Molecular Determinants of Cellular Sensitivity to Flavopiridol an Anti- Cell Signaling Anticancer Agent

摘要

Flavopiridol is an investigational drug undergoing Phase II clinical trials for the treatment of various solid tumors. This drug has been shown to inhibit of the cyclin-dependent protein kinases, which are essential mediators of the cell division cycle. While this activity is likely to be responsible for its anticancer activity, it is nevertheless unclear how this drug achieves selective toxicity. To address this question, we created a clavopiridol-resistant cell line. The experiments described in this proposal are designed to identify the mechanism(s) responsible for rendering this cell line drug-resistant Levels of cyclin-dependent protein kinase activity in this resistant cell line will be determined, and compared to those seen in the parental, drug- sensitive cell. In addition, levels of relevant drug-detoxifying enzymes, such as UDP-glucoronosyl transferase and glutathione S-transferase will be measured in these two cell lines, as will levels of drug transporters. Additional strategies will examine whether other gene products are over or under expressed in drug-resistant cells, as well. It is anticipated that the results of these studies will shed light on the mechanism of flavopiridol resistance. This information could be of value in designing second generation drugs that may prove more effective in the treatment of cancer.