A new study investigated the effectiveness of S-adenosylmethionine (SAMe) in the prevention and treatment of hepatocellular carcinoma (HCC) or primary liver cancer. SAMe, a widely available nutritional supplement, with little known side effects, was found to be effective in preventing the formation of HCC in rats. However, high enough levels of SAMe were not attainable to successfully treat established HCC. The findings are available in the August issue of Hepatology, a journal published by John Wiley & Sons on behalf of the American Association for the Study of Liver Diseases.

HCC is the fifth most common cancer and the third most frequent cause of cancer death worldwide. Risk factors for HCC include chronic infection with hepatitis B virus, hepatitis C virus (HCV), dietary aflatoxin, excessive alcohol use, cigarette smoking, diabetes and obesity. The overall 5-year survival for HCC patients is less than 10% and the disease rate is expected to rise due to the high prevalence of HCV in many areas of the world.

Shelly Lu, M.D., of the Keck School of Medicine at the University of Southern California, and colleagues studied the effects of SAMe on chemoprevention and treatment of HCC. In the U.S. the incidence of HCC doubled from 1979 to 1995 and the number of HCC cases for the following 20 to 30 years is projected to increase. Given these projections, there is a tremendous interest in developing effective chemoprevention strategies, said Dr. Lu. And an important property of SAMe that makes it an attractive agent for chemoprevention and treatment of HCC is its ability to selectively kill liver cancer cells, she added.

During the study researchers injected H4IIE cells into rats and found a 1cm tumor developed in the liver two weeks after injection. A regimen of IV SAMe was started one day after injecting the cells and continued for ten days. The researchers monitored the animals using MRI, ultrasound, and visual inspection to assess the liver tumors. Treatment with IV SAMe by continuous infusion significantly reduced the tumor size and significantly prevented tumor development after 11 days, researchers discovered.

Researchers found that if SAMe infusion was started after sizable tumors had already formed it failed to reduce the rate of tumor growth after 24 days of treatment. This is because of a compensatory response of the liver to metabolize SAMe and prevent its accumulation. The observation that SAMe failed to exert any therapeutic effect in already established HCC is disappointing, said Dr. Lu. But whether SAMe can be effective in treating HCC in man remains unclear because this compensatory mechanism may not work properly in human HCC. Nevertheless, effectiveness of SAMe in chemoprevention of human HCC deserves study now.

#############################

Article: S-Adenosylmethionine in the Chemoprevention and Treatment of Hepatocellular Carcinoma in a Rat Model, Shelly Lu, Komal Ramani, Xiaopeng Ou, Mark Lin, Victor Yu, Kwangsuk Ko, Ryan Park, Teodoro Bottiglieri, Hidekazu Tsukamoto, Gary Kanel, Samuel French, Jos Mato, Rex Moats, Edward Grant Hepatology, August 2009

http://www3.interscience.wiley.com/journal/122305560/abstract

A study will be published on March 21, 2009 in World Journal of Gastroenterology addresses the question. A research group in King Saud University, Kingdom of Saudi Arabia investigated, for the first time, the role of carnitine, a naturally occurring compound that is synthesized mainly in the liver, during the development of hepatocarcinogenesis. Authors of the study reported that carnitine deficiency is a risk factor and should be viewed as a mechanism in hepatic carcinogenesis, and that long-term L-carnitine supplementation prevents the development of liver cancer. Therefore, carnitine supplementation alone or in combination with other natural chemopreventive compounds could be used to prevent, slow or reverse the occurrence of liver cancer.

Chemoprevention is defined as the use of naturally occurring and/or synthetic compounds in cancer therapy in which the occurrence of cancer can be entirely prevented, slowed or reversed. L-carnitine is a naturally occurring compound which is primarily located in mitochondria and possesses potential protective effects against many mitochondrial toxic agents. It is derived from two sources; endogenous synthesis, in the liver and kidney, and from exogenous dietary sources such as red meat and dairy products. L-carnitine is an essential cofactor for the translocation of long chain fatty acids from the cytoplasmic compartment into mitochondria, where beta-oxidation enzymes are located for ATP production. Despite the liver being the main organ responsible for endogenous synthesis of L-carnitine, we were unable to find any studies investigating the role of long-term endogenous carnitine depletion and/or carnitine deficiency during induction of hepatic carcinogenesis.

The research team by Professor Sayed-Ahmed from College of Pharmacy, King Saud University used an experimental model of hepatocarcinogenesis under conditions of carnitine depletion and carnitine supplementation.

In the carnitine-depleted rat model, there were a progressive increase in the activities of liver enzymes as well as massive degenerative changes and evidence of pre-neoplastic lesions in liver tissues including clusters of hepatocytes with atypia and an increased proliferative rate, diffuse bridging fibrosis and nodule formation, bile ducts with marked reactive atypia showing nuclear enlargement, high nuclear/cytoplasmic ratio and prominent nucleoli. Interestingly, L-carnitine supplementation resulted in a complete reversal of the increase in liver enzymes compared to normal values, as well as normal liver histology with unremarkable central vein and no evidence of pre-neoplastic lesions in liver tissues.

Due to the fact that liver cancer is one of the major health problems in the world and a large sector of patients seek medical attention at a relatively late stage which increases the cost of treatment, King Saud University granted Prof. Sayed-Ahmed and his colleagues a research project with the following specific aims: (1) to understand the possible molecular mechanisms whereby carnitine deficiency provokes hepatic carcinogenesis. (2) to understand the relationship between hepatic cancer and its resistance to cancer chemotherapy, and (3) to gain knowledge on the possible mechanisms by which carnitine supplementation alone or in combination with other natural chemopreventive compounds could be used to prevent, slow or reverse the occurrence of liver cancer.

Reference: Al-Rejaie SS, Aleisa AM, Al-Yahya AA, Bakheet SA,Alsheikh A, Fatani AG, Al-Shabanah OA, Sayed-Ahmed MM. Progression of diethylnitrosamine-induced hepatic carcinogenesis in carnitine-depleted rats World J Gastroenterol 2009; 15(11): 1373-1380 http://www.wjgnet.com/1007-9327/15/1373.asp

Correspondence to: Dr. Mohamed M Sayed-Ahmed, Department of Pharmacology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Kingdom of Saudi Arabia. mmsayedahmed@hotmail.com Telephone: +966-506065734 Fax: +966-1-14677200

World Journal of Gastroenterology

The Department of Gene Therapy and Hepatology of the Center for Applied Medical Research (CIMA) of the University of Navarra has identified a molecule as possibly effective for improving the treatment of chronic hepatitis and liver cancer. This research, coordinated by the doctors Jess Prieto, Esther Larrea, Pablo Sarobe, Iranzu Gonzlez and Rafael Aldabe, has been published in the Journal of Virology; a journal of the American Society of Microbiology.

When organisms suffer a viral infection, dendritic cells (natural proteins produced as a response of the immune system to foreign agents) release type I interferon. The researchers of the CIMA observed that dendritic cells also produced Oncostatin M. “What was remarkable was the evidence that Oncostatin improved the effect of interferon in inhibiting the replication of viruses as well as noticeably increasing the antiviral response of the immune system”, said Dr. Jess Prieto.

These findings suggest that the combination of both molecules may be useful for treating viral diseases that do not respond to isolated treatment with interferon, something which occurs in patients with viral B or C chronic hepatitis. “In addition, it is possible that this combination could be effective for designing strategies against different tumor processes in which conventional therapy is unsuccessful”, suggested Dr. Prieto.

The Center for Applied Medical Research has patented this therapeutic formula, based on the combination of type I interfon and oncostatin for oncology treatment and antiviral therapy. Its development for clinical application is being carried out by the Spanish biotechnology company Digna Biotech.

Basque Research

Researchers at the University of Pennsylvania School of Medicine and Abramson Cancer Center reported today at the annual meeting of the American Association for Cancer Research that combining two targeted therapies overcomes treatment resistance in liver cancer cell lines. The team is currently desi…

A combined therapeutic approach of stenting and photodynamic therapy may improve survival rates for patients suffering from advanced liver bile duct cancer, according to a study published this month in Clinical Gastroenterology and Hepatology, the official journal of the American Gastroenterological…

Many scientists believe up to 40 percent of liver cancer is caused by stem cells gone wild – master cells in the organ that have lost all growth control. But, despite years spent looking, no one has ever found these liver “cancer stem cells” – or even normal stem cells in the organ. Until no…

Liver cancer is the fifth most common cancer in the world with a poor prognosis. About three quarters of the cases of liver cancer are found in Southeast Asia, including China, Hong Kong, Taiwan, Korea, India, and Japan. The frequency of liver cancer in Southeast Asia and sub-Saharan Africa is great…

As the incidence of liver cancer continues to grow– fueled in large part, by rising rates of hepatitis C infections – so too does the need for tests to help diagnose the disease at an earlier stage. A study appearing in the January 15 issue of Clinical Cancer Research demonstrates that a novel ma…