title: Low-dose metronomic chemotherapy with cisplatin: can it suppress angiogenesis in H22 hepatocarcinoma cells?
abstract: Low-dose chemotherapy drugs can suppress tumours by restraining tumour vessel growth and preventing the repair of damaged vascular endothelial cells. Cisplatin is a broad-spectrum, cell cycle-non-specific drug, but has serious side effects if used at high doses. There have been few reports on the anti-angiogenic effects of low-dose cisplatin and hence the effect of low-dose metronomic (LDM) chemotherapy on the proliferation and neovascularization of H22 hepatocarcinoma cells is discussed in this research. The influence of LDM chemotherapy with cisplatin on human umbilical vascular endothelial cells (HUVECs) and proliferation of the HepG(2) human hepatocarcinoma cell line were measured using MTT assays. The LDM group was treated with cisplatin 0.6 mg/kg/day; the control group with saline 0.2 ml; the maximum tolerated dose (MTD) group with cisplatin 9 mg/kg/day. Vascular endothelial growth factor (VEGF) and matrix metallopeptidase 2 (MMP-2) were detected using immunohistochemical staining. A chicken chorio-allantoic membrane (CAM) model was used to check the inhibitory effect of LDM chemotherapy with cisplatin on neovascularization in vivo. Low-dose cisplatin inhibited HUVEC proliferation in a dose- and time-dependent manner, but was ineffective in inhibiting HepG(2) cell proliferation. Tumour growth was delayed in mice receiving LDM cisplatin, without apparent body weight loss, compared with mice that received MTD cisplatin. Microvessel density and expression of VEGF and MMP-2 were much lower in mice receiving LDM cisplatin than in the control and MTD groups. Continuous low-dose cisplatin suppressed CAM angiogenesis in vivo. LDM chemotherapy with cisplatin can inhibit the growth of blood vessel endothelial cells in vitro and shows anti-angiogenic ability in vivo.
authors.affiliation: Department of Oncology, Affiliated Hospital of Medical College, Qingdao University, Qingdao, China. fangzhenshen@126.com
authors.forename: Fang-Zhen
authors.initials: FZ
authors.lastname: Shen
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.forename: Kun
authors.initials: K
authors.lastname: Mu
authors.forename: Ji-Yuan
authors.initials: JY
authors.lastname: Hou
authors.forename: Yan-Tao
authors.initials: YT
authors.lastname: Wang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply; D002945:Cisplatin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020714:Maximum Tolerated Dose; D051379:Mice; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D002945:Cisplatin