PDF (1.5 MB)

Original
Anti Tumor Effects of Thalidomide Against Liver Metastasis in a Murine Model of Colon Cancer

Shutaro Ozawa, Hideyuki Tawara, Isamu Koyama
First Department of Surgery, Saitama Medical School, Moroyama, Iruma-gun, Saitama 350-0495, Japan

Background: Thalidomide was introduced in the 1950s as a nontoxic sedative, but was removed from the market because of its teratogenicity. Recent studies have demonstrated that the most likely etiology of limb defects produced by fetal exposure to thalidomide is the inhibition of angiogenesis in the developing limb bud. Also many studies have shown that thalidomide inhibits tumor growth in several malignancies by the inhibition of VEGF. Methods: We determined whether the systemic administration of thalidomide inhibits colon cancer liver metastasis in mice. We also evaluated the optimal schedule of this treatment against murine colon cancer liver metastasis. Murine colon cancer CT-26 cells were implanted into the spleens of BALB/c mice. 7 days after tumor implantation, the mice received an intra-peritoneal injection of thalidomide (0, 30 mg/kg) daily or every other day (3 times per week). After the treatments, all mice were sacrificed. The numbers of liver metastases were counted and the expression of VEGF and the micro vessel density were analyzed by immunohistochemistry against liver metastases. Results: 4 out of 10 mice which received a daily administration of thalidomide (30 mg/kg) died. But in this group, we found a significant reduction in the number of liver metastases compared with the control group (0 mg/kg). All mice which received thalidomide every other day survived. In this group, there was also a significant reduction in the number of liver metastases compared with the control. Immunohistochemical analysis revealed lower expressions of VEGF and CD31 in the liver metastases of mice which received thalidomide every other day compared with the control. Conclusion: The systemic administration of thalidomide inhibits liver metastasis of colon cancer in mice by the downregulation of VEGF and angiogenesis. The every other day administration of thalidomide was the optimal schedule in this model.
Keywords: Thalidomide, VEGF, Liver metastasis, tumor vasculature
J Saitama Med School 2005;32:31-36
(Received January 25, 2005)

Abbreviations: FBS, fetal bovine serum; HBSS, Hanks' balanced salt solution; EMEM, Eagle's minimum essential medium; VEGF, vascular endothelial growth factor