The overall aim is to develop deoxynucleoside analogs for the treatment of patients with cancer. This includes the study of mechanism of action and resistance as well as the exploration of novel strategies to develop new nucleoside analogs with unique properties. In this application, we will continue to focus on the study of the anticancer action of a novel L-deoxynucleoside analog, L(-)dioxolane cytidine (L(-)OddC or BCH 4664) discovered in this laboratory and currently undergoing Phase II clinical studies. Based on the progress made, the Specific Aims are as follows: A. Study the role of AP endonuclease (APE/ref-I), which was identified to be the key activity in the removal of L(-)OddCMP from its 3'terminated DNA for the cytotoxic action of L(-)OddC. (1) Study the impact of unique mutations which could alter AP endonuclease activity or its redox regulatory activity, on its excision activity for the removal of L(-)OddCMP from its 3' -terminated DNA. (2) Study the impact of APE/ref-I, with or without unique mutations, on the action of L(-)OddC in cells. (3) Study the impact of thalidomide on the action of L(-)OddC with a focus on APE/ref-i expression. . Examine the functional role of CMP/UMP kinase for the phosphorylation of L(-)OddCMP or dCMP to their diphosphate nucleotide forms. (1) Examine the impact of altering CMP/UMP kinase protein expression in cells on dCyd or L(-)OddC metabolism. (2) Examine the possible alteration of the state of CMP/UMP kinase protein through post-translational modification or protein interaction in facilitating L(-)OddCMP or dCMP phosphorylation. (3) Examine the possible presence of dCMP kinase, which has not been identified, and its interaction with dCMP, CMP, UMP, L(-)OddCMP, AraCMP and dFdCydMP. The proposed study is based on some of the novel observations made during this funding period. It should provide information not only in terms of the action of all deoxycytidine analogs and their potential interaction with other classes of anticancer compounds, but also some basic knowledge regarding the biochemistry of nucleotide metabolism and DNA repair.
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