Die Erforschung der Mechanismen und Interaktionen zwischen Bioaktivation von 5-FU und HSV-1 Onkolyse und die Entwicklung einer quantitativen Erfassung der Virus Replikation mittels PET bei der Behandlung diffuser kolorektaler Metastasen der Leber mit gent

药物治疗弥漫性结直肠肝转移瘤中 5-FU 和 HSV-1 溶瘤作用的机制和相互作用的研究以及使用 PET 定量检测病毒复制的进展

• 批准号: 5455348
• 负责人: Dr. Yakup Kulu
• 金额: --
• 依托单位: Division of Surgical Oncology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2005
• 资助国家: 德国
• 起止时间: 2004-12-31 至 2006-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5455348?language=en
• 关键词: Die; Erforschung; der; Mechanismen; und

Unlike patients with other solid tumors, patients with colon and rectal carcinoma commonly develop liver metastases without concomitant spread to other organs. Nonetheless, for patients with unresectable liver metastases from colon carcinoma, current therapies only prolong survival on average by several months. Thus, investigation into new therapeutic approaches is clearly warranted. Viral replication in tumor cells leads to their destruction, with release of progeny virion that can infect adjacent cancer cells in a process referred to as viral oncolysis. Intratumoral conversion of 5-FC to 5-FU by the yeast cytosine deaminase transgene when added to HSV-1 oncolysis enhances efficacy. We propose experiments to elucidate mechanisms of interaction between prodrug bioactivation and HSV-1 oncolysis. We also propose to develop positron emission tomographic (PET) imaging to quantitatively assess viral replication. While PET has been used to examine gene expression, we propose to develop PET to quantitatively image viral replication. Presently, detection of viral replication requires biopsy (or removal) of tissue followed by analysis using molecular techniques such as immunohistochemical staining, or PCR amplification of viral DNA or RT-PCR of viral mRNA. Because these techniques are invasive, cumbersome, and non-quantitative, they are not useful in human clinical trials of HSV-1 oncolysis. Accordingly a strong rationale exists for development of minimally invasive imaging methods to quantitatively assess sites of HSV-1 replication.

与其他实体瘤患者不同，结肠癌和直肠癌患者通常会发生肝转移，但不会同时扩散到其他器官。尽管如此，对于无法切除的结肠癌肝转移患者，目前的治疗只能将生存期平均延长几个月。因此，显然有必要研究新的治疗方法。肿瘤细胞中的病毒复制导致肿瘤细胞被破坏，释放出的子代病毒粒子可以在称为病毒溶瘤的过程中感染邻近的癌细胞。当添加到 HSV-1 溶瘤中时，酵母胞嘧啶脱氨酶转基因可在肿瘤内将 5-FC 转化为 5-FU，从而增强疗效。我们提出实验来阐明前药生物激活和 HSV-1 溶瘤之间相互作用的机制。我们还建议开发正电子发射断层扫描（PET）成像来定量评估病毒复制。虽然 PET 已用于检查基因表达，但我们建议开发 PET 来定量成像病毒复制。目前，病毒复制的检测需要对组织进行活检（或切除），然后使用分子技术进行分析，例如免疫组织化学染色、病毒 DNA 的 PCR 扩增或病毒 mRNA 的 RT-PCR。由于这些技术具有侵入性、繁琐且非定量，因此它们在 HSV-1 溶瘤的人体临床试验中没有用处。因此，开发微创成像方法来定量评估 HSV-1 复制位点是有充分理由的。