[Inhibitory effect of fumagillol combined with cyclophosphamide on metastasis of lung adenocarcinoma cell line LA795 xenograft in mice].
OBJECTIVE
Treating tumor with angiogenesis inhibitor and chemotherapeutic drugs is a research hot spot now. This study was designed to observe the synergetic inhibitory effect of fumagillol (TNP-470) in combination with cyclophosphamide (CTX) on metastasis of lung adenocarcinoma cell line LA795 xenograft in mouse, and to explore the related mechanism of suppressing tumor metastasis by TNP-470.


METHODS
Forty T739 nude mice bearing highly metastatic LA795 cells were randomized into 5 groups: control group, vehicle group, TNP-470 (30 mg/kg) group, CTX (40 mg/kg) group, and combination group (TNP-470 plus CTX). All mice were killed 3 weeks laterû the subcutaneous tumors were weighted to calculate inhibitory rate. The metastatic tumor foci on lung surface in mice were counted to calculate occurrence rate and inhibitory rate of metastases on lung surface. The microvessel density (MVD) and the expression of tumor metastasis-related factor P-selectin in subcutaneous tumor were detected by immunohistochemistry and analyzed with image analysis system.


RESULTS
The inhibitory rate of tumor was significantly higher in combination group (81.5%) than in other groups (P<0.01). TNP-470 plus CTX showed synergetic effect on inhibiting metastasis on lung surface with a Q value of 1.21. The metastatic foci on lung surface were significantly fewer in combination group, TNP-470 group, and CTX group than in control group (1.75+/-1.71, 4.75+/-3.34, and 8.50+/-2.67 vs. 12.13+/-4.02, P<0.05). The MVD and the expression of P-selectin in subcutaneous tumor were also significantly lower in combination group and TNP-470 group than in control group (9.13+/-1.61 and 12.13+/-2.84 vs. 20.50+/-3.12, P<0.01; 5.25+/-2.27 and 7.13+/-3.01 vs. 13.75+/-3.38, P<0.01).


CONCLUSIONS
TNP-470 and CTX have synergetic inhibitory effect on lung metastasis of LA795 xenograft tumor. TNP-470 may inhibit lung metastasis of LA795 xenograft tumor by suppressing the expression of P-selectin.
Wang
Xiao-Hua
XH
Department of Respiration Medicine, The First Affiliated Hospital, Nanhua University, Hengyang, Hunan 421001, P. R. China.
Wang
Zheng
Z
Duan
Bao-Chun
BC
Song
Jie-Tao
JT
He
Jian-Bin
JB
Ou
Li-Wen
LW
Zhang
Ping
P
D000230:Adenocarcinoma / Q000098:blood supply / Q000473:pathology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D045744:Cell Line, Tumor; D003510:Cyclohexanes / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000494:pharmacology*; D004357:Drug Synergism; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000187:drug effects; D009362:Neoplasm Metastasis; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D019007:P-Selectin / Q000378:metabolism*; D011897:Random Allocation; D012717:Sesquiterpenes / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D003510:Cyclohexanes; D019007:P-Selectin; D012717:Sesquiterpenes; D003520:Cyclophosphamide; D000077609:O-(Chloroacetylcarbamoyl)fumagillol