Establishment and Characterization of 6‐2‐(Dimethylamino)ethylamino‐3‐hydroxy‐7H‐indeno21‐cquinolin‐7‐one dihydrochloride (TAS‐103)‐resistant Cell Lines

摘要

6‐[[2‐(Dimethylamino)ethyl]amino]‐3‐hydroxy‐7H‐indeno[2,1‐c]quinol in‐7‐one dihydrochloride (TAS‐103) is a novel anticancer agent that was developed to target both topoisomerase (Topo) I and Topo II. To elucidate its mechanism of action, we have established and characterized TAS‐103‐resistant cells, derived from mouse leukemia (P388), human colon cancer (DLD‐1), and human lung adenocarcinoma (A549) cell lines, by exposure to stepwisely increasing concentrations of TAS‐103 in the culture medium. P388/TAS cells showed only cross‐resistance to VP‐16 and adriamycin (ADR). The Topo II activity in these cells was decreased to below one‐fourth of that in the parental cells, while the Topo I activity remained unchanged. DLD/TAS cells appeared to be cross‐resistant to VP‐16, ADR, camptothecin (CPT), SN‐38 and vincristine (VCR). The enzymatic activities of both Topo I and Topo II in these cells were decreased to one‐fourth of that observed in the parental cells. Furthermore, the decreased activities were accompanied by lower expression at the mRNA and protein levels. A549/TAS cells acquired cross‐resistance to VP‐16, ADR and VCR, though the Topo activities were virtually unchanged. In this cell line, the intracellular accumulation of TAS‐103 was significantly decreased and the expression of multidrug resistance associated protein (MRP) was elevated when compared with the parental cells. The results indicate that the affected activities of Topo I and/or Topo II, and in some instances decreased accumulation of TAS‐103, are associated with the development of resistance to TAS‐103, although the main mechanism of resistance to TAS‐103 varied among cell lines.