Enhancement of Capecitabine by PHY906 in Liver Cancer

描述(由申请人提供)： 在抗击癌症的斗争中，人们越来越关注的是肝癌的增加。肝细胞癌是最常见的原发性肝癌，在远东的发病率为每10万人中有30例，在美国也是一个日益严重的问题，每年约有13,000例新发病例。肝癌的病因是多因素的，但危险因素包括乙肝病毒感染、丙型肝炎病毒感染和酒精性肝硬变。肝癌的预后很糟糕，中位生存期只有几个月，目前没有FDA批准的化疗。全身化疗如5-FU、CPT-11或阿霉素的有效率在10%-20%之间，而且有很高的不良反应，甚至危及生命的副作用。卡培他滨是5-FU的一种口服活性前体药物，似乎是一种耐受性更好的治疗方法，最近已被FDA批准为结直肠癌和乳腺癌的一线治疗药物。然而，单用卡培他滨对肝癌的有效率仅为13%。植物药是一种很有前景的与西方化疗药物联合治疗的药物，已被证明可以增强治疗效果，同时减少不良副作用。PHY-906是一种中国植物制剂，用于治疗一般胃肠道疾病已有很长的历史，最近的动物研究表明，它不仅可以减少与限制剂量CPT-11或5-FU治疗相关的死亡率和体重减轻，而且还可以协同增强结肠癌的抗肿瘤活性。目前，PHY-906正在进行传统结直肠癌治疗毒副作用的临床试验，目前正在考虑进行一项临床试验，以提高肝癌的抗肿瘤疗效。肝癌今天仍然没有足够的化疗治疗，是一个日益严重的未得到治疗的健康问题。卡培他滨与PHY906联合治疗肝癌是否更有效？本研究旨在确定卡培他滨和PHY-906在人Hep-G2肿瘤和小鼠肝癌模型中的协同作用和最佳治疗方案，并探索一组趋化因子/细胞因子，以可能深入了解PHY-906的协同作用和可能的作用机制。这项研究的结果将有助于指导临床给药方案的开发，并支持未来FDA批准的进一步研究。

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.