The focus of this application is the development of novel derivatives of dideoxynucleosides and 6-anilinouracils for the treatment of specific forms of lymphoblastic leukemia and lymphoma. We have shown that members of both classes of compounds can specifically interact with a unique DNA synthetic enzyme, terminal deoxynucleotidyl transferase (TdT), which is present in lymphoblastic/lymphoma cells. The dideoxynucleosides, and dideoxyadenosine in particular, are recognized as substrates by TdT. Their addition by TdT to nascent DNA results in chain termination. The lack of a 3'-OH group on dideoxynucleoside monophosphate makes further 5'-> 3' phosphodiester linkage impossible. Certain 6-anilinouracils are direct inhibitors of TdT. Their addition to highly purified TdT results in classic uncompetitive inhibition by Lineweaver-Burk analysis. When either dideoxynucleosides or 6-anilinouracils are added to TdT-positive cell lines, specific toxicity is seen. In contrast, TdT-negative lines are unaffected. Although the mechanism of cell killing remains to be defined, the central role of TdT in mediating this cytotoxicity was established (for dideoxyadenosine) by showing that a TdT-negative cell line became sensitive to dideoxyadenosine after being rendered TdT-positive by a DOL retroviral expression vector. In this application we propose the development of novel derivatives of both classes with more potent cytotoxic characteristics than the lead compounds we have so far identified. We plan to identify the structural features of each compound which confer TdT-specificity, and to explore the mechanisms of cell killing for each. In addition, we will explore the effect of these agents on normal hematopoietic and immunologic parameters. Finally, a lethal TdT-positive disease model in nude mice will be used to test the potential clinical efficacy of the most potent agents we identify. The long term goal of this collaborative effort is to develop a new group of highly specific and potent chemotherapeutic agents for clinical use in TdT-positive leukemia and lymphoma.
| Kim, H O; Schinazi, R F; Nampalli, S et al. (1993) 1,3-dioxolanylpurine nucleosides (2R,4R) and (2R,4S) with selective anti-HIV-1 activity in human lymphocytes. J Med Chem 36:30-7 |
| Kim, H O; Ahn, S K; Alves, A J et al. (1992) Asymmetric synthesis of 1,3-dioxolane-pyrimidine nucleosides and their anti-HIV activity. J Med Chem 35:1987-95 |
