The long term objective of this program is the discovery of new compounds and the improved use of the drugs for the treatment of cancer and virus-associated diseases. The compounds of particular interest are nucleoside analogs and those affecting DNA metabolism. The major targets are cancers which are difficult to treat and viruses which have a strong association to cancer. Due to limited budget approved the specific aims as proposed in the original application are narrowed down to six projects with details as described in the original application. 1. Study the possibility of exploiting the elevated cytidine deaminase levels in human immunodeficiency virus (HIV) chronically infected cells for the development of analogs which when deaminated would preferentially toxify those HIV chronically infected cells. 2. Examine the mechanism of action of L-213'-dideoxycytidine and its fluoro derivatives as anti-hepatitis B virus and anti-HIV compounds. 3. Identify and characterize the membrane proteins interacting with oligodeoxynucleotide and phosphorothioate oligodeoxynucleotide which are currently being explored as chemical entities for the treatment of cancer. 4. Study the mechanisms of action and potential clinical usage of the dipyridamole analog, BIBW22, a bifunctional modulator for nucleoside transport and multiple drug-resistant (MDR) phenotype. This will entail the characterization of the putative receptor of BIBW22 from the gp170 (MDR) overproducing KB cell line, the identification of mechanisms responsible for differential sensitivity to BIBW22 in two gp170-overproducing KB cell lines, and the exploration of the potential use of BIBW22 in combination with antimetabolites and MDR- associated drugs for the treatment of tumors in mice. 5. Study of a new mechanism of drug uptake-deficient pleiotropic drug-resistance (PDR), which is not related to MDR. The molecular basis of VP-16 uptake-deficient (PDR) KB cells that are non-gp170 associated will be identified. The biochemical basis of the modulating activity by verapamil in overcoming this resistance and supersensitivity in terms of growth of this resistant phenotype to verapamil will be examined, and the clinical importance of the resistant phenotype in cancer patients will be assessed. 6. Study the novel mechanisms of resistance to DNA topoisomerase 1 (Topo 1)-mediated cytotoxic compound, camptothecin (CPT) and potential collateral sensitivity to etoposides. The mechanism of the down regulation of Topo 1 in cells to CPT will be studied. Unique mechanisms which render cells susceptible to growth inhibition, but resistant to cell killing by CPT will be characterized. The clinical importance of this resistance mechanism to the action of CPT-like compounds will be determined.
| Zhou, Shaoman; Kern, Earl R; Gullen, Elizabeth et al. (2006) 9-{[3-fluoro-2-(hydroxymethyl)cyclopropylidene]methyl}adenines and -guanines. Synthesis and antiviral activity of all stereoisomers1. J Med Chem 49:6120-8 |
