Abstract

Pancreatic cancer has the highest mortality rate of all major cancers because of limited treatment options. Surgical removal of the tumour is possible only in its early stage, nevertheless the asymptomatic development very often makes unable an accurate diagnose. In the case of metastatic pancreatic cancer only chemotherapy, mainly with gemcitabine, can be offered to patients. However, common resistance towards gemcitabine imposes the research for new active compounds. The compound 9-(2′-hydroxyethylamino)-4-methyl-1-nitroacridine, C-1748 is the most potent antitumour derivative among 1-nitroacridines developed in our department. It possesses strong cytotoxic activity against colon and prostate cancer cells what allowed its selection for preclinical studies. Preliminary results indicate therapeutic potential of C-1748 against pancreatic cancers. The cytotoxic effect of an antitumour agent often depends on its metabolism leading to the activation or detoxification of the parent compound. The metabolism of C-1748 with human liver microsomes, human P450 reductase and in HepG2 cells was well studied and structures of four metabolites were identified. The aim of the current study is to investigate the metabolism of C-1748 in pancreatic cancer cell lines: Panc-1, MiaPaCa-2 and BxPC-3, which show different expression of cytochrome P450 isoenzymes. Both: medium and cellular extracts were analysed by HPLC/UV-Vis after drug treatment of the cells. A few metabolites were accumulated inside the cells whereas two products were found in the medium; but the metabolic profiles depended on the type of pancreatic cell line. One of the metabolite observed in all cancer cells was identified as the acridine derivative with an additional 6-membered ring. In conclusion, P450 mediated metabolism of C-1748 in pancreatic cancer cell lines strongly influenced its cytotoxicity. Moreover, C-1748 as a substrate for P450 isoenzymes in pancreatic cancer cells and a modulator of UGT activity, could be responsible for drug-drug interactions in the combined therapy.

Authors (3)