Enhancement of Capecitabine by PHY906 in Liver Cancer

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DESCRIPTION (provided by applicant): A growing concern in the fight against cancer is the increase of liver cancer. Hepatocellular carcinoma is the most common primary cancer of the liver with an incidence rate of 30 per 100,000 in the Far East and a growing problem in the USA with approximately 13,000 new cases annually. The causes of liver cancer are multifactorial but risk factors include hepatitis B viral infection, hepatitis C viral infection and alcoholic cirrohisis. The prognosis for liver cancer is grim; with a median survival time of a few months and no current FDA approved chemotherapy. Systemic chemotherapy such as 5-FU, CPT-11 or adriamycin have demonstrated response rates in 10-20% range and a high degree of undesired, even life threatening side effects. Capecitabine, an orally active, prodrug of 5-FU appears to be a better tolerated therapy and has recently been approved by the FDA both as a first line therapy for colorectal cancer and for breast cancer. However, Capecitabine alone is still marginally effective with only a 13% response rate for liver cancer. Botanical drugs are promising co-therapies with western chemotoxic agents and have been shown to potentiate the therapeutic effect while reducing the undesirable adverse side effects. PHY-906, a Chinese botanical formulation with a long history of use for general gastrointestinal ailments, has recently been shown in animal studies not only to reduce mortality and weight loss associated with dose limiting CPT-11 or 5-FU therapy, but also to synergistically enhance the anti-tumor activity in colon cancer. Currently in clinical trials for the toxic side effects of conventional colorectal cancer treatment, PHY-906 is now being considered for a clinical trial to improve anti-tumor efficacy for liver cancer - a cancer that still today has no adequate chemotherapeutic treatment and is a growing unmet health problem. Can Capecitabine, in combination with PHY906, be a more effective treatment for liver cancer? This study is designed to determine the synergy and optimal therapeutic regimen of Capecitabine and PHY-906 in mouse models of human Hep-G2 carcinoma and murine Hepal-6 hepatoma and to explore a panel of chemokine/cytokines for possible insights into the synergistic effects and possible mechanisms of action of the PHY-906. The results of this study will help to guide the development of a clinical dosing regimen protocol and to support further investigations for future FDA approval.