Metronomic docetaxel chemotherapy inhibits angiogenesis and tumor growth in a gastric cancer model
Tóm tắt
Low-dose metronomic (LDM) chemotherapy represents a new strategy to treat solid tumors by stronger antiangiogenic activity and less side effects. The aim of the study is to rationally develop a docetaxel metronomic regimen in preclinical settings of gastric cancer. In vitro cell proliferation, apoptosis, and thrombospondin-1/vascular endothelial growth factor (TSP-1/VEGF) expression analyses were performed on human umbilical vein endothelial cells (HUVECs) and gastric cancer (BGC-823) cells exposed for 144 h to metronomic concentrations of docetaxel. BGC-823 human gastric cancer xenograft model was used, and tumor growth and side effects were closely monitored. Quantitative real-time PCR was used to determine TSP-1/VEGF mRNA levels in tumor samples. Expression of VEGF and CD31 was observed by immunohistochemistry. Our results indicated that LDM docetaxel preferentially inhibited HUVEC cell proliferation and induced HUVEC apoptosis. Docetaxel significantly increased TSP-1 expression and secretion in HUVEC cells whereas the expression and secretion of VEGF significantly decreased in BGC-823 cells. LDM docetaxel significantly inhibited BGC-823 tumor growth in the absence of toxicity, which was accompanied by decreases in microvessel density (MVD) and VEGF and increases in TSP-1 gene expression in tumor tissues. In vitro results show the antiangiogenic properties of LDM docetaxel. In vivo, LDM docetaxel treatment is effective against gastric tumor and microvessel growth without toxic effect on nude mice.
Tài liệu tham khảo
Albert A (2008) New drugs in the treatment of gastric tumors. Clin Transl Oncol 10:256–261
Ooyama A, Oka T, Zhao HY, Yamamoto M, Akiyama S, Fukushima M (2008) Anti-angiogenic effect of 5-Fluorouracil-based drugs against human colon cancer xenografts. Cancer Lett 267:26–36
Orlando L, Cardillo A, Rocca A et al (2006) Prolonged clinical benefit with metronomic chemotherapy in patients with metastatic breast cancer. Anticancer Drugs 17:961–967
Scharovsky OG, Mainetti LE, Rozados VR (2009) Metronomic chemotherapy is changing the paradigm that more is better. Curr Oncol 16:7–15
Tetzlaff ED, Cheng JD, Ajani JA (2008) Review of docetaxel in the treatment of gastric cancer. Ther Clin Risk Manag 4:999–1007
Benelli R, Monteghirfo S, Balbi C et al (2009) Novel antivascular efficacy of metronomic docetaxel therapy in prostate cancer: hnRNP K as a player. Int J Cancer 124:2989–2996
Bocci G, Falcone A, Fioravanti A et al (2008) Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib. Br J Cancer 98:1619–1629
Liu TG, Huang Y, Cui D et al (2009) Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis and growth of lung cancer in mice statistical analysis. BMC Cancer 9:250
Kamat AA, Kim TJ, Landen CN et al (2007) Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer. Cancer Res 67:281–288
Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4:423–436
Bocci G, Nicolaou KC, Kerbel RS (2002) Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs. Cancer Res 62:6938–6943
Lawler J (2002) Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth. J Cell Mol Med 6:1–12
Dawson DW, Pearce SF, Zhong R, Silverstein RL, Frazier WA, Bouck NP (1997) CD36 mediates the In vitro inhibitory effects of thrombospondin-1 on endothelial cells. J Cell Biol 138:707–717
Guo N, Krutzsch HC, Inman JK, Roberts DD (1997) Thrombospondin 1 and type I repeat peptides of thrombospondin 1 specifically induce apoptosis of endothelial cells. Cancer Res 57:1735–1742
Jiménez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck N (2000) Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med 6:41–48
Damber JE, Vallbo C, Albertsson P, Lennernas B, Norrby K (2006) The antitumour effect of low-dose continuous chemotherapy may partly be mediated by thrombospondin. Cancer Chemother Pharmacol 58:354–360
Laquente B, Lacasa C, Ginestà MM, Casanovas O, Figueras A, Galán M, Ribas IG, Germà JR, Capellà G, Viñals F (2008) Antiangiogenic effect of gemcitabine following metronomic administration in a pancreas cancer model. Mol Cancer Ther 7:638–647
Bocci G, Francia G, Man S, Lawler J, Kerbel RS (2003) Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci USA 100:12917–12922
Bando H (2007) Vascular endothelial growth factor and bevacitumab in breast cancer. Breast Cancer 14:163–173
Hayes DF, Miller K, Sledge G (2007) Angiogenesis as targeted breast cancer therapy. Breast 16(Suppl 2):S17–S19
Colleoni M, Rocca A, Sandri MT et al (2002) Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 13:73–80
Colleoni M, Orlando L, Sanna G et al (2006) Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol 17:232–238
Correale P, Cerretani D, Remondo C et al (2006) A novel metronomic chemotherapy regimen of weekly platinum and daily oral etoposide in high-risk non-small cell lung cancer patients. Oncol Rep 16:133–140
Bocci G, Nicolaou KC, Kerbel R (2002) Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs. Cancer Res 62:6938–6943
Magnon C, Galaup A, Rouffiac V et al (2007) Dynamic assessment of antiangiogenic therapy by monitoring both tumoral vascularization and tissue degeneration. Gene Ther 14:108–117
Maria RR, Francesca C, Francesca G (2005) Microdensity vessels and with vascular endothelial growth factor expression in ovarian carcinoma. Int J Surg Pathol 13:135–142
Ji Y, Hayashi K, Amoh Y et al (2007) The camptothecin derivative CPT-11 inhibits angiogenesis in a dual-color imageable orthotopic metastatic nude mouse model of human colon cancer. Anticancer Res 27:713–718
Zhang Q, Kang X, Zhao W (2006) Antiangiogenic effect of low-dose cyclophosphamide combined with ginsenoside Rg3 on Lewis lung carcinoma. Biochem Biophys Res Commun 342:824–828
Zhang M, Tao W, Pan S et al (2009) Low-dose metronomic chemotherapy of paclitaxel synergizes with cetuximab to suppress human colon cancer xenografts. Anticancer Drugs 20:355–363