Clinical And Experimental Study Of The Correlation Between L-carnitine And Cancer Cachexia

Background and ObjectiveMalignant tumors are the main causes of death.,especially tumors of digestive system.The incidence of digestive system tumors as the commonest tumor has gradually risen. The rate of death caused by cachexia conditions in patients suffering from termimal malignant tumors has been as high as 80%.Its main features are anorexia, weight loss, reduction of muscle and fat,deterioration of organic functions. Under such conditions the patients are more susceptible to infection, thrombosis and heart failure,with low-level quality of life. Study shows that the occurrence of cachexia may relates to metabolic abnormalities, inflammatory cytokines release,inflammatory response, reduced food intake, leptin and neuropeptide role of other factors. However, the exact mechanism remains unclear. The therapy of achexia has been one of the difficulties in tumour research.Carnitine (3 - hydroxy -4 - three amino butyric acid),one of the basic ingredients for human cells, is an essential substance which participate in with theβ-oxidation of long-chain fatty acids. It has two isomeridea: L-carnitine (LC) and D-carnitine (DC) .Only LC has biological activity and its biological effects are wide. First of all, it can transfer long chain fatty acid from the cytoplasm into the mitochondrial, producing ATP forβ-oxidation, which helps to remove the accumulation of fat in the mitochondria. Secondly, LC can improve the ratio of mitochondrial acetyl CoA / CoA, decrease the poisonous effects caused by the accumulation of toxic acyl to maintain the biomembrane stability; Thirdly, LC combined with malonyl-CoA can affect the ketogenic process in liver.When lacking of LC the process can be interfered, and thus cause metabolic disorder. LC also can fight against with free radicals by preventing the formation of Ao iron complexes, playing a important role in antioxidating. LC can stimulate gluconeogenesis, and promote the absorption of fat-soluble vitamins and calcium and phosphorus. LC is available through normal dietary intake and liver synthesis. Lacking LC can cause a variety of metabolic disorders, lipid diseases, such as chronic fatigue syndrome. At present, LC has been used in clinical treatment of cardiac disease, chronic heart failure, chronic renal failure. It is reported that LC plays positive roles in improvement of cardiac functions and reduction of fatigueness in patients with chronic heart failure and in patients with hemodialysis of chronic renal failure .Generally speaking, the deficiency of LC can lead to weight loss in patients with chronic heart failure, osteoporosis and reduction of muscle, fat and even cachexia. Supplement of LC, coenzyme Q10 and inosine can improve physical activity in patients with chronic heart failure. Previous animal experiments have shown that the tumor could decrease the glutamic acid and glutathione of the tumor-bearing rat muscle tissue. A randomized clinical trial results have shown that LC treatment could significantly decrease the glutamate levels in cancer patients.These studies and observations suggest that LC may play a positive role by improving the metabolism of the LC in treating patients lack of LC, malnutrition, and even those who suffers from cachexia diseases.We aims to explore the relationship between LC and the digestive malignant cachexia and develop its clinical values. Because LC has been applied in clinical treatment for years, its dosage, safety, prevention and treatment of side effects have been widely understood. If it is confirmed that the reduction of LC has something to do with cachexia, this treatment can be quite benefits to patients with terminal malignant tumors.Methods:(1) clinical trials: Test LC level of patients with advanced liver cancer(n =42) by a tandem mass spectrometry detection,and contrast with normal healthy controls(n =30) to make clear that the changes of the LC level of patients with liver cancer as well as their body weight index; hepatocellular carcinoma; serum albumin; prealbumin and hemoglobin then,test their relationship with nutritional status indicators,the rates of quality of life of tumor and correlation between score.(2) Animal experiments: Establish BALB / c mouse model of colon cancer cachexia (n = 24), set negative control group (NST,n = 8), low concentration of LC Group (LLC,n = 8),high concentration of Group LC Group (HLC, n = 8), then, given medroxyprogesterone acetate, normal saline, LC (4.505mg/kg),LC (9.01mg/kg) by using stomach tube. LC Cancer Prevention Unit gives LC (9.01mg/kg) at the same time of tumor vaccination. Set normal BALB / c mice in control group (NTB,n = 8). 12 days after tumor cell inoculation,mice colon cancer cachexia model will be set up, sub-intervention will be carried out afterwards,then,executing the mice 7 days after that. Test blood glucose,serum albumin, serum cholesterol,then,test TNF-α,IL-6 by the method of ELISA and simultaneously measure tumor weight and tumor index (tumor mass / go tumor weight).Results:1.The comparison between hepatocellular carcinoma in patients with normal serum levels of L-carnitine: patients with liver cancer serum free carnitine level was significantly lower than control (19.04±3.58 vs 37.1±2.64,P<0.01),serum liver acetyl-carnitine was significantly lower than control (1.05±0.26 vs 3.04±0.34,P<0.01),liver cancer serum propionyl-carnitine was significantly lower than control (0.37±0.09 vs 0.75±0.19,P<0.01) .2. The comparison between hepatocellular carcinoma in patients with serum free L-carnitine and cachexia correlation analysis: patients with liver cancer serum free carnitine levels and TNF-αshowed a linear negative correlation (r =- 0.678,P<0.01),and IL -6 linear negative correlation (r =- 0.788,P<0.01),and leptin levels were related linearly (r = 0.816,P<0.01); and BMI is linearly related (r = 0.486,P<0.01),and prealbumin linear positive correlation (r = 0.801,P<0.01),and albumin were linear positive correlation (r = 0.852,P<0.01),with the KPS score in a linear positive correlation ( r = 0.831,P<0.01),and QOL score showed a linear positive correlation (r = 0.872,P<0.01).3. Comparison of body weight of mice in each group: There were no significant difference in the tumor weight and tumor index between the tumor-bearing groups.4. comparison of each group's serum cytokines of mice: the serum TNF-αlevels of the model intervention groups were higher than group NTB(26.62±5.51,26.42±3.21,43.09±4.93 vs 20.20±3.81, P<0.05); compared with group NST, the other model intervention groups' serum TNF-αlevels were significantly lower and there is statistically significance(26.62±5.51,26.42±3.21 vs 43.09±4.93,P<0.05); there was no difference of serum TNF-αlevel among groups with different LC concentrations and beween groups with different LC concentrations; the mice serum IL-6 of each model intervention group was higher than that of group NTB (27.73±3.98,25.50±2.21,32.06±4.66 vs 20.01±2.91, P<0.05); compared with group NST,the serum IL-6 levels of group HLC decreased significantly (32.06±4.66 vs 25.50±2.21, P<0.05); compared with group NST, the other model intervention groups' serum IL-6 levels have no significant changes.Conclusions1. Advanced liver cancer cachexia in patients with serum free carnitine,acetyl-carnitine and propionyl-carnitine were significantly decreased, suggesting that serum levels of carnitine should be an evaluation of prognosis and treatment for the advanced liver cancer cachexia.2. Advanced liver cancer cachexia in patients are negatively correlated with serum free carnitine,TNF-αand IL-6,whereas positively with leptin, prealbumin, albumin. With the KPS and QOL score, BMI is positively correlated.3. Added LC can improve colon tumor-bearing mice's levels of blood glucose and decrease the level of TNF-αand IL-6 and would not affect the growth of tumor.The results suggest that:The decrease of serum LC in liver cancer cachexia may be related to the mechanism of tumor cachexia , and exogenous LC supplementary improves the cachexia status and does not accelerate tumor growth.