[Inhibitory effects of TNP-470 in combination with 5-fluorouracil on growth of human colon cancer].
OBJECTIVE
Neovascularization is critical for growth of primary tumors and their distant metastasis. This study was designed to investigate the effects of angiogenesis inhibitor TNP-470 in combination with 5-fluorouracil (5-FU) on the growth of human colon cancer cell line, LOVO, in vitro and in vivo.


METHODS
In vitro, the growth inhibitory effect of TNP-470 or 5-FU on LOVO cells was examined by MTT assay, and synergetic effect of these two agents was evaluated by Burgi analysis. In vivo, human colon cancer xenografts were transplanted into BALB/C nude mice and treated with TNP-470 alone and combination with 5-FU. Tumor microvessel density (MVD) was measured by immunostaining with anti-von Willebrand factor monoclonal antibody; the expression of vascular endothelial growth factor (VEGF) in tumor tissue was detected using an immunohistochemical method with image analysis system.


RESULTS
In vitro, TNP-470 and 5-FU inhibited the growth of LOVO cells, with the IC50 at 55.8 ng/ml and 4.6 ng/ml, respectively. Burgi analysis revealed synergism of these two agents, a remarkable growth inhibitory effect on LOVO cells was obtained. In vivo, in every treatment group, tumor growth was suppressed significantly. The combination group showed significant enhancement in antitumor efficacy. Expression of VEGF in tumors was clearly inhibited by TNP-470 in combination with 5-FU or 5-FU alone compared to the control. Tumor MVD was lower in TNP-470 combination with 5-FU group or TNP-470 group compared to control group.


CONCLUSIONS
TNP-470 suppressed the growth of LOVO cells and human colon cancer xenografts and the angiogenesis; TNP-470 in combination with 5-FU might product synergetic effect.
Fan
Ying-fang
YF
Department of Surgery, Zhujiang Hospital, First Military Medical University, Guangzhou 510282, P. R. China. fanyingfang@263.net
Huang
Zong-hai
ZH
Nie
Jing
J
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D003510:Cyclohexanes; D004195:Disease Models, Animal; D004338:Drug Combinations; D016228:Endothelial Growth Factors / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays
D003510:Cyclohexanes; D004338:Drug Combinations; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D005472:Fluorouracil; D000077609:O-(Chloroacetylcarbamoyl)fumagillol