This application is one of four interactive R01 projects, the goal of which is to improve the long term survival of patients with colorectal carcinoma metastatic to the liver. The focus of this application is firstly to further define prognostic factors and mechanisms of resistance (both intrinsic and acquired) to fluoropyrimidines and related agents that remain the major drug class to treat this disease. This aspect will be pursued in collaboration with Dr. S. Jhanwar who will identify genetic abnormalities. The second goal is to develop new strategies and therapeutic approaches that will be addressed in animal models and eventually tested in man, in collaboration with the investigators of the other interactive projects. Tumor tissue from patients with colorectal cancer metastatic to liver is to be obtained through cooperation with Drs. N. Kemeny and Y. Fong, principal investigators of the other interactive projects and studies in nude rats are planned with the help of Dr. Fong and colleagues with imaging that will demonstrate successful expression in vivo of the HSV thymidine kinase gene. The gene therapy approach planned is a novel use of a retroviral vector that expresses both a mutated dihydrofolate reductase gene and the HSV thymidine kinase gene with the expectation that successful integration of this retrovirus into colon cancer cells with subsequent gene amplification as a consequence of trimetrexate treatment will allow selective cell killing with gancyclovir. Additional studies are planned using a similar approach but with cytosine deaminase cDNA instead of HSV thymidine kinase to generate 5-fluorouracil from the prodrug 5-fluorocytosine in hepatic colorectal tumor metastasis.
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