Abstract
Unresectable colorectal liver metastases are commonly treated with systemic chemotherapy (SCT). Clinical studies on the effect of additional systemic application of bevacizumab (BE), a monoclonal antibody directed against vascular endothelial growth factor, to SCT showed a slight increase of patient survival. Herein, we studied in a rat model of colorectal liver metastasis whether a locoregional application of oxaliplatin (OX) and BE via hepatic arterial infusion (HAI) is more effective to inhibit metastatic growth compared to systemic drug application. Ten days after implantation of CC531 colorectal cancer cells into the left liver lobe of WAG/Rij rats, animals underwent either HAI or systemic intravenous application of BE (5 mg/kg body weight), OX (85 mg/m2 body surface) or a combination of both. Sham-treated animals received saline and served as controls. Tumor volume was measured at days 10 and 13 using three dimensional ultrasound. At day 13 tumor tissue was analyzed histologically and immunohistochemically. Systemic application of OX, BE or their combination did not affect tumor volume when compared to controls. In contrast, HAI of BE and particularly the combination of BE and OX significantly reduced tumor volume. In the tumor tissue this was associated with a decrease of vascularization and cell proliferation as well as an increase of cell apoptosis, as indicated by a decreased number of PECAM-1- and PCNA-positive cells and an increased number of cleaved caspase-3-positive cells. Locoregional administration of BE, particularly in combination with OX, enhances the inhibitory effect on hepatic metastatic growth compared to systemic application of the drugs.
Similar content being viewed by others
References
Reinacher-Schick AC, Bechstein WO (2007) Colorectal liver metastases. Neoadjuvant chemotherapy: aspects of medical and surgical oncology. Internist 48:51–58
Sperti E, Faggiuolo R, Gerbino A, Magnino A, Muratore A, Ortega C, Ferraris R et al (2006) Outcome of metastatic colorectal cancer: analysis of a consecutive series of 229 patients. The impact of a multidisciplinary approach. Dis Colon Rectum 49:1596–1601
Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP et al (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23–30
André T, Bensmaine MA, Louvet C, François E, Lucas V, Desseigne F, Beerblock K et al (1999) Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol 17:3560–3568
André T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, Gilles-Amar V et al (1999) CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer 35:1343–1347
de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C et al (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947
de Gramont A, Tournigand C, Louvet C, André T, Molitor JL, Raymond E, Moreau S et al (1997) Oxaliplatin, folinic acid and 5-fluorouracil (folfox) in pretreated patients with metastatic advanced cancer. The GERCOD. Rev Med Interne 18:769–775
Hebbar M, Tournigand C, Lledo G, Mabro M, André T, Louvet C, Aparicio T et al (2006) Phase II trial alternating FOLFOX-6 and FOLFIRI regimens in second-line therapy of patients with metastatic colorectal cancer (FIREFOX study). Cancer Invest 24:154–159
Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E et al (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22:229–237
Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L et al (2006) OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer—a GERCOR study. J Clin Oncol 24:394–400
Omura K (2008) Advances in chemotherapy against advanced or metastatic colorectal cancer. Digestion 77:13–22
Mocellin S, Pilati P, Lise M, Nitti D (2007) Meta-analysis of hepatic arterial infusion for unresectable liver metastases from colorectal cancer: the end of an era? J Clin Oncol 25:5649–5654
Cohen AD, Kemeny NE (2003) An update on hepatic arterial infusion chemotherapy for colorectal cancer. Oncologist 8:553–566
Mocellin S, Pasquali S, Nitti D (2009) Fluoropyrimidine-HAI (hepatic arterial infusion) versus systemic chemotherapy (SCT) for unresectable liver metastases from colorectal cancer. Cochrane Database Syst Rev, Issue 3. Art. No.: CD007823. doi:10.1002/14651858.CD007823.pub2
United Kingdom Co-ordinating Committee on Cancer Research (1998) Guidelines for the welfare of animals in experimental neoplasia (second edition). Br J Cancer 77:1–10
Benedict FG (1934) Die Oberflächenbestimmung verschiedener Tiergattungen [Determination of body surface area in different animal species]. Monatsschrift Kinderheilkunde 36:300–346
Ranieri G, Patruno R, Ruggieri E, Montemurro S, Valerio P, Ribatti D et al (2006) Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Curr Med Chem 13:1845–1857
Bock F, Onderka J, Dietrich T, Bachmann B, Kruse FE, Paschke M, Zahn G et al (2007) Bevacizumab as a potent inhibitor of inflammatory corneal angiogenesis and lymphangiogenesis. Invest Ophthalmol Vis Sci 48:2545–2552
Heiduschka P, Julien S, Hofmeister S, Bartz-Schmidt KU, Schraermeyer U (2008) Bevacizumab (avastin) does not harm retinal function after intravitreal injection as shown by electroretinography in adult mice. Retina 28:46–55
Yoeruek E, Ziemssen F, Henke-Fahle S, Tatar O, Tura A, Grisanti S, Bartz-Schmidt KU et al (2008) Safety, penetration and efficacy of topically applied bevacizumab: evaluation of eyedrops in corneal neovascularization after chemical burn. Acta Ophthalmol 86:322–328
Barros LF, Belfort R (2007) The effects of the subconjunctival injection of bevacizumab (Avastin) on angiogenesis in the rat cornea. An Acad Bras Cienc 79:389–394
Habot-Wilner Z, Barequet IS, Ivanir Y, Moisseiev J, Rosner M (2010) The inhibitory effect of different concentrations of topical bevacizumab on corneal neovascularization. Acta Ophthalmol 88:862–867
Hashemian MN, Moghimi S, Kiumehr S, Riazi M, Amoli FA (2009) Prevention and treatment of corneal neovascularization: comparison of different doses of subconjunctival bevacizumab with corticosteroid in experimental rats. Ophthalmic Res 42:90–95
Hosseini H, Nejabat M, Mehryar M, Yazdchi T, Sedaghat A, Noori F (2007) Bevacizumab inhibits corneal neovascularization in an alkali burn induced model of corneal angiogenesis. Clin Experiment Ophthalmol 35:745–748
Manzano RP, Peyman GA, Khan P, Carvounis PE, Kivilcim M, Ren M, Lake JC et al (2007) Inhibition of experimental corneal neovascularisation by bevacizumab (Avastin). Br J Ophthalmol 91:804–807
Papathanassiou M, Theodossiadis PG, Liarakos VS, Rouvas A, Giamarellos-Bourboulis EJ, Vergados IA (2008) Inhibition of corneal neovascularization by subconjunctival bevacizumab in an animal model. Am J Ophthalmol 145:424–431
Oh JY, Kim MK, Shin MS, Lee HJ, Lee JH, Wee WR (2009) The anti-inflammatory effect of subconjunctival bevacizumab on chemically burned rat corneas. Curr Eye Res 34:85–91
Abcouwer SF, Lin CM, Wolpert EB, Shanmugam S, Schaefer EW, Freeman WM, Barber AJ et al (2010) Vascular permeability and apoptosis are separable processes in retinal ischemia-reperfusion injury: effects of ischemic preconditioning, bevacizumab and etanercept. Invest Ophthalmol Vis Sci. Epub ahead of print
Kim EC, Lee WS, Kim MS (2010) The inhibitory effects of bevacizumab eyedrops on NGF expression and corneal wound healing in rats. Invest Ophthalmol Vis Sci 51:4569–4573
Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676
Mac Gabhann F, Popel AS (2008) Systems biology of vascular endothelial growth factors. Microcirculation 15:715–738
Roy H, Bhardwaj S, Yla-Herttuala S (2006) Biology of vascular endothelial growth factors. FEBS Lett 580:2879–2887
Fernando NH, Hurwitz HI (2003) Inhibition of vascular endothelial growth factor in the treatment of colorectal cancer. Semin Oncol 30:39–50
Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N (1995) Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 95:1789–1797
Gordon MS, Margolin K, Talpaz M, Sledge GW Jr, Holmgren E, Benjamin R, Stalter S et al (2001) Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 19:843–850
Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, Griffing S et al (2003) Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60–65
Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA et al (2007) 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 25:1539–1544
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342
de Gramont A, Tournigand C, Andre T, Larsen AK, Louvet C (2006) Targeted agents for adjuvant therapy of colon cancer. Semin Oncol 33:42–45
Saltz LB, Lenz HJ, Kindler HL, Hochster HS, Wadler S, Hoff PM, Kemeny NE et al (2007) Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol 25:4557–4561
Goldberg RM, Hurwitz HI, Fuchs CS (2006) The role of targeted therapy in the treatment of colorectal cancer. Clin Adv Hematol Oncol 4(1–10):11–12
Wedam SB, Low JA, Yang SX, Chow CK, Choyke P, Danforth D, Hewitt SM et al (2006) Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol 24:769–777
Sobrero A, Ackland S, Clarke S, Perez-Carrión R, Chiara S, Gapski J, Mainwaring P et al (2009) Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. Oncology 77:113–119
Iqbal S, Lenz HJ (2004) Integration of novel agents in the treatment of colorectal cancer. Cancer Chemother Pharmacol 54(Suppl 1):S32–S39
Wagner AD, Arnold D, Grothey AA, Haerting J, Unverzagt S (2009) Anti-angiogenic therapies for metastatic colorectal cancer. Cochrane Database Syst Rev 8:CD005392
Fernando NH, Hurwitz HI (2004) Targeted therapy of colorectal cancer: clinical experience with bevacizumab. Oncologist 9:11–18
Yang H, Jager MJ, Grossniklaus HE (2010) Bevacizumab suppression of establishment of micrometastases in experimental ocular melanoma. Invest Ophthalmol Vis Sci 51(6):2835–2842
Breedis C, Young C (1954) The blood supply of neoplasms in the liver. Am J Pathol 30:969–985
Burkel WE (1970) The fine structure of the terminal branches of the hepatic arterial system of the rat. Anat Rec 167:329–349
Gonda T, Ishida H, Yoshinaga K, Sugihara K (2000) Microvasculature of small liver metastases in rats. J Surg Res 94:43–48
Okuno K, Hirai N, Lee YS, Tarabar D, Ueno H, Yasutomi M et al (1998) Superiority of hepatic arterial infusion in preventing catabolism of 5-FU compared with portal vein infusion revealed by an in vivo 19F NMR study. Cancer Chemother Pharmacol 42:341–344
Ducreux M, Mitry E, Ould-Kaci M, Boige V, Seitz JF, Bugat R, Breau JL et al (2004) Randomized phase II study evaluating oxaliplatin alone, oxaliplatin combined with infusional 5-FU, and infusional 5-FU alone in advanced pancreatic carcinoma patients. Ann Oncol 15:467–473
Cusack JC Jr, Liu R, Xia L, Chao TH, Pien C, Niu W, Palombella VJ et al (2006) NPI-0052 enhances tumoricidal response to conventional cancer therapy in a colon cancer model. Clin Cancer Res 12:6758–6764
Acknowledgments
We appreciate the excellent technical assistance of Janine Becker, Claudia Scheuer and Christina Marx.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sperling, J., Schäfer, T., Ziemann, C. et al. Hepatic arterial infusion of bevacizumab in combination with oxaliplatin reduces tumor growth in a rat model of colorectal liver metastases. Clin Exp Metastasis 29, 91–99 (2012). https://doi.org/10.1007/s10585-011-9432-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10585-011-9432-6