CELL CYCLE REGULATION AND CHEMOSENSITIVITY

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Our research group is utilizing enabling technologies to exploit emerging knowledge of molecular events that participate in the evolution of cancer to both decipher the molecular basis of chemosensitivity and to discover new and more selective chemotherapeutic agents. Current emphasis is placed on the (1) development of isogenic model systems derived from normal human cells to study the biological and pharmacological impact of genes commonly altered in human cancer and (2) investigation of control elements in cell cycle pathways for anticancer drug discovery. Our current research portfolio was shaped, in part, by our studies on the role of the p53 tumor suppressor in chemosensitivity (OConnor et al., Cancer Res., 53: 4776, 1993; Fan et al., Cancer Res., 54:5824, 1994; Fan et al., Cancer Res., 55:1649, 1995; Fan et al., Oncogene, 14: 2127, 1997). These studies have recently been extended to the 60 cell lines of the NCI anticancer drug screen (OConnor et al., Cancer Res., 57:4285, 1997; Weinstein et al., Science, 275:343, 1997) and agents identified in this assay that might exploit defective-p53 function for their activity are presently being analyzed. We are now focused on the generation of in vitro model systems based on normal human mammary epithelial cells and derivatives lacking p53 function due to a retrovirally-delivered dominant-negative mutant p53 transgene. These studies act as a starting point to assess the influence of other common genetic alterations seen in human breast cancer on the biology and pharmacology of normal cells. We have also found that drugs, such as pentoxifylline and UCN-01, preferentially abrogated the G2 checkpoint in p53-defective cancer cells (Fan et al., Cancer Research, 55:1649, 1995: Wang et al., JNCI, 88:956, 1996). We have found that UCN-01 abrogates G2 arrest through a Cdc2-dependent pathway by relieving Cdc2- inhibitory phosphorylations. We have excluded the Wee1 kinase as a direct target of UCN-01 action. Current investigations include a structure-activity relationship study of the UCN-01 molecule coupled with in vitro assessment of other targets of the G2/M regulatory machinery. Enabling technologies being used include retroviral gene delivery, microgridded cDNA arrays, multiwell-based drug analysis tools and high-throughput biochemical analysis.