Oncolytic HSV-based vectors selectively replicate in tumor cells causing direct killing i.e., oncolysis, while at the same time sparing normal cells. Although the use replication- competent HSV viruses for tumor therapy have proven to be effective to a certain degree, a number of issues remain that preclude its successful use in clinical trials. One major drawback is its limited capacity to spread intercellularly and kill neighboring cancer cells. The goal of this project is to identify small molecule compounds that augment the spread of the oncolytic HSV-based G47?? virus expressing the green fluorescent protein (G47?? -CMV-GFP) in prostate cancer cells using a simple """"""""mix and measure"""""""" 384-well formatted cell-based fluorescent assay. PC3 prostate cancer cells will be inoculated with G47?? -CMV-GFP at a low multiplicity of infection (MOI) and augmented viral spread promoted by pretreatment with the chemical library will be quantified by fluorescence. The identification and validation of chemical amplifiers of G47? spread will permit the exploration of two long-term objectives: 1) to develop therapeutic agents not only for treating prostate cancer but also as """"""""generalized"""""""" therapeutic enhancers of viral oncolysis for treating other forms of cancers and 2) to use as a """"""""chemical toolbox"""""""" in order to dissect the molecular pathways involved in viral oncolysis. Understanding the molecular events that govern viral oncolysis will not only have direct implications in developing novel anti-cancer HSV therapeutics but it may also provide unexpected insights into the pathology of HSV. ? ? ?
| Passer, Brent J; Cheema, Tooba; Zhou, Bingsen et al. (2010) Identification of the ENT1 antagonists dipyridamole and dilazep as amplifiers of oncolytic herpes simplex virus-1 replication. Cancer Res 70:3890-5 |
