller KD, Wang M, Gralow J, Dickler M, Cobleigh MA, Perez EA, et al  A randomized phase III trial of pacli-taxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100) . Breast Cancer Res . 2005;94(Suppl):S6; (abstract 3).
  45. Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, et al  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
  46. Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, et al  Addition of bevacizumab to bolus flu-orouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial . J Clin Oncol . 2005;23:3697–3705
  47. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al  Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer . N Engl J Med . 2006;355:2542–2550
  48. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, et al  Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer . J Clin Oncol . 2004;22:2184–2191
  49. Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M, et al  Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer . J Clin Oncol . 2005;23:8033–8040
  50. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer . N Engl J Med . 2004;350:2335–2342
  51. Cassidy J , Clarke S , Rubio E Diaz . First efficacy and safety results from XELOX-1/NO16966, a randomised 2 × 2 factorial phase III trial of XELOX vs FOLFOX4 plus bevacizumab or placebo in first-line metastatic colorectal cancer (MCRC) . Ann Oncol . 2006;17(Suppl):LBA3; [Abstract]
  52. Saltz LB, Clarke S, Diaz-Rubio W, Scheithauer A, Figer A, Wong R, et al  Bevacizumab in combination with XELOX or FOLFOX4: efficacy results from XELOX-1/NO16966, a randomized phase III trial in the first-line treatment of metastatic colorectal cancer (MCRC) . Gastrointestinal Cancers Symposium . 2007; abstract 238.
  53. Hochster HS , Hart LL , Ramanathan RK , Hainsworth JD , Hedrick EE , Childs BH . Safety and efficacy of oxaliplatin/flu-oropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC): final analysis of the TREE-Study . Proc Am Soc Clin Oncol . 2006; abstract 3510.
  54. Hu L , Hofmann J , Holash J , Yancopoulos GD , Sood AK , Jaffe RB . Vascular endothelial growth factor trap combined with paclitaxel strikingly inhibits tumor and ascites, prolonging survival in a human ovarian cancer model . Clin Cancer Res . 2005;11:6966–6971
  55. Haroon ZA , Amin K , Saito W , Wilson W , Greenberg CS , Dewhirst MW . SU5416 delays wound healing through inhibition of TGF-beta 1 activation . Cancer Biol Ther . 2002;1:121–126
  56. Saltz LB, Douillard JY, Pirotta N, Alakl M, Gruia G, Awad L, et al  Irinotecan plus fluorouracil/leucovorin for metastatic colorectal cancer: a new survival standard . Oncologist . 2001;6:81–91
  57. Izumiya Y , Shiojima I , Sato K , Sawyer DB , Colucci WS , Walsh K . Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload . Hypertension . 2006;47:887–893
  58. Jain RK . Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy . Nat Med . 2001;7:987–989

PII: S1726-4901(10)70062-9

doi:10.1016/S1726-4901(10)70062-9

Journal of the Chinese Medical Association
Volume 73, Issue 6 , Pages 281-288, June 2010