The goal of this project is to perform mechanistic and translational studies with a new and highly effectivehypoxia-activated drug, PR-104, particularly in evaluating its potential for combination with radiotherapy andwith gemcitabine. PR-104 is a dinitrobenzamide mustards (DNBM), recently discovered by our collaboratorsDrs. Denny and Wilson, with improved properties over the current prototype of a hypoxic cytotoxin,tirapazamine (TPZ), including a substantial bystander killing that gives it activity against aerobic as well ashypoxic cells in solid tumors. It entered Phase 1 clinical trials in January 2006. The benefit of combining ahypoxic cytotoxin with conventional anticancer therapy is based on the fact that most human solid tumorshave regions at low oxygen levels (hypoxia) and the cells in these regions are resistant to killing by radiationand many chemotherapeutic drugs. TPZ has already demonstrated clinical benefit in combination withradiotherapy and cisplatin based chemotherapy. Our preliminary studies show that PR-104 is superior toTPZ in combination with fractionated radiation with two different human tumor xenografts as well as havingsubstantial single agent activity. We will focus on head and neck and pancreatic cancers, the former withfractionated radiation and the latter with gemcitabine. The tumor efficacy studies with radiation will beperformed with different human head and neck tumor xenografts with PR-104 in parallel with TPZ in order tocompare their relative efficacies, and the studies with PR-104 in combination with gemcitabine will beperformed with pancreatic xenografts both as subcutaneous and orthotopic models.
Our specific aims are 1)to compare the efficacy of PR-104 and TPZ in potentiating fractioned irradiation to head and neckxenografts, 2) to measure the distribution of active PR-104 metabolites in tumors by assaying DMAinterstrand crosslinks by the alkaline comet assay 3) to assay the efficacy and mechanism of action of PR-104 in combination with gemcitabine with pancreatic tumor xenografts, 4) to determine the extent to whichthe activity of PR-104 with or without irradiation can be increased by increasing tumor hypoxia using vasculartargeting agents 5) to determine the extent to which the activity of PR-104 can be increased using NTRexpressing C.sporogenes, and 6) to test the hypothesis that the Gl toxicity of PR-104 can be reduced byreduction of intestinal microflora. This project has direct applicability to human health: It's rationale is thesame as that of TPZ, the first hypoxic cytotoxin to show clinical benefit, yet PR-104 appears to be superior toTPZ, and therefore has the potential of improving cancer cure rates to a greater extent than does TPZ
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