Core B will test compounds for the ability to inactivate AGT and to render tumor cells in culture sensitive to killing by BCNU. The three types of assay that will be carried out are: (a) new potential inhibitors of AGT will be tested for AGT inactivating potential using purified recombinant human AGT. Compounds designed as pro-drugs will also be tested in the presence of activating enzymes/ (b) the ability of the potential AGT inhibitors to inactive the AGT in HT29 colon carcinoma cells in culture will be determined; and (c) The ability of the AGT inhibitors to sensitize lung, colon, breast and prostate tumor cells to killing by BCNU will be measured. The compounds to be assayed include those produced during the first period of support, compounds designed based on data generated in the first period of support and compounds designed based on the studies in Program 1. Useful inhibitors which are identified in this core will be made available to all programs in the proposal either directly or via core C. These studies will indicate whether compounds have inherent ability to inactivate the AGT and whether they are active in cells thus providing preliminary information on uptake and metabolic conversion to more active or less active species. The compounds to be tested will be designed to provide compounds that are more potent or resistant to metabolism than BG, compounds that act as prodrugs generating AGT inhibitors in tumors, compounds likely to inactivate the BG-resistant mutants and compounds that would be suitable for regional therapy by virtue of a high potency and a rapid rate of metabolism.
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