Treatment for Colorectal Cancer Liver Metastasis by AAV-HGFK1 or ...

[Abstract]

Background & ObjectiveColorectal cancer is one of the most common malignancies and the development of metastases is the main cause of death.Liver metastases are diagnosed in 15-25% of patients at the time of resection of their primary colorectal tumor and 30% of the patients whose metastases are confined to the liver.There are several treatment options, including partial hepatic resection, local ablative therapy, administration of chemotherapy by hepatic artery infusion, systemic chemotherapy and isolated hepatic perfusion (IHP) with high-dose chemotherapy.But all these treatment has a poor therapeutic effect.Gene therapy is a technique whereby the absent or faulty gene is replaced by a working gene, so that the body can make the correct enzyme or protein and consequently eliminate the root cause of the disease. Angiogenesis inhibitors primarily target the proliferation and migration of endothelial cells, providing a complimentary approach,along with direct tumor cytotoxic chemotherapy, for treating cancer.Hepatocyte growth factor (HGF), also known as scatter factor (SF), is a known angiogenic factor that stimulates angiogenesis both in vitro and in vivo. HGFK1,which is one of the four kringle domains of HGF,is an HGF antagonist.so it may act as an angiogenesis inhibitor and provide therapeutic effect for cancer patients. Our main aim of this study is to observe the therapic effect of AAV- HGFKl,which is a Adeno-associated virus containing HGFK1,or combination with 5-fu on treatment for colorectal cancer liver metastasis.Meathods1.The murine colon carcinoma cells(CT26) and the human colon cancer cells (lovo) were injected into the spleen of BALB/C mice and BALB/C nude mice, separately. The conditions of all the mice were observed, the survival time and the conditions of liver metastases were recorded.2. In vitro, the effects of treatment with AAV-HGFK1 on the migration potential of CT26 cells were measured by Wound healing assay and the inhibitory effects of 5-fu on the growth of colorectal cancer cells by MTT assay.3.In vivo, CT26 cells were transplanted into balb/c mice,and the mice were divided into six group randomly: A:PBS?B:AAV-EGFP?C: 5-fu?D: AAV-HGFK1?E:AAV-HGFKI+5-fu. The survival time of the animals was recorded after oeperation.4.The expression of HGFK1 and EGFP in liver was detected by immunohisto-chemistry, and tumor microvessel density(MVD) was measured by immunostaining with CD31.and apoptosis index(AI)of tumor by TUNEL.Results1. All animals inoculated with CT26 cells and a few of animals inoculated with lovo cells developed liver metastases. There were no metastases were observed in other organs. The pathological results showed that tumor cells of liver metastases accorded with poorly differentiated colonic adenocarcinoma. Compared with the animals inoculated with lovo cells, animals inoculated with CT26 cells showed a higher incidence of liver metastases and a shorter survival time.2. in vitro, AAV-HGFK1 could inhibit the migration ability of CT26 cells obviously. With the treatment of 5-fu at a dose of 0.1ug/ml,the growth inhibition rates of lovo cells and CT26 cells were 9.3% and 17.1%, respectively.3.. In vivo, the average survival time of group D was significantly longer than group B[(46.6?3.63)d vs (21.2?1.08)d, p?0.01] and a little shorter than group E [( 47.5?2.24)d, p?0.05]. The average survival time of group C was longer than group A[(28.5?1.06)d],with no significant difference between them(p?0.05).4. HGFK1 and EGFP were highly expressed in the liver of mice.MVD decreased remarkablely in group D and E compared with group B[ (17.7?2.3) and (16.7?2.5) vs (36.9?4.4), respectively, p?0.01], but there is no significantly difference between the former tow groups(p?0.05). AI increased significantly in group C and E compared with groupA[(7.1?2.0)%?(7.5?2.8) % and(3.4?1.1) %, p?0.01].ConclusionsAAV-HGFK1 could prolong the survival time of mice which inoculated with CT26 cells through inhibiting tumor angiogenesis. But AAV-HGFK1 in combination with 5-fu doesn?t have additive effect on inhibitory activity against liver metastasis. Our experiment may provide a new treatment option against colorectal liver metastasis?

Title: Treatment for Colorectal Cancer Liver Metastasis by AAV-HGFK1 or Combination with 5-fu in Vitro and in Vivo.

Category: Cancer Letters

Filename: Treatment for Colorectal Cancer Liver Metastasis by AAV-HGFK1 or Combination with 5-fu in Vitro and in Vivo..pdf

Pages: 127

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