[Effects of recombinant human endostatin and docetaxel on MMP and its following anti-neoplastic effect under different administration sequences].
OBJECTIVE
The aim of this study is to observe the changes of MMP-2 and its regulators, and to investigate the mechanism of the two administration sequences of recombinant human endostatin (rh-endostatin) and docetaxel.


METHODS
The experiment was performed as 2 stages. Firstly, nude mice with xenograft tumor were randomized into 2 groups as rh-endostatin-treated group with rh-endostatin 400 microg x d(-1), d1-d14 and docetaxel-traeted group with docetaxel 10 mg x kg(-1) x 3d(-1), d1-d14. Secondly, nude mice with xenograft tumor were randomized into 3 groups as concurrent administration group (rh-endostatin 400 microg x d(-1), d1-d35, docetaxel 10 mg x kg(-1) x 3d(-1), d1-d19), endo-first group (rh-endostatin 400 microg x d(-1), d1-d35, docetaxel 10 mg x kg(-1) x 3(d-1), d16-d34) and model group (positive control, mice burdened tumor without treatment). The volume of tumor was measured during treatment. Detection of the expressions of MMP-2, TIMP-2, EMMPRIN and the count of microvessel density (MVD) by immunohistochemistry stain examination were carried out at the end of experiment.


RESULTS
Compared with the docetaxel-treated group, more obvious down-regulation of expression of MMP-2, EMMPRIN (P = 0.024, P = 0.081) were observed in rh-endostatin-treated group. No significant difference was found in TIMP-2 expression between the 2 groups. In combined treatment groups, at the endpoint tumor volumes of concurrent administration group and the endo-first group were remarkably smaller than that in model group (P < 0.001, P = 0.003). According to the administration procedure, concurrent administration inhibited tumor growth stronger than endo-first treatment did. Both of the combined groups down-regulated the expression of MMP-2 and decreased microvessel density (P < 0.05). Compared with model group, the expression of TIMP-2 was upregulated (P = 0.001) as well as EMMPRIN down-regulated (P = 0.018) in concurrent adminis- tration group. Oppositely, the same results were not observed in the endo-first group.


CONCLUSIONS
The schedule of the concurrent administration group could inhibit the tumor growth better, and it down-regulated MMP-2 expression through TIMP-2 and EMMPRIN, and thus slow down the tumor growth superiorly to another schedule of treatment.
Yuan
Jing
J
Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, Lung Cancer Center of Tianjin, Tianjin 300060, China.
Li
Kai
K
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D051926:Basigin / Q000032:analysis; D000077143:Docetaxel; D043169:Endostatins / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000008:administration & dosage; D043823:Taxoids / Q000008:administration & dosage*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis; D023041:Xenograft Model Antitumor Assays
C497887:Bsg protein, mouse; D043169:Endostatins; D011994:Recombinant Proteins; D043823:Taxoids; D019716:Tissue Inhibitor of Metalloproteinase-2; D051926:Basigin; D000077143:Docetaxel; D020778:Matrix Metalloproteinase 2