Inhibition of growth and metastasis of human gastric cancer implanted in nude mice by d-limonene.
OBJECTIVE
To investigate the effects and mechanism of d-limonene on the growth and metastasis of gastric cancer in vivo.


METHODS
Metastatic model simulating human gastric cancer was established by orthotopic implantation of histologically intact human tumor tissue into gastric wall of nude mice. One percent d-limonene was orally administered at dose of 15 ml/kg every other day for seven weeks. Eight weeks after implantation, tumor weight, inhibition rate, apoptotic index (AI), microvessel density (MVD), vascular endothelial growth factor (VEGF), variation of ultrastructure, and the presence of metastasis were evaluated, respectively, after the mice were sacrificed.


RESULTS
The tumor weight was significantly reduced in 5-FU group (2.55+/-0.28 g), d-limonene group (1.49+/-0.09 g) and combined treatment group (1.48+/-0.21 g) compared with the control group(2.73+/-0.23 g, P<0.05). In 5-FU group, d-limonene group, combined treatment group, the inhibition rates were 2.60%,47.58% and 46.84% and 0, respectively; AI was (3.31+/-0.33)%, (8.26+/-1.21)%, (20.99+/-1.84)% and (19.34+/-2.19)%, respectively; MVD was (8.64+/-2.81), (16.77+/-1.39), (5.32+/-4.26) and (5.86+/-2.27), respectively; VEGF expression was (45.77+/-4.79), (41.34+/-5.41), (29.71+/-8.92) and (28.24+/-8.55), respectively. The incidences of peritoneal metastasis also decreased significantly in 5-FU group(77.8%), d-limonene group (20.0%) and combined group (22.2%) compared with control group (100%) versus 62.5%,30% and 22.2%) (P<0.05). Liver metastasis was also inhibited and the incidences decreased significantly in 5-FU group, d-limonene group and combined group than that in control group (87.5% vs 55.5%, 20.0% and 22.2% respectively)(P<0.05). The incidence of ascites in control group, 5-FU group, d-limonene group and combined group was 25.0%, 22.2%, 0, 0, respectively and 12.5%, 11.1% 0, 0, with respect to the metastasis rate to other organs.


CONCLUSIONS
d-limonene has antiangiogenic and proapoptotic effects on gastric cancer, thereby inhibits tumor growth and metastasis. Combination of d-limonene with cytotoxic agents may be more effective.
Lu
Xiao-Guang
XG
Department of General Surgery, Fourth Hospital of Dalian Medical University, Dalian 116001, Liaoning Province, China. dllxg@yahoo.com.cn
Zhan
Li-Bin
LB
Feng
Bing-An
BA
Qu
Ming-Yang
MY
Yu
Li-Hua
LH
Xie
Ji-Hong
JH
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053138:Cyclohexenes; D006801:Humans; D000077222:Limonene; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D013274:Stomach Neoplasms / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology; D013729:Terpenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D053138:Cyclohexenes; D013729:Terpenes; D000077222:Limonene