This proposal has as its objective the evaluation of 5-bromo-2'- deoxyuridine (BUDR) and 5-iodo-2'-deoxyuridine (IUDR) pharmacokinetics and crucial target effect (drug incorporation into DNA) pharmacodynamics in normal and hepatic VX2 tumor- bearing rabbits. By exploiting and combining two therapeutic strategies, namely, regional delivery of chemotherapy and biochemical modulation of antimetabolite action, the proposed studies should provide a rational basis for the design of more efficient and selective clinical therapies involving these agents. The pharmacokinetics of regional drug administration as well as antimetabolite modulation should facilitate the extrapolation of active and interesting preclinical regimens into rationally designed clinical trials. Since the crucial target effect of BUDR or IUDR is the replacement of DNA thymine by 5-bromouracil (BU) or 5-iodouracil (IU), a sensitive and specific GC/MS-SIM assay of DNA thymine and BU (or IU) content has been developed in this laboratory. With this assay the relevant pharmacodynamic target effects of BUDR and IUDR can be measured in hepatic VX2 tumor and appropriate normal tissues, such as those showing dose-limiting toxicity (bone marrow and gut mucosa) or normal tissue within the tumor's regional perfusion (normal liver). The proposed studies will define for both BUDR and IUDR the tissue specific relationships of drug target effect with such variables as 1) regional vs systemic administration, 2) drug infusion rates and durations, and 3) coadministration of biochemical modulators. Using monoclonal antibody-based immunohistochemical procedures, the percentage of the tissue cell population with incorporated BUDR (or IUDR) will be determined in relation to the above-mentioned experimental conditions. It is anticipated that the unique approach taken in this proposal to evaluate host vs tumor response to administration of these antimetabolites, will provide the necessary insight into the biological variables pertinent to the efficient development of safer and more effective clinical regiments.
| Maybaum, J; Burton, E C; Shelton, D A et al. (1991) Divergent patterns of incorporation of bromodeoxyuridine and iododeoxyuridine in human colorectal tumor cell lines. Biochem Pharmacol 42:131-7 |
| Stetson, P L; Normolle, D P; Knol, J A et al. (1991) Biochemical modulation of 5-bromo-2'-deoxyuridine and 5-iodo-2'-deoxyuridine incorporation into DNA in VX2 tumor-bearing rabbits. J Natl Cancer Inst 83:1659-67 |
| Lawrence, T S; Davis, M A; Maybaum, J et al. (1990) The dependence of halogenated pyrimidine incorporation and radiosensitization on the duration of drug exposure. Int J Radiat Oncol Biol Phys 18:1393-8 |
| Lawrence, T S; Davis, M A; Maybaum, J et al. (1990) The effect of single versus double-strand substitution on halogenated pyrimidine-induced radiosensitization and DNA strand breakage in human tumor cells. Radiat Res 123:192-8 |
