[Observation of the antitumor effect of endostar combined with docetaxel under different administration sequences].
OBJECTIVE
To observe and analyze the antitumor effect of endostar combined with docetaxel under different administration sequences.


METHODS
Nude mice with xenograft tumor (A549 cell line) were randomized into 3 groups, 8 mice/group: (1) Concurrent administration group (each mouse: endostar 400 µg/d, d1-d35, docetaxel 10 mg/kg, every 3 days, d1-d19); (2) Endo-first group (each mouse: endostar 400 µg/d, d1-d35, docetaxel 10 mg/kg, every 3 days, d16-d34); (3) Model group (positive control, tumor-bearing mice without treatment, each mouse: physiological saline, 100 µl/d, d1-d35, water for injection, 200 µl/d, d1-d35, every 3 days), and blank control group (negative control, normal mice without treatment, 8 mice), the administration method was the same to the model group. The volume of tumor and the weight of mouse were measured during treatment. Circulating endothelial cells (CECs) were detected by flowcytometry, and the expression of matrix metalloproteinase (MMP-2, MMP-9), the tissue inhibitor of MMP (TIMP-1, TIMP-2), the extracellular MMP inducer (EMMPRIN), CD34, α-smooth muscle actin (α-SMA) were determined by immunohistochemistry.


RESULTS
The tumor growth of concurrent administration group (39.94 mm(3)) was lower than that of the endo-first group [(99.57 ± 74.48) mm(3)] during treatment, both of them were smaller than that of the model group [(217.67 ± 95.44) mm(3), P < 0.05]. The amount of CECs in the endo-first group [(77.25 ± 24.02) cells/10(4) cells] was more than that of the concurrent administration group [(25.86 ± 11.77) cells/10(4) cells], the model group [(14.71 ± 11.07) cells/10(4) cells], and the blank control group [(12.90 ± 11.20) cells/10(4) cells, P < 0.01]. The expression of MMPs in the treatment groups was obviously downregulated. The expressions of TIMP-1 in the endo-first group and TIMP-2 in the concurrent administration group were upregulated (P < 0.05). The expression of EMMPRIN was significantly down-regulated in the concurrent administration group (P < 0.05). The MVD and α-SMA expressions of the treatment groups were less than that of the model group (P < 0.05).


CONCLUSIONS
In comparison with the endo-first group, the anti-tumor effect and survival quality of the concurrent administration group are better. Both of the administration groups may have "vascular normalization effect" by down-regulating MMPs expression through different points, and inhibit the cancer-induced stromal reaction, restraining the cancer progress to a certain extent. The changes of CECs should be a dynamic process with an initial rise in the early-stage suggesting the decrease of vascular bed and subsequent decline ascribed to apoptosis of CECs and the tumor-regression after combined therapy. Investigation of its dynamic changes may be helpful to know the change of tumor burden and vascular bed and predict the antitumor effect.
Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, Lung Cancer Center of Tianjin, Tianjin, China.
Jing
J
Yuan
Chun-wa
CW
Wu
Zhu-jun
ZJ
Liu
Xi-yin
XY
Wei
Kai
K
Li
D000199:Actins / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D051926:Basigin / Q000378:metabolism; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004334:Drug Administration Schedule; D043169:Endostatins / Q000008:administration & dosage / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
C541116:ACTA2 protein, human; D000199:Actins; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D043169:Endostatins; D011994:Recombinant Proteins; D043823:Taxoids; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D051926:Basigin; D000077143:Docetaxel; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C522911:endostar protein