ABSTRACT
<p><b>OBJECTIVE</b>The purpose of this study was to screen for frequencies of different CYP450 genotypes in the Chinese population and explore the relationship between sorafenib toxicity and CYP450 polymorphism.</p><p><b>METHODS</b>A total of 600 peripheral blood samples were obtained from two groups for this study. The first group of 300 samples were from Chinese patients with HBV/HCV-associated HCC, while the remaining 300 samples were from a healthy population of recruited subjects. Allele-specific PCR and long-fragment gene sequencing was used to identify the frequencies of CYP450 polymorphism. Aflatoxin-induced HCC rat models expressing CYP3A4*1, CYP3A5*3, CYP2C19*2, and CYP2D6*10 were established and treated with sorafenib at certain time points. Hepatic and renal function, along with plasma concentration of sorafenib, were monitored regularly.</p><p><b>RESULTS</b>The most common forms of CYP mutations in the Chinese population were identified. The levels of sorafenib plasma concentration, as well as damage to hepatic and renal function in aflatoxin-induced HCC rat models varied significantly across the different CYP genotypes.</p><p><b>CONCLUSION</b>The mutational frequencies of CYP3A5, CYP3A4, CYP2C19, and CYP2D6 genotypes varied among different ethnic groups and populations. Individuals with CYP3A5*3 demonstrated minimal sorafenib metabolism, which led to severe hepatic and renal damage. Inter-individual variability in sorafenib-toxicity may be interpreted by CYP450 genetic polymorphisms, suggesting that identification of CYP polymorphism within a certain population should be considered in sorafenib therapy.</p>
ABSTRACT
<p><b>OBJECTIVE</b>To explore the effect and mechanism of resveratrol against human colon cancer ls174t cells in vitro and the growth of colon cancer in tumor-bearing nude mice.</p><p><b>METHODS</b>MTT method was used to test the inhibiting effect of resveratrol on the growth and proliferation of ls174t cells. Transmission electron microscopy was used to observe the morphological changes of cell apoptosis, and FCM assay was performed to measure the changes of cell apoptosis rate and cell cycle. RT-PCR method was used to detect the expression of bcl-2 and bax mRNA, and Western blot was used to detect the expression of bcl-2 and bax protein.</p><p><b>RESULTS</b>MTT test revealed that resveratrol showed significant inhibiting effect on ls174t cells in a concentration- and time-dependent manner. In the concentration range of 25, 50, 100, 200 and 400 micromol/L, the inhibition rate after resveratrol treatment for 24 hours was respectively 1.0%, 9.1%, 17.4%, 27.8% and 66.5%, while the inhibition rate after treatment for 48 hours was respectively 3.6%, 13.7%, 30.2%, 58.4% and 86.1%, and the inhibition rate after treatment for 72 hours was 18.1%, 33.0%, 48.6%, 61.2% and 89.4%, respectively, showing a very significant difference (P < 0.01). Typical ultrastructural apoptotic changes were observed in resveratrol-treated ls174t cells. It was found through FCM assay that resveratrol caused apoptosis in ls174 cells and blocked the cell cycle at S phase. RT-PCR and Western blot test showed that after the treatment of colon cancer cells with resveratrol at different concentrations (25, 50, 100 and 200 micromol/L), the expression level of bcl-2 was decreased, while expression level of bax was increased. The highest inhibition rate was 47.9%. In 200 mg/kg and 800 mg/kg resveratrol treatment groups, the weight of subcutaneously transplanted tumors in nude mice was 4.10 +/- 0.18 g and 3.05 +/- 0.35 g, respectively, the difference was significant compared with that of the control group (P < 0.01).</p><p><b>CONCLUSION</b>Resveratrol can inhibit the growth of ls174t cells through apoptosis induction. The mechanism is probably related to inhibition of anti-apoptotic factor bcl-2 and enhancement of expression of apoptotic factor bax.</p>