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

与其他实体瘤不同，结直肠癌患者通常会发生肝转移，而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，目前的治疗方法平均只能延长生存期几个月。因此，研究新的治疗方法显然是必要的。病毒在肿瘤细胞中的复制导致肿瘤细胞的破坏，释放出的子代病毒粒子可以感染邻近的癌细胞，这一过程被称为病毒溶瘤。当加入HSV-1溶瘤时，酵母胞嘧啶脱氨酶转基因将5-FC转化为5-FU增强了疗效。我们建议通过实验来阐明药物前生物活化与HSV-1溶瘤之间相互作用的机制。我们还建议发展正电子发射断层扫描（PET）成像来定量评估病毒复制。虽然PET已被用于检测基因表达，但我们建议开发PET来定量成像病毒复制。目前，检测病毒复制需要对组织进行活检（或切除），然后使用分子技术进行分析，如免疫组织化学染色，或对病毒DNA进行PCR扩增或对病毒mRNA进行RT-PCR。由于这些技术是侵入性的、繁琐的和非定量的，它们在HSV-1溶瘤的人类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复制部位是有充分理由的。

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.