TRANSPLANTATION AND HEPATOTOXINS FOR LIVER CANCER

肝癌的移植和肝毒素

基本信息

批准号：
2008181
负责人：
JOHN Paul ROBERTS
金额：
$ 10.09万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-01-01 至 1997-12-31
项目状态：
已结题

项目摘要

Human hepatocellular carcinoma is a common disorder which carries a poor prognosis. Since many hepatomas arise in patients with existing liver disease, liver transplantation seems to be a logical therapy. Unfortunately, the survival rates have been dismal. The major reason for failure is tumor recurrence, either from unrecognized metastatic disease already present at the time of operation (subclinical metastatic disease), or from newly metastatic disease which may be related to manipulation of the host liver at the time of transplantation. A strategy to prevent recurrent disease would involve administering an adjunctive agent that is toxic to the hepatoma cells prior to transplantation. The administered toxin would kill any subclinical metastatic hepatoma cells as well as potential metastatic cells related to the primary tumor. Although there are known toxins which are effective in killing hepatoma cells, they are not specific and result in the death of normal hepatocytes with subsequent liver failure. The absence of selectivity of chemotherapeutic agents in the proposed treatment plan is overcome by liver transplantation. The idea of using combinations of hepatotoxins to kill hepatomas has been explored by Weber, et.al., using the concept of enzyme pattern directed chemotherapy to increase the specificity of toxins for tumor. To protect normal hepatocytes from the administered hepatotoxins, Wu, et.al., have used the approach of receptor mediated rescue, taking advantage of receptors that are expressed on normal hepatocytes, but not on tumors. These receptors can be utilized to facilitate uptake of a protective antidote to the administered toxin. Our proposed therapy will utilize combinations of hepatotoxins suggested by Weber to kill hepatoma cells, while liver transplantation will be used to rescue damaged normal hepatocytes. Our preliminary results indicate that both rat hepatomas and human hepatomas are susceptible in vitro to galactosamine, the prototypic hepatotoxin. We have established a reproducible rat model of metastatic hepatocellular carcinoma, and have demonstrated that orthotopic liver transplantation is feasible in rats receiving lethal, hepatotoxic doses of galactosamine. In addition, we have demonstrated that our proposed therapy has an effect on decreasing the incidence of metastatic tumors. We plan to test the proposed therapeutic approach in several different in-vitro and in-vivo systems. Initial experiments will utilize a syngeneic transplant system with no postoperative immunosuppression. Later experiments will evaluate the effect of immunosuppression on tumor recurrence following this treatment protocol in an allogeneic rat transplant system. Eventual work will focus on the applicability of this treatment concept to established human hepatoma cell lines and cells from surgical resection specimens. Tumor cells will initially be tested in- vitro for susceptibility to hepatotoxic agents. The nude rat will ultimately serve as a liver transplant model to evaluate the treatment protocol in an in-vivo system with human hepatoma cells.

人肝细胞癌是一种常见疾病，可带来较差的疾病预后。由于现有肝脏患者出现了许多肝瘤疾病，肝移植似乎是一种逻辑疗法。不幸的是，生存率令人沮丧。主要原因失败是肿瘤复发，要么是由于未识别的转移性疾病在操作时已经存在（亚临床转移疾病），或可能与新的转移性疾病有关在移植时操纵宿主肝脏。一个防止复发性疾病的策略将涉及辅助剂对肝癌细胞有毒移植。施用的毒素会杀死任何亚临床转移性肝癌细胞以及潜在的转移细胞相关到原发性肿瘤。虽然有已知的毒素有效地杀死肝癌细胞，它们不是具体的，并且导致正常肝细胞死亡，随后肝衰竭。这在拟议中没有化学治疗剂的选择性通过肝移植克服治疗计划。使用肝毒素组合杀死肝瘤的想法一直是由Weber等人探索的，使用定向的酶模式的概念化学疗法以增加毒素对肿瘤的特异性。保护来自施用的肝毒素的正常肝细胞Wu等使用受体介导的救援方法，利用在正常的肝细胞上表达的受体，但不在肿瘤上表达。这些受体可用于促进保护性对施用的毒素的解毒剂。我们提出的疗法将利用韦伯建议杀死肝癌细胞的肝毒素的组合，而肝移植将用于挽救正常损坏肝细胞。我们的初步结果表明，这两种大鼠肝瘤人类肝瘤在体外对银乳糖胺很容易受到影响，原型肝毒素。我们已经建立了可再现的大鼠模型转移性肝细胞癌，并证明在接受致命的大鼠中，原位肝移植是可行的肝毒性剂量的半乳糖胺。此外，我们已经证明了我们建议的治疗对降低的发生率有影响转移性肿瘤。我们计划在几种不同的地方测试拟议的治疗方法体内和体内系统。最初的实验将使用没有术后免疫抑制的合成性移植系统。后来的实验将评估免疫抑制对肿瘤的影响在同种异体大鼠中遵循此治疗方案的复发移植系统。最终的工作将重点放在此的适用性上从建立人类肝癌细胞系和细胞的治疗概念手术切除标本。肿瘤细胞最初将在体外对肝毒性剂的敏感性。裸鼠会最终充当肝移植模型来评估治疗人类肝癌细胞的体内系统中的方案。