Continuous administration of bevacizumab plus capecitabine, even after acquired resistance to bevacizumab, restored anti-angiogenic and antitumor effect in a human colorectal cancer xenograft model

Iwai,Toshiki; Sugimoto,MasamichI; Harada,Suguru; Yorozu,Keigo; Kurasawa,Mitsue; Yamamoto,Kaname

doi:10.3892/or.2016.4902

Continuous administration of bevacizumab plus capecitabine, even after acquired resistance to bevacizumab, restored anti-angiogenic and antitumor effect in a human colorectal cancer xenograft model

Authors:
- Toshiki Iwai
- MasamichI Sugimoto
- Suguru Harada
- Keigo Yorozu
- Mitsue Kurasawa
- Kaname Yamamoto
View Affiliations

Affiliations: Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan
Published online on: June 22, 2016 https://doi.org/10.3892/or.2016.4902
Pages: 626-632
Copyright: © Iwai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Vascular endothelial growth factor (VEGF)-neutralizing therapy with bevacizumab has become increasingly important for treating colorectal cancer. It was demonstrated that second-line chemotherapy together with bevacizumab after disease progression (PD) on first-line therapy including bevacizumab showed clinical benefits in metastatic colorectal and breast cancers (ML18147 trial, TANIA trial). One of the rationales for these trials was that the refractoriness to first-line therapy is caused by resistance to not so much bevacizumab as to the chemotherapeutic agents. Nevertheless, resistance to bevacizumab cannot be ruled out because VEGF-independent angiogenesis has been reported to be a mechanism of resistance to anti-VEGF therapy. In this study, we used a xenograft model with the human colon cancer HT-29 cells to investigate the mechanisms underlying the effect of continued administration of bevacizumab plus capecitabine even after resistance to bevacizumab was acquired. The combination of capecitabine plus bevacizumab exhibited significantly stronger antitumor and anti-angiogenic activities than did monotherapy with either agent. Capecitabine treatment significantly increased the intratumoral VEGF level compared with the control group; however, the combination with bevacizumab neutralized the VEGF. Among angiogenic factors other than VEGF, intratumoral galectin-3, which reportedly promotes angiogenesis both dependent on, and independently of VEGF, was significantly decreased in the capecitabine group and the combination group compared with the control group. In an in vitro experiment, 5-fluorouracil (5-FU), an active metabolite of capecitabine, inhibited galectin-3 production by HT-29 cells. These results suggested that capecitabine has a dual mode of action: namely, inhibition of tumor cell growth and inhibition of galectin-3 production by tumor cells. Thus, capecitabine and bevacizumab may work in a mutually complementary manner in tumor angiogenesis inhibition to overcome the resistance caused by angiogenic factors other than VEGF. These results suggest the clinical relevance and the mechanism of action of treatment with bevacizumab in combination therapy beyond PD.

View Figures

View References

1	Ferrara N and Kerbel RS: Angiogenesis as a therapeutic target. Nature. 438:967–974. 2005. View Article : Google Scholar : PubMed/NCBI
2	Ellis LM and Hicklin DJ: VEGF-targeted therapy: Mechanisms of anti-tumour activity. Nat Rev Cancer. 8:579–591. 2008. View Article : Google Scholar : PubMed/NCBI
3	Hurwitz HI, Tebbutt NC, Kabbinavar F, Giantonio BJ, Guan ZZ, Mitchell L, Waterkamp D and Tabernero J: Efficacy and safety of bevacizumab in metastatic colorectal cancer: Pooled analysis from seven randomized controlled trials. Oncologist. 18:1004–1012. 2013. View Article : Google Scholar : PubMed/NCBI
4	Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P and Kerbel RS: Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest. 105:R15–R24. 2000. View Article : Google Scholar : PubMed/NCBI
5	Klement G, Huang P, Mayer B, Green SK, Man S, Bohlen P, Hicklin D and Kerbel RS: Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts. Clin Cancer Res. 8:221–232. 2002.PubMed/NCBI
6	Bennouna J, Sastre J, Arnold D, Österlund P, Greil R, Van Cutsem E, von Moos R, Viéitez JM, Bouché O, Borg C, et al ML18147 Study Investigators: Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): A randomised phase 3 trial. Lancet Oncol. 14:29–37. 2013. View Article : Google Scholar
7	von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, et al: Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): An open-label, randomised phase 3 trial. Lancet Oncol. 15:1269–1278. 2014. View Article : Google Scholar : PubMed/NCBI
8	Jubb AM, Oates AJ, Holden S and Koeppen H: Predicting benefit from anti-angiogenic agents in malignancy. Nat Rev Cancer. 6:626–635. 2006. View Article : Google Scholar : PubMed/NCBI
9	Shi H, Jiang J, Ji J, Shi M, Cai Q, Chen X, Yu Y, Liu B, Zhu Z and Zhang J: Anti-angiogenesis participates in antitumor effects of metronomic capecitabine on colon cancer. Cancer Lett. 349:128–135. 2014. View Article : Google Scholar : PubMed/NCBI
10	Yuan F, Shi H, Ji J, Cai Q, Chen X, Yu Y, Liu B, Zhu Z and Zhang J: Capecitabine metronomic chemotherapy inhibits the proliferation of gastric cancer cells through anti-angiogenesis. Oncol Rep. 33:1753–1762. 2015.PubMed/NCBI
11	Yanagisawa M, Yorozu K, Kurasawa M, Nakano K, Furugaki K, Yamashita Y, Mori K and Fujimoto-Ouchi K: Bevacizumab improves the delivery and efficacy of paclitaxel. Anticancer Drugs. 21:687–694. 2010.PubMed/NCBI
12	Kopetz S, Hoff PM, Morris JS, Wolff RA, Eng C, Glover KY, Adinin R, Overman MJ, Valero V, Wen S, et al: Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: Efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol. 28:453–459. 2010. View Article : Google Scholar :
13	Fujimoto-Ouchi K, Sekiguchi F, Yamamoto K, Shirane M, Yamashita Y and Mori K: Preclinical study of prolonged administration of trastuzumab as combination therapy after disease progression during trastuzumab monotherapy. Cancer Chemother Pharmacol. 66:269–276. 2010. View Article : Google Scholar
14	Iwai T, Moriya Y, Shirane M, Fujimoto-Ouchi K and Mori K: Continuous inhibition of epidermal growth factor receptor phosphorylation by erlotinib enhances antitumor activity of chemotherapy in erlotinib-resistant tumor xenografts. Oncol Rep. 27:923–928. 2012.PubMed/NCBI
15	Maniati E and Hagemann T: IL-17 mediates resistance to anti-VEGF therapy. Nat Med. 19:1092–1094. 2013. View Article : Google Scholar : PubMed/NCBI
16	Casanovas O, Hicklin DJ, Bergers G and Hanahan D: Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 8:299–309. 2005. View Article : Google Scholar : PubMed/NCBI
17	Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes HP, Menger MD, Ullrich A and Vajkoczy P: Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 18:338–340. 2004.
18	Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z, Kaminker J and Ferrara N: PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell. 15:21–34. 2009. View Article : Google Scholar
19	Bergers G and Hanahan D: Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 8:592–603. 2008. View Article : Google Scholar : PubMed/NCBI
20	Yamashita-Kashima Y, Fujimoto-Ouchi K, Yorozu K, Kurasawa M, Yanagisawa M, Yasuno H and Mori K: Biomarkers for antitumor activity of bevacizumab in gastric cancer models. BMC Cancer. 12:372012. View Article : Google Scholar : PubMed/NCBI
21	Waugh DJ and Wilson C: The interleukin-8 pathway in cancer. Clin Cancer Res. 14:6735–6741. 2008. View Article : Google Scholar : PubMed/NCBI
22	Li D, Xie K, Ding G, Li J, Chen K, Li H, Qian J, Jiang C and Fang J: Tumor resistance to anti-VEGF therapy through up-regulation of VEGF-C expression. Cancer Lett. 346:45–52. 2014. View Article : Google Scholar
23	Griffioen AW and Thijssen VL: Galectins in tumor angiogenesis. Ann Transl Med. 2:902014.PubMed/NCBI
24	Endo K, Kohnoe S, Tsujita E, Watanabe A, Nakashima H, Baba H and Maehara Y: Galectin-3 expression is a potent prognostic marker in colorectal cancer. Anticancer Res. 25:3117–3121. 2005.PubMed/NCBI
25	Croci DO, Cerliani JP, Dalotto-Moreno T, Méndez-Huergo SP, Mascanfroni ID, Dergan-Dylon S, Toscano MA, Caramelo JJ, García-Vallejo JJ, Ouyang J, et al: Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors. Cell. 156:744–758. 2014. View Article : Google Scholar : PubMed/NCBI
26	Markowska AI, Liu FT and Panjwani N: Galectin-3 is an important mediator of VEGF- and bFGF-mediated angiogenic response. J Exp Med. 207:1981–1993. 2010. View Article : Google Scholar : PubMed/NCBI
27	Markowska AI, Jefferies KC and Panjwani N: Galectin-3 protein modulates cell surface expression and activation of vascular endothelial growth factor receptor 2 in human endothelial cells. J Biol Chem. 286:29913–29921. 2011. View Article : Google Scholar : PubMed/NCBI
28	D'Haene N, Sauvage S, Maris C, Adanja I, Le Mercier M, Decaestecker C, Baum L and Salmon I: VEGFR1 and VEGFR2 involvement in extracellular galectin-1- and galectin-3-induced angiogenesis. PLoS One. 8:e670292013. View Article : Google Scholar : PubMed/NCBI
29	Partridge EA, Le Roy C, Di Guglielmo GM, Pawling J, Cheung P, Granovsky M, Nabi IR, Wrana JL and Dennis JW: Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science. 306:120–124. 2004. View Article : Google Scholar : PubMed/NCBI