The overall goal of this program project is to study the cellular effects and radiotherapeutic interactions of the halopyrimidines and to apply such knowledge to the treatment of intrahepatic malignancies and pancreatic cancer. The drugs that will be the focus of investigation are bromodeoxyuridine (BUDR), fluorodeoxyuridine (FUDR), and fluorouracil (FU). The work performed during the current award period has shown that the chemotherapeutic agents FUDR and FU are radiosensitizers when used alone and improve the efficacy of the thymidine analog and radiosensitizer BUDR by increasing its incorporation into the DNA of tumor cells. this proposal seeks to gain new insights into the mechanism of action of these agents and to apply knowledge gained in our previous preclinical studies to clinical trials. Project 1 extends recent findings concerning the basis for fluoropyrimidine-induced cytotoxicity and DNA damage, and proposes to test hypotheses that: a) the activities of dUTPase and/or uracil-DNA-glycosylase may be the limiting determinants for sensitivity of human colorectal tumor cells to high concentrations of fluoropyrimidines (as are applied during regional administration), and b) in certain tumor cells, resistance to fluoropyrimidines may be overcome by coadministration of a dUTPase inhibitor. Project 2 seeks to determine the mechanism by which BUDR affects radiation induced DNA damage at the individual chromosomal and subchromosomal level through the use of pulsed field gel electrophoresis and fluorescence in situ hybridization. The goals are to determine if BUDR incorporation alters the type and number of DNA lesions produced by radiation and to identify the lesions most closely associated with radiation sensitivity. Project 3 will systematically study the effect of liver impairment (loss of hepatocyte mass vs. loss of function) on the disposition kinetics of FU and BUDR after systemic and regional administration. The studies in Project 3 will have direct relevance to proposed clinical studies involving regional drug infusion in patients with reduced liver function. for clinical studies (Project 4), the approach taken will be to generate regional chemo-radiosensitization regimens combining BUDR with precise, 3-D planned focal external beam radiotherapy. A biopsy study will be conducted of tumor and normal tissue uptake of BUDR (by GC/MS assay and by immunohistochemical assay) given on a relevant infusional schedule (hepatic arterial for hepatic and intravenous IV for pancreatic tumors) to determine whether significant (>5%) incorporation occurs. Based upon our preclinical studies, a concurrent BUDR infusion will be used in hepatic tumors and a BUDR infusion with a """"""""washout"""""""" period will be studied in pancreatic cancers to maximize tumor to dose-limiting normal tissue uptake of drug. In summary, this proposal defines an approach furthering basic understanding of these agents while combining pharmacologic data with sophisticated technology to rationally generate unique clinical protocols with potentially improved potency in the treatment of these common, exceptionally lethal GI malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA042761-05
Application #
2090938
Study Section
Special Emphasis Panel (SRC (1J))
Project Start
1988-08-01
Project End
1996-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Levi, Micha; Knol, James A; Ensminger, William D et al. (2002) Regional pharmacokinetics of amifostine in anesthetized dogs: role of the liver, gastrointestinal tract, lungs, and kidneys. Drug Metab Dispos 30:1425-30
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
Lawrence, T S; Rehemtulla, A; Ng, E Y et al. (1998) Preferential cytotoxicity of cells transduced with cytosine deaminase compared to bystander cells after treatment with 5-flucytosine. Cancer Res 58:2588-93
Kuan, H Y; Smith, D E (1998) Splanchnic clearance and its relationship with drug elimination by the liver and gastrointestinal tract. J Pharm Sci 87:904
Parsels, L A; Parsels, J D; Wagner, L M et al. (1998) Mechanism and pharmacological specificity of dUTPase-mediated protection from DNA damage and cytotoxicity in human tumor cells. Cancer Chemother Pharmacol 42:357-62
Sondak, V K; Robertson, J M; Sussman, J J et al. (1998) Preoperative idoxuridine and radiation for large soft tissue sarcomas: clinical results with five-year follow-up. Ann Surg Oncol 5:106-12
Kuan, H Y; Smith, D E; Ensminger, W D et al. (1998) Regional pharmacokinetics of 5-fluorouracil in dogs: role of the liver, gastrointestinal tract, and lungs. Cancer Res 58:1688-94
Parsels, L A; Zellars, R C; Loney, T L et al. (1997) Prevention of fluorodeoxyuridine-induced cytotoxicity and DNA damage in HT29 colon carcinoma cells by conditional expression of wild-type p53 phenotype. Mol Pharmacol 52:600-5
Wygoda, M R; Wilson, M R; Davis, M A et al. (1997) Protection of herpes simplex virus thymidine kinase-transduced cells from ganciclovir-mediated cytotoxicity by bystander cells: the Good Samaritan effect. Cancer Res 57:1699-703
Lawrence, T S; Chang, E Y; Davis, M A et al. (1996) Effect of irradiation on bromodeoxyuridine incorporation in human colon cancer xenografts. Int J Radiat Oncol Biol Phys 34:617-21

Showing the most recent 10 out of 57 publications