The Study Of Inducing Apoptosis On Human Colon Cancer Cell Line LS-174T And Efficacy Kinetics In Treatment Of Liver Metastasis From Human Colon Cancer In Nude Mice With Arsenic Trioxide

The liver is a common site for metastases from various forms of primary tumors, most commonly colorectal cancer. Metastatic liver disease is the commonest cause of death in patients with colorectal cancer. Surgical resection is the only form of curative treatment for liver metastasis from colorectal cancer. But only a small proportion of these patients (10%) may be treated by surgical resection with five year survival approaching 35%~40%. So most patients need non-surgical therapy. Recent clinical studies have shown that inorganic arsenic trioxide (As2O3) at low concentration induces complete remission achieved in 80%~90% with minimal toxicity in patients with refractory or relapsed acute promyelocytic leukemia (APL). Preclinical studies suggest that As2O3 induces apoptosis and possibly differentiation in APL cells. Preliminary reports suggest that the apoptotic effect of As2O3 is not specific for APL but can also be observed in some solid tumors.In this experimental study, the cultured LS-174T cells were treated with As2O3 of different concentrations (1.0 μmol/L,2.0 μmol/L,4.0 μmol/L,8.0 μmol/L,16.0 μmol/L), and the effect of As2O3 in induction of apoptosis and inhibition of proliferation of LS-174T in vitro were explored. After we established a BALB/C-nu/nu nude mice model of human colon adenocarcinoma liver metastasis, As2O3 were injected into the mice at different time(in 15min, 10d and 20d later) via the tail vein. Then the efficacy kinetics of As2O3 and its mechanism in treatment of liver metastasis fromhuman colon adenocarcinoma in nude mice in vivo were observed.The main results and conclusions were as follows:1. As2O3 of 1.0 μmol/L ~16.0 μmol/L could significantly inhibited the proliferation of LS-174T cell. The inhibiting rate increased followed by increasing of the concentration of As2O3. In concentration of 1.0 μmol/L ~8.0 μmol/L, As2O3 could obviously induced the apoptosis of human colon adenocarcinoma LS-174T cells with dose and time-dependent.2. The 8.0 μmol/L might be the best concentration of inducing apoptosis on human colon adenocarcinoma LS-174T cell. As2O3 of high concentration( > 8.0 μmol/L) would make the cell necrosis rather than apoptosis.3. After treating with As2O3, more significant inhibition the numbers, the diameters, the weight of the hepatic metastatic lesions and the percentage of hepatic replacement by tumour were observed compared with the control animals(P<0.05 or P<0.01), and the survival period of tumor-loading nude mice was prolonged. The CEA level in serum,ascites and cancer tissue in nude mice was also significantly lowered in the treated group.4. The curative effects of the group injected As2O3 at early time were significently better than those at metaphase and later period.5. Inducing apoptosis of cancer cells might be the important mechanism of As2O3 in the treatment of liver metastasis from human colon adenocarcinoma in nude mice...