| 乙型肝炎病毒（HBV）感染和肝细胞肝癌（HCC）仍然是我们在肝脏疾病治疗中所面临的主要挑战。虽然近年来有了一些发展，但仍需要开发新的药物和治疗方法。
 拉米夫定（LAMIVUDINE，L-SDDC,3TC）和恩曲他滨（EMTRICITABINE，L-FSddC,FTC）都属于L－脱氧胞啶类似物，是最早发现具有潜在抗HBV活性而没有细胞毒性和线粒体毒性的两个化合物。它们是由我们和DR.Tyrell实验室，以及加拿大的生物制药公司各自独立发现。GSK制药公司进一步将拉米夫定（LAMIVUDINE）开发为HBV感染的治疗药物。而恩曲他滨（EMTRICITABINE）由Gilead开发并已经临床证实具有潜在的抗HBV活性。此后，阿德福韦（Adefovir），一种腺嘌呤D-核苷酸类似物，以及恩替卡韦（Entecavir,）,一种鸟苷D－核苷酸类似物，又分别由Gilead和BMS2家制药公司开发为抗HBV药物。我们还发现了克拉夫定（CLEVUDINE，L-FMAU），由BUKWANG制药公司开发。IDENIX 制药公司发现了替比定（TELBIVUDINE，L-DT），并与BOVARTIS制药公司合作开发。这2种药物的临床实验都已经处于抗HBV实验的最后阶段，且这2种化合物都是L-胸腺嘧啶类似物。所有上述化合物在三磷酸代谢中都由细胞中的一系列特异酶所磷酸化。不同个体间代谢酶的变化会影响代谢酶的效果以及药物的潜在毒性。作为三磷酸代谢物，它们与HBV逆转录酶（RT）高度特异性作用，从而抑制HBV DNA复制。RT突变可改善病毒对这些药物的抗药性。抗拉米夫定（LAMIVUDINE）病毒也能对恩曲他滨（EMTRICITABINE）,克拉夫定（CLEVUDINE）, 替比定（TELBIVUDINE）, 恩替卡韦（ENTECAVIR）产生抗药性，但对阿德福韦（ADEFOVIR）却仍然敏感。临床上发现了除克拉夫定（CLEVUDINE）外，在其他化合物的使用中都出现了抗药性。
病毒抗药性出现的机会取决于药物的疗效，疗程，用量。所有的化合物均能抑制病毒复制而不直接影响细胞中作为病毒DNA和RNA合成模板的cccDNA。为了使病人体内病毒减少，需要长期使用这些化合物，这能减少或延迟病毒性肝硬化和HCC的发生。临床研究表明停止使用除克拉夫定（CLEVUDINE）外的任一上述药物1年或2年后，会在2个月内出现病毒再次增多和ALT升高。克拉夫定（CLEVUDINE）似乎还具有其他作用。在以土拔鼠(Woodchuck)为模型的研究中发现克拉夫定（CLEVUDINE）能减少cccDNA。来自于BUKWANG制药公司及其合作者的实验室和临床观察的非直接证据表明克拉夫定（CLEVUDINE）也许还能调节体内先天性免疫力。这也许能解释为什么多数病人指标正常后未出现ALT升高，以及为何仅经过3个月抑制血清中HBV浓度的治疗（低于3×103 HBV DNA/m，）却能够维持6个月甚至更多。由于克拉夫定（CLEVUDINE）在调节免疫力中的特殊性质，虽然在细胞培养物中缺乏抗HCV活性，但其作为HCV感染治疗的潜力仍值得开发。除了寻找标靶RT的抗HBV化合物，还可寻找以其他HBV特异大分子作为标靶的抗HBV化合物。最近，我们发现HELIOXATHIN类似物在抑制HBV RNA，蛋白和DNA合成中具有高度选择性。此类化合物也许能为治疗HBV感染提供一条新的治疗方向。
由于HBV感染患者可能伴随 HBV感染相关的HCC,或者非HBV感染相关的HCC，甚至其他类型癌症，因此HBV感染治疗将是非常复杂的。对于此类病人，通常考虑在进行免疫抑制癌症治疗的同时使用抗HBV药物治疗HBV感染。因此既抗癌又抗HBV的药物便是最好的选择。我们发现曲沙他滨 TROXACITABINE(L-ODDC),L-脱氧胞嘧啶类似物具有这种性质，此药现在正由SGX制药公司进行开发，研究此化合物对其他治疗无效的AML的治疗的3期临床实验。1期和2期临床实验将在对包括HCC的实体瘤的治疗上开展。我们应对HBV感染的癌症病人给予更多的关注。HCC不仅仅与HB有着强烈的相关性，它和HCV以及酒精，烟草的使用等都有着强烈的相关性。不同个体HCC的生化改变是不一样的。此外，自然中HCC细胞基因不稳定并处于杂和状态。随着治疗的开展HCC抗药性也会升高。单标靶的药物仅能对HCC治疗产生少量改善，但反应并不持久。较理想的方法是使用聚合物进行多标靶和多疗法治疗。中药处方（PHY906）是在1800年前就已经发现，现在已能在GMP下重复制备。基于前人的结论和我们实验室对中药处方（PHY906）的一些特殊性质的观察。我们和PHYTOCEUTICA（耶鲁大学资助公司，我是其中的一个研究人员）联合使用PHY906和截瘤达XELODA(FU,口服前体药)对重度HCC病人的治疗开展了1期和2期临床实验。“东西结合”的联合治疗结果还不清楚，结合前人关于使用某些中药的信息，将中药和现行治疗药物联合使用将对未来药物治疗指明方向，比如在肝炎，肝纤维化， 肝硬化以及HCC等肝脏疾病病人的治疗中防止疾病发展，提高生命质量，在不减少现行药物药效的前提下减少药物毒性。
Drug discovery in liver diseases
YUNG-CHI "TOMMY" CHENG
Yale University School of Medicine, New Haven, CT, USA
Chronic hepatitis virus (HBV) infection and hepatocellular carcinoma (HCC) remain as major challenges in liver disease management. Although some progress has been made during recent years, new drugs or treatments are needed. Lamivudine (L-SddC, 3TC) and Emtricitabine (L-FSddC, FTC) both of which are L-deoxycytidine analogs, were the first two compounds to have potent anti HBV activity without cytotoxicity and mitochondrial toxicity. They were discovered by us and also independently by Dr. Tyrell's lab together with Biochemical Pharm. in Canada. GSK Pharm. further developed Lamivudine as a drug for the treatment of HBV infection.
Emtricitabine was developed by Gilead and demonstrated potent anti-HBV activity in clinical studies. Subsequently, Adefovir, an adenine D-nucleotide analog, and Entecavir, a guanosine D-nucleoside analog were discovered and developed by Gilead and BMS Pharm. respectively as anti HBV drugs. Clevudine (L- FMAU) was discovered by us and is being developed by Bukwang Pharm. Telbivudine (L-dT) was discovered by Idenix Pharm. and is being developed by them in collaboration with Novartis Pharm. They are at the final approval stage of the process for anti HBV usage. Both of these compounds are L-thymidine analogs. All of these compounds are phosphorylated to their triphosphate metabolite by their unique set of enzymes in cells. The variation of these enzymes among different individuals could affect their effectiveness and the potential toxicity of those drugs. As triphosphate metabolites, they interact with HBV reverse transcriptase (RT) with a high degree of specificity resulting in the inhibition of HBV DNA replication. Mutations of RT could render virus resistance to these drugs. Lamivudine resistant virus was found to also be resistant to Emtricitabine, Clevudine, Telbivudine, and Entecavir but sensitive to Adefovir. The emergence of drug resistant virus to each of these compounds in the clinic with the exception of Clevudine was observed. The frequency rate of the emergence of drug resistant virus in the clinic will depend on their potency, duration of the treatment and dosage employed in patients. All of these compounds are expected to suppress
virus replication without directly affecting ccc-DNA, which is the template of virus DNA and RNA synthesis, in cells. Long term usage of these compounds is required in order to decrease virus burden in patients. This could lead to a decrease in the incidence or to a delay of the onset of virus associated cirrhosis and HCC. Clinical studies have shown that stopping treatment of any one of these drugs with the exception of Clevudine after one or two years could lead to virus rebound and ALT elevation within 2 months. Clevudine appears to have additional actions. It was shown by others to decrease ccc-DNA in woodchucks in vivo model upon treatment. Indirect evidence from this laboratory and clinical observations made by Bukwang Pharm and its collaborators indicated that Clevudine may also modulate innate immunity in vivo. This could be responsible for the lack of ALT elevation after normalization and delay or absence of virus rebound in a majority of patients in the 6 month period following treatment for only 3 months at a dosage which suppresses HBV titer to lower then 3 x 10 3 HBV DNA/ml of serum. Given this unique property of Clevudine in modulating immunity, its potential use for the treatment of HCV infection in spite of its lack of anti HCV activity in cell culture should also be explored. In addition to looking for anti HBV compounds targeting on RT, other HBV specified macromolecules could also serve as targets. Recently, we discovered Helioxanthin analogs which could inhibit HBV RNA, protein and DNA synthesis with a high degree of selectivity. Such a class of compounds may offer a new possibility for the treatment of HBV infection. HBV infection could be a complication for the treatment of patients with not only HBV associated HCC but also HBV non-associated HCC as well as other types of cancer. The use of anti-HBV drugs together with the treatment of cancer which often suppresses immunity should be considered for those patients who have HBV infection. An anticancer drug having potent anti HBV activity will be desirable. Troxacitabine (L-OddC), an L-deoxycytidine analog, was discovered by us to have such properties and is currently being developed by SGX Pharm. The compound is currently undergoing Phase III clinical trials for the treatment of AML patients refractory to other treatments. Phase I/II clinical trials will be initiated for the treatment of solid tumors including HCC. Special attention should be paid to these cancer patients with HBV infection. HCC has strong association not only with HBV but also with HCV, alcohol, tobacco usage, etc. The biochemical changes responsible for HCC could be different among different individuals. Furthermore, HCC cells are not genetically stable and heterogeneous in nature. HCC resistant to drugs could evolve upon treatment. A single target drug approach for developing treatment of HCC may only yield incremental improvements if any and the response will not be sustained. Novel approaches with multiple targets and modalities using polychemicals should be entertained. Based on historical claims and our laboratory observations of some unique features of a Chinese medicine formula (PHY906) which was described 1800 years ago and can be prepared in a consistent fashion following GMP; we together with PhytoCeutica (a Yale University sponsored company which I am a scientific founder) initiated clinical phase I/II studies of combined usage of PHY906 with Xeloda (FU, oral prodrug) for the treatment of patients with advanced HCC. The final outcome of this "East meets West" combination study is not clear yet. Given the historical information concerning the usage of certain Chinese medicine, the combined usage of current medicine together with Chinese medicine could serve as a lead for the development of future medicine for the treatment of patients with liver diseases such as hepatitis, liver fibrosis and cirrhosis as well as HCC by preventing disease progression, improving quality of life and decreasing toxicity associated with the use of current drugs without compromising its toxicity
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