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

与其他实体瘤患者不同，结肠癌和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，对于结肠癌肝转移不可切除的患者，目前的治疗方法只能延长平均生存数个月。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它们的破坏，伴随着子代病毒体的释放，其可以在称为病毒溶瘤的过程中感染相邻的癌细胞。当加入HSV-1溶瘤治疗时，通过酵母胞嘧啶脱氨酶转基因将5-FC肿瘤内转化为5-FU可增强疗效。我们提出实验来阐明前药生物活化和HSV-1肿瘤溶解之间的相互作用机制。我们还建议开发正电子发射断层扫描（PET）成像定量评估病毒复制。虽然PET已被用来检查基因表达，我们建议开发PET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或病毒DNA的PCR扩增或病毒mRNA的RT-PCR。因为这些技术是侵入性的、麻烦的和非定量的，所以它们在HSV-1溶瘤的人类临床试验中是无用的。因此，开发微创成像方法以定量评估HSV-1复制部位存在很强的理论基础。

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.