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 gentechnisch veränderten Herpes Simplex Viren
Final Report Abstract
Background: Viral replication in tumor ceils leads to their destruction, with release of progeny virion that can infect adjacent cancer cells in a process referred to as viral oncolysis. 1) Intratumoral conversion of 5-FC to 5-FU by the yeast cytosine deaminase transgene when added to HSV-1 oncolysis enhances efficacy. 2) 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. 3) hrR3 is an oncolytic herpes virus - 1 that replicates preferentially in tumors compared with normal tissue. In immunocompetent mice bearing colon carcinoma peritoneal metastases we examined the biodistribution and toxicity of intravenous and intraperitoneal administered virus. 4) Clinical trials of HSV-1 oncolytic mutants to treat colorectal carcinoma metastases are being conducted, and involve administration of HSV-1 before, during, or after administration of chemotherapy agents such as 5-FU and CPT-11. It is therefore of importance to study chemotherapy-induced modulation of cellular pathways that are intimately linked to viral replication. Aim: 1) We proposed experiments to elucidate mechanisms of interaction between prodrug bioactivation and HSV-1 oncolysis. 2) We also proposed 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. 3) We aimed to compare survival benefit and biodistribution of hrR3 following intravenous and intraperitoneal administration in immunoconipetent mice bearing colon carcinoma peritoneal metastases. 4) We examined viral replication foilowing treatment with three common cytotoxic chemotherapeutic agents (5-fluorouracil (5-FU), irinotecan (CPT-11), methotrexate (MTX)) and examined viral titers, cell survival and nuclear factor-kappa B (NF- KB) activation. Results: 1) Due to difficulties in the viral construct we have not been able to finalize specific aim 1. Currently the generation of a more stable HSVIyCD virus is in progress. 2) We have been able to demonstrate that it is feasible to image eariy stages of viral oncolysis with microPET. 3) Intraperitoneal administration of hrR3 is associated with a more restricted biodistribution, less toxicity and greater efficacy against peritoneal metastases compared with intravenous administration. 4) Cellular responses to chemotherapeutic agents provide an unfavorable environment for HSV-1 mediated oncolysis. Conclusion: Modifications to address the stability of the viral construct are warranted. PET is useful for identification of sites of initial HSV-1 infection. Additional experiments are necessary to determine whether PET imaging of HSV-1 infection is applicable following intravascular administration. To involve oncolytic HSV-1 as a part of multimodality approach to treatment in intraperitoneal disseminated cancer, further studies examining chemotherapy and hyperthermia induced cellular pathways that are intimately linked to viral replication are required.
Publications
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Comparison of intravenous versus intraperitoneal administration of oncolytic herpes simplex virus 1 (HSV-1) for peritoneal carcinomatosis in mice. 2007: American Association for Cancer Research, Annual Meeting 2007, Los Angeles, CA, USA
Y. Kulu, D. Kuruppu, B.C. Fuchs, J.M. Goodwin, J.D. Dorfman, T. Fujii, M. Lanuti, K.K. Tanabe
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Epithelial to mesenchymal transition determines sensitivity of hepatocellular carcinoma to epidermal growth factor receptor inhibition. 2007: American Association for Cancer Research, Annual Meeting 2007, Los Angeles, CA, USA
B.C. Fuchs, J.M. Goodwin, Y. Kulu, T. Fujii, M. Lanuti and K.K. Tanabe
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Positron Emission Tomography of Herpes simplex virus 1 oncolysis. Cancer Res. 2007 Apr 1;67(7):3295-300
D. Kuruppu, A.L. Brownell, A. Zhu, M. Yu, X. Wang, Y. Kulu, B.C. Fuchs, H. Kawasaki, K.K. Tanabe
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Radiofrequency Ablation for Colon and Rectal Carcinoma Liver Metastases: What's Missing? Gastrointest Cancer Res 1(suppl2): S42-46, 2007
Tanabe, K.K., Kulu Y.
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Using multicellular tumor spheroids as a model to study the effect of extracellular matrix on viral oncolysis. 2007: American Association for Cancer Research, Annual Meeting 2007, Los Angeles, CA, USA
J.M. Goodwin, B.C. Fuchs, Y. Kulu, K.K. Tanabe, M. Lanuti
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Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA. 2008 Jan 2;299(1):53-60
K.K. Tanabe, H. Kawasaki, D.M. Finkelstein, A. Lemoine, T. Fujii, R.T. Chung, Y. Kulu, G.Y. Lauwers, D. Kuruppu, D. Azoulay, and B.C. Fuchs
