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

摘要

Flavopiridol (FP) is an investigational new drug currently in Phase II clinical trials for the treatment of solid tumors (Senderowicz et al., 1998). The precise mechanism of action of this compound is unknown, however, it is known to inhibit several members of the cyclin-dependent protein kinase family, and to induce cell death (Senderowicz, 1999, Schrump, et al., 1998, Bible and Kaufmann, 1996). The objective of this proposal is to gain insight into the molecular mechanism(s) whereby human tumor cells become resistant to FP. To gain greater insight into this question, a FP-resistant clone was generated from the human MCF-7 breast adenocarcinoma cell line. This clone was obtained by exposing growing cultures of MCF-7 cells to increasing concentrations of FP over a several month period of time. The resulting clone, named MCF-71F, has an IC50 for FP that is 24-fold lower than that of the parental MCF-7 cell line cell line from which it was derived. Specifically, the experiments described in this proposal are designed to identify the molecular basis for FP resistance in MCF- 7/FP cells. We have evaluated, or are in the process of evaluating cellular levels of known FP targets, i.e. cyclin-dependent protein kinases in MCF-7/FP and MCF-7 cells. In addition, we have begun to examine the relative resistance of these cells to a number of drugs. Finally, we have been examining the relative expression levels of a number of drug efflux pumps in these cell lines. It is anticipated that FP or FP-like molecules will ultimately assume a place in the modern cancer chemotherapeutic armamentarium. Thus, insight gained into the molecular basis of FP drug resistance in MCF-7/FP cells may ultimately prove beneficial in the design of second or third generation FP analogues. It is also conceivable that this information may aid in the development of chemotherapy strategies to minimize the emergence of clinical resistance to these agents.