The therapeutic selectivity of a chemotherapeutic regimen is defined by its relative effect on tumor cells vs. critical host tissues. Although most strategies for improving selectivity have been directed towards increasing the host toxic effects of drugs in tumor cells, selective protection of host tissues from these drugs should also enhance therapeutic effect, by increasing the intensity of treatment that can be tolerated by the host. When FdUrd is administered to humans by extended hepatic arterial infusion for the treatment of intrahepatic neoplasms, the dose-limiting toxicity is biliary sclerosis (also called sclerosing cholangitis). Several lines of evidence suggest that this sclerosis is caused by the direct injury of biliary epithelium due to drug-induced inhibition of thymidylate synthase (TS). If this mechanism is correct, then we would expect the following hypothesis to be true: Expression of TS in biliary epithelial cells will attenuate or prevent FdUrd-induced biliary sclerosis. The overall objective of this project is to test this hypothesis, by evaluating the ability of an adenoviral vector for TS expression to prevent biliary toxicity in animal models when administered by retrograde biliary infusion. If the hypothesis is correct, the applicant plans to apply his studies to humans, where protection of the biliary tree should permit the administration of FdUrd treatments that are significantly more intense than can ordinarily be tolerated, and where it has been demonstrated that even a modest intensification of FdUrd treatment can have significant therapeutic benefit. These studies will proceed in three phases: first he will produce an adenoviral vector for expression of TS and characterize it in cell culture systems. Next he will characterize the ability of the vector to transduce and protect biliary epithelial cells in rats, which represent the most practical and economical animal model for initial studies on the properties of this vector in vivo. Finally he will test the therapeutic efficacy of transduction with TS adenovirus in a canine model, which is the only model that is currently known to closely mimic the toxic syndrome seen in humans.
| Ensminger, William; Knol, James; DeRemer, Susan et al. (2004) Effects of dexamethasone or celecoxib on biliary toxicity after hepatic arterial infusion of 5-fluorodeoxyuridine in a canine model. Cancer Res 64:311-5 |
| Parsels, Leslie Anne; Parsels, Joshua David; Tai, Daniel Chung-Ho et al. (2004) 5-fluoro-2'-deoxyuridine-induced cdc25A accumulation correlates with premature mitotic entry and clonogenic death in human colon cancer cells. Cancer Res 64:6588-94 |
| Parsels, L A; Kowalski, M P; Wagner, L M et al. (2000) Escherichia coli thymidylate synthase expression protects human cells from the cytotoxic effects of 5-fluorodeoxyuridine more effectively than human thymidylate synthase overexpression. Cancer Gene Ther 7:1179-87 |
